EA047684B1 - DEXMEDETOMIDINE TREATMENT SCHEMES WITHOUT SEDATIVE EFFECT INDUCTION - Google Patents

Description

Cross-reference to related applications

This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 62/876,371, filed July 19, 2019; U.S. Provisional Patent Application No. 62/877,056, filed July 22, 2019; U.S. Provisional Patent Application No. 62/963,769, filed January 21, 2020; U.S. Provisional Patent Application No. 62/970,411, filed February 5, 2020; U.S. Provisional Patent Application No. 62/977,554, filed February 17, 2020; U.S. Provisional Patent Application No. 63/037,759, filed June 11, 2020; U.S. Provisional Patent Application No. 62/943,022, filed December 3, 2019; the disclosures of each of which are incorporated herein by reference in their entirety.

Field of technology

Described herein are methods for treating a human subject having a pathological condition (e.g., agitation) that can be ameliorated by an alpha-2 adrenergic receptor agonist. The methods comprise administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a suitable dose and via an appropriate route of administration to achieve a plasma concentration profile that provides rapid improvement in the subject's condition without causing significant sedation. The administration regimens are also selected to provide maximum therapeutic benefit to the subject without any significant side effects, such as adverse cardiovascular events. Suitable routes of administration include sublingual, buccal, oral, intranasal, and parenteral. The described methods are particularly suitable for the treatment of agitation or signs of agitation, especially when associated with neurodegenerative and/or neuropsychiatric diseases such as schizophrenia, bipolar condition such as bipolar disorder or mania, dementia, depression and delirium.

In December 1999, the U.S. Food and Drug Administration approved a dexmedetomidine-based product, PRECEDEX®, as a continuous intravenous infusion solution, which is indicated as a sedative for primarily intubated and mechanically ventilated patients during treatment in the intensive care setting. PRECEDEX® was later approved as a sedative for non-intubated patients prior to and/or during surgical and other procedures.

Dexmedetomidine has also been administered intravenously and by other routes to treat a number of conditions, often in the peri- or postoperative period, including the treatment of pain, anxiety, delirium, opioid withdrawal symptoms, sleep disturbances, and agitation. However, administering dexmedetomidine in an appropriate dosage form to provide effective and rapid relief to the patient without causing significant sedation is challenging. The use of dexmedetomidine in clinical practice is also limited by its common side effects, such as hypotension and bradycardia. For example, significant cardiovascular side effects have occurred at therapeutic doses after administration of dexmedetomidine hydrochloride as a sublingual spray or tablet or intravenously. There is thus a continuing unmet need for an effective dexmedetomidine product that does not cause significant sedation and, preferably, is effective without also causing significant side effects such as cardiovascular events. The unmet need is particularly acute for non-addictive medications that can effectively treat agitation or signs of agitation without causing the aforementioned side effects and sedation.

The inventors of the present application have unexpectedly found that relatively high doses of dexmedetomidine hydrochloride can be well tolerated in humans without causing significant concomitant sedation when administered via certain treatment regimens. For example, according to the present invention, a dose of at least 180 mcg of dexmedetomidine hydrochloride administered sublingually has been demonstrated to be effective in treating agitation without causing significant sedation and is safe and well tolerated. Unexpectedly, it has been found that doses of 120 and 180 mcg of dexmedetomidine hydrochloride administered sublingually, such as via film, exhibit superior pharmacokinetic profiles to PRECEDEX®, resulting in fewer cardiovascular side effects. In addition, the inventors have found that subjects respond well to treatment when dexmedetomidine hydrochloride is administered at doses of at least 180 mcg, and demonstrate a significant reduction in agitation as early as 45 minutes after administration, with the calming effect lasting for an extended period of time, such as at least 24 hours.

The essence of the invention

In some embodiments, the present invention provides methods for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder (e.g., bipolar I disorder) without inducing significant sedation.

- 1,047,684 effects involving the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a mean total exposure to dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of approximately 3800 ng*h/L.

In some embodiments, the present invention provides methods for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a mean total dexmedetomidine exposure, measured by AUC in plasma from _T0 to T0, of about 1800 ng*hr/L.

In some embodiments, the present invention provides methods for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a total dexmedetomidine exposure, measured by AUC in plasma from T ₀ to T 0 , of about 600 to about 12,600 ng*hr/L.

In some embodiments, the present invention provides methods for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose that results in a cumulative dexmedetomidine exposure, measured by AUC in plasma from T ₀ to T 0 , of about 590 to about 8750 ng*hr/L.

The present invention also provides methods for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In another embodiment, an additional dose of 90 or 60 mcg may be administered 2 hours after the first dose.

The present invention further provides methods for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In another embodiment, an additional dose of 90 or 60 mcg may be administered 2 hours after the first dose.

In some embodiments, the present invention provides for the administration of about 180 mcg of dexmedetomidine hydrochloride sublingually as a single dose to a human subject, wherein said administration results in substantially lower levels of systemic exposure to dexmedetomidine than administration of PRECEDEX® at its highest approved dose, as measured by comparative Cmax and AUC values.

In some embodiments, the present invention provides for the administration of about 120 mcg of dexmedetomidine hydrochloride sublingually as a single dose to a human subject, wherein said administration results in substantially lower levels of systemic exposure to dexmedetomidine than administration of PRECEDEX® at its highest approved dose, as measured by comparative Cmax and AUC values.

The lower systemic exposure reduces the risk of decreased blood pressure and/or respiratory depression that would normally occur with the administration of effective amounts of PRECEDEX®.

In some embodiments, administration of about 180 mcg of dexmedetomidine hydrochloride sublingually as a single dose provides about a three-fold decrease in Cmax compared to administration of PRECEDEX®. In some embodiments, said sublingual administration provides about a 7.5-fold decrease in AUC compared to administration of PRECEDEX®. In one specific embodiment, administration to a human subject of a sublingual film containing about 180 mcg of dexmedetomidine hydrochloride provides about a three-fold decrease in Cmax and about a 7.5-fold decrease in AUC compared to administration of PRECEDEX®.

In some embodiments, the present invention provides for the administration to a human subject of about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally, wherein said administration results in mean plasma absorption levels of dexmedetomidine of about 80 to about 125% of the following values: Cmax of about 400 ng/L and AUC from T ₀ to T 0 of about 2900 ng*hr/L.

In some embodiments, the present invention provides for the administration to a human subject of about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally, wherein said administration results in mean plasma absorption levels of dexmedetomidine of about 80 to about 125% of the following values: Cmax of about 220 ng/L and AUC from T ₀ to T 0 of about 1420 ng*hr/L.

In some embodiments of the present invention, there is provided the administration to a human subject of about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally, wherein said administration results in plasma absorption levels of dexmedetomidine

- 2 047684 from about 80 to about 125% of the following values: Cmax from about 100 L to about 800 ng/L and AUC from T ₀ to T0 from about 600 to about 9500 h*ng/L.

In some embodiments, the present invention provides for the administration to a human subject of about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually or buccally, wherein said administration results in plasma absorption levels of dexmedetomidine of about 80 to about 125% of the following values: Cmax of about 110 to about 400 ng/L and AUC from T ₀ to T 0 of about 590 L to about 4400 h*ng/L.

The present invention also provides methods for treating agitation or signs of agitation in a human subject suffering from dementia without inducing significant sedation, comprising administering from about 30 to about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof. The present invention also provides methods for treating agitation or signs of agitation in a human subject suffering from dementia without inducing significant sedation, comprising administering from about 30, 60 or 90 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose per day. In some embodiments, the present invention provides methods for treating agitation or signs of agitation in a human subject suffering from dementia without inducing significant sedation, comprising oromucosally administering a single dose containing about 30 to about 90 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to six times a day at intervals of at least 2 hours (e.g., 2, 4, 6, 8, or 12 hours) in case of persistent or recurrent agitation. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) is administered orally (e.g., sublingually or buccally) as a film.

The present invention provides a method for reducing the period of opioid withdrawal in a human subject in need thereof, comprising administering to said subject dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily, wherein the period of withdrawal is up to 14 days. In some embodiments, the period of withdrawal may be 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days. In another embodiment, the human subject is an adult (at least 18 years of age). In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally (i.e., sublingually, buccally), orally, intranasally, or parenterally. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) is administered sublingually as a film. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in a dosage range of about 30 to about 200 mcg. In a particular embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in a unit dose of about 30 mcg, about 60 mcg, about 90 mcg, 120 or 180 mcg twice daily. In some embodiments, the opioid may be selected from the group consisting of, but not limited to, fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanylcarfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil or pentazocine.

The present invention also provides methods for controlling or treating agitation in delirium in subjects, without inducing significant sedation, comprising administering about 20 to about 240 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is hospitalized. In some embodiments, the subject is hospitalized in an intensive care unit. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in a unit dose containing about 20 or 60 mcg as a single dose. In some embodiments, each dose unit can be administered one to four times at a suitable dosing interval (e.g., at least 0.5 h) to achieve the desired effect; for example, a 20 mcg dose is administered four times at 0.5 hour dosing intervals within 6 hours after the first dose to achieve the effect of an 80 mcg dose, or a 60 mcg dose is administered four times at 0.5 hour dosing intervals within 6 hours after the first dose to achieve the effect of a 240 mcg dose. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally (e.g., sublingually or buccally) as a film.

The present invention also provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 120 mcg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient suffers from schizophrenia, in some embodiments, the patient suffers from bipolar disorder (e.g., bipolar I disorder), and in some embodiments, the patient suffers from both schizophrenia and bipolar disorder (e.g., bipolar I disorder).

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In some embodiments, the present invention provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 180 mcg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar I disorder), and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g., bipolar I disorder).

The present invention also provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 120 to about 180 mcg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient suffers from schizophrenia, in some embodiments, the patient suffers from bipolar disorder (e.g., bipolar I disorder), and in some embodiments, the patient suffers from both schizophrenia and bipolar disorder (e.g., bipolar I disorder).

The present invention also provides methods for treating or alleviating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a human patient in need thereof, wherein the patient is at least 18 years of age and wherein the withdrawal period is up to 14 days. The term opioid withdrawal syndrome refers to a variety of symptoms and complaints that occur upon abrupt cessation or rapid reduction of the usual dose of opioids. Physical manifestations may include sweating, nausea, yawning, chills, diarrhea, dilated pupils, piloerection, tachycardia, increased blood pressure, hypersensitivity to pain, stomach cramps, and muscle spasms. Observed psychological manifestations of opioid withdrawal syndrome may include agitation, dysphoria, restlessness, irritability, anxiety, and depression. In some embodiments, the opioid withdrawal symptom is agitation. The first manifestations often begin within 6-24 hours after the last opioid use. In some embodiments, treating or alleviating opioid withdrawal refers to treating or reducing one or more of the aforementioned symptoms. Treatment or improvement can be measured using a variety of methods well known in the art, including, but not limited to, the Clinical Opioid Withdrawal Scale (COWS) and/or the Short Opioid Withdrawal Scale-Gossop (SOWS-Gossop).

The present invention also provides a pharmaceutical composition comprising from about 20 to about 240 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In some embodiments, the dose of dexmedetomidine is about 120 mcg. In some embodiments, the dose of dexmedetomidine is about 180 mcg.

The present invention also provides methods for achieving a >40% reduction in agitation within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the PEC scale. In some embodiments, agitation is reduced after a period of time from about 20 minutes to about 1 hour; for example, about 20 minutes, about 30 minutes, or about 40 minutes. In some embodiments, the reduction in agitation is >40%, >50%, >60%, >70%, >80%, >90%, or >100%. In some embodiments, the reduction in agitation lasts for more than about 2 hours. For example, the reduction in agitation lasts for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 mcg of dexmedetomidine. In some embodiments, the composition comprises about 180 mcg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

The present invention also provides a method for achieving a reduction in the PEC score for agitation over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the reduction in the PEC score is from about -8 to about -10, and wherein said extended period is from about 2 to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, said extended period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,

- 4 047684 about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, about 23 h, or about 24 h. In some embodiments, the decrease in PEC score is about -8, about -9, or about -10.

The present invention also provides a method for achieving an improvement in ACES score over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the improvement in ACES score is from about 3 to about 4 and wherein said extended period is from about 2 to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the long period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the ACES score is about 4.

The present invention also provides a method for achieving an improvement in the CGI-I score over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the improvement in the CGI-I score is about 1 (very strong improvement) or about 2 (strong improvement), and wherein said extended period is from about 2 to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the long period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the CGI-I score is about 1.

Brief description of graphic materials

Fig. 1 shows the mean change from baseline in total RES score in patients with schizophrenia (intention-to-treat population) who received sublingual film containing dexmedetomidine hydrochloride (60, 80, 120, and 180 μg) compared to the placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is described in Example 1 and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 μg) is described in Example 2.

Fig. 2 shows the percentage of responders in the overall RES score among patients with schizophrenia over time (intention-to-treat population) who received sublingual film containing dexmedetomidine hydrochloride (60, 80 g, 120, and 180 μg) compared with the placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 μg) is described in Example 2.

Figure 3 shows the resolution of agitation, as measured by achieving at least 4 points on the ACES scale, among patients with schizophrenia over time (intention-to-treat population) who received sublingual film containing dexmedetomidine hydrochloride (60, 80, 120, and 180 μg) compared to the placebo group. Error bars in the figure represent standard error. The preparation of dexmedetomidine hydrochloride sublingual films (60 μg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 μg) is described in Example 2.

Figure 4 shows the percentage of CGI-I responders in patients with schizophrenia (intention-to-treat population) treated with dexmedetomidine hydrochloride sublingual film (60, 80, 120, and 180 μg) compared with placebo. Error bars in the figure represent standard error. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120 g, and 180 μg) is described in Example 2.

Fig. 5A shows the mean plasma dexmedetomidine concentration versus nominal time, sorted by dose and repeat dose (semi-log scale) in patients with schizophrenia (pharmacokinetic population) receiving a sublingual film containing dexmedetomidine hydrochloride (20, 20 mcg (repeat dose), 60, 80, 120, and 180 mcg), compared to the placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 and 60 mcg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films

- 5 047684 (80, 120 and 180 mcg) is described in Example 2.

Fig. 5B shows the mean plasma dexmedetomidine concentration versus nominal time, sorted by dose and repeat dose (linear scale) in patients with schizophrenia (pharmacokinetic population) receiving a sublingual film containing dexmedetomidine hydrochloride (20, 20 mcg (repeat dose), 60, 80, 120, and 180 mcg) compared to the placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 and 60 mcg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 mcg) is described in Example 2.

Fig. 6A shows the mean resting systolic blood pressure (SBP) values in patients with schizophrenia over time (safety population) who received sublingual film containing dexmedetomidine hydrochloride (60, 80, 120, and 180 mcg) compared to the placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 mcg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 mcg) is described in Example 2.

Fig. 6B shows the mean resting diastolic blood pressure (DBP) values in patients with schizophrenia over time (safety population) who received sublingual film containing dexmedetomidine hydrochloride (60, 80, 120, and 180 mcg) compared to the placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 mcg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 mcg) is described in Example 2.

Fig. 6C shows the mean resting heart rate (HR) values in patients with schizophrenia over time (safety population) receiving sublingual film containing dexmedetomidine hydrochloride (60, 80, 120, and 180 mcg) compared to the placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 mcg) is described in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 mcg) is described in Example 2.

Fig. 7A shows the mean change from baseline in systolic blood pressure (SBP) at rest over time in patients with schizophrenia (safety population) treated with dexmedetomidine hydrochloride sublingual film (60, 80, 120, and 180 mcg) compared to placebo. The preparation of dexmedetomidine hydrochloride sublingual film (60 mcg) is described in Example 1 and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 mcg) is described in Example 2.

Fig. 7B shows the mean change from baseline in diastolic blood pressure (DBP) at rest over time in patients with schizophrenia (safety population) treated with dexmedetomidine hydrochloride sublingual film (60, 80, 120, and 180 mcg) compared to placebo. The preparation of dexmedetomidine hydrochloride sublingual film (60 mcg) is described in Example 1 and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 mcg) is described in Example 2.

Fig. 7C shows the mean change from baseline in resting heart rate (HR) in patients with schizophrenia over time (safety population) treated with dexmedetomidine hydrochloride sublingual film (60, 80, 120, and 180 mcg) compared to placebo. The preparation of dexmedetomidine hydrochloride sublingual film (60 mcg) is described in Example 1 and the preparation of dexmedetomidine hydrochloride sublingual films (80, 120, and 180 mcg) is described in Example 2.

Fig. 8 shows the logarithmic plot of mean plasma dexmedetomidine concentration versus time for dose levels of 10, 20 g, and 40 mcg dexmedetomidine sublingual film (semi-log scale). Error bars represent 1 standard deviation.

Fig. 9A shows individual dexmedetomidine concentration-time profiles for all subjects as a function of dose following administration of dexmedetomidine sublingual film (10 μg), semi-log scale. An example of dexmedetomidine sublingual film is provided in Example 1.

Fig. 9B shows individual dexmedetomidine concentration-time profiles for all subjects as a function of dose following administration of dexmedetomidine sublingual film (20 μg), semi-log scale. An example of dexmedetomidine sublingual film is provided in Example 1.

Fig. 9C shows individual dexmedetomidine concentration-time profiles for all subjects as a function of dose following administration of dexmedetomidine sublingual film (40 μg), semi-logarithmic scale. The preparation of dexmedetomidine sublingual film is described in Example 1.

Fig. 10 shows the mean VAS/S score as a function of nominal time after administration of dexmedetomidine sublingual film (10, 20, 40 μg) and placebo. Preparation of dexmedetomidine sublingual film (10 and 20 μg) and dexmedetomidine sublingual film (40

- 6 047684 μg) is described in Example 1.

Fig. 11 shows the standing systolic VR values as a function of nominal time after administration of dexmedetomidine sublingual film (10, 20, 40 μg) and placebo. The preparation of dexmedetomidine sublingual film (10 and 20 μg) and dexmedetomidine sublingual film (40 μg) is described in Example 1.

Fig. 12 shows the systolic RT values in the supine position as a function of nominal time after administration of sublingual film with dexmedetomidine 10, 20 and 40 μg and placebo. The preparation of sublingual film dexmedetomidine (10 and 20 μg) and sublingual film dexmedetomidine (40 μg) is described in Example 1.

Fig. 13 shows the diastolic RT values in the supine position as a function of the nominal time after administration of sublingual film with dexmedetomidine 10, 20 and 40 μg and placebo. The preparation of sublingual film dexmedetomidine (10 and 20 μg) and sublingual film dexmedetomidine (40 μg) is described in Example 1.

Fig. 14 shows the diastolic RT values in the supine position as a function of the nominal time after administration of sublingual film with dexmedetomidine 10, 20 and 40 μg and placebo. The preparation of sublingual film dexmedetomidine (10 and 20 μg) and sublingual film dexmedetomidine (40 μg) is described in Example 1.

Fig. 15 shows the pulse rate values as a function of nominal time after administration of sublingual film with dexmedetomidine 10, 20 and 40 mcg and placebo. The preparation of sublingual film dexmedetomidine (10 and 20 mcg) and sublingual film dexmedetomidine (40 mcg) is described in Example 1.

Fig. 16 shows the percentage of patients with schizophrenia who achieved RASS-1 in the treatment group (IV dexmedetomidine hydrochloride group) compared to the placebo group.

Fig. 17 shows the mean decrease in RES score over time in patients with schizophrenia in the treatment group (IV dexmedetomidine hydrochloride group) compared to the placebo group.

Fig. 18 shows the maximum IV doses of dexmedetomidine hydrochloride given to patients with schizophrenia for the treatment of agitation.

Fig. 19 shows the total intravenous dose of dexmedetomidine hydrochloride given to patients with schizophrenia for the treatment of agitation.

Fig. 20 shows the mean plasma concentration (pg/mL) versus actual time in patients with schizophrenia treated with dexmedetomidine hydrochloride.

Fig. 21A shows the change in RES score from baseline in patients with schizophrenia to 2 hours after administration of 120 and 180 mcg dexmedetomidine as a sublingual thin film (as described in Example 2) compared to placebo.

Fig. 21B shows the change in RES score from baseline in patients with schizophrenia to 6 hours after administration of 120 and 180 mcg dexmedetomidine sublingual film (as described in Example 2) compared to placebo.

Fig. 22 shows the improvement in calmness in patients with schizophrenia at 2 and 4 hours after administration of 120 mcg (middle column) and 180 mcg (right column) dexmedetomidine as a sublingual film (as described in Example 2) compared to placebo (left column), as measured by the Agitation and Calmness Evaluation Scale (ACES).

Fig. 23 shows the response rate in patients with schizophrenia at 30, 60, 120 and 240 min after administration of 120 μg (middle column) and 180 μg dexmedetomidine (right column) in the form of a sublingual film (as described in Example 2) compared with placebo (left column), as measured by the Clinical Global Impression (CGI) scale.

Fig. 24A shows the change in RES score from baseline in patients with bipolar disorder to 2 hours after administration of 120 and 180 mcg dexmedetomidine sublingual film (as described in Example 2) compared to placebo.

Fig. 24B shows the change in RES score from baseline in patients with bipolar disorder to 6 hours after administration of 120 and 180 mcg dexmedetomidine sublingual film (as described in Example 2) compared to placebo.

Fig. 25 shows the improvement in calmness in patients with bipolar disorder at 2 and 4 hours after administration of 120 mcg (middle column) and 180 mcg (right column) dexmedetomidine as a sublingual film (as described in Example 2) compared to placebo (left column), as measured by the Agitation and Calmness Evaluation Scale (ACES).

Fig. 26 shows the response rate in patients with bipolar disorder at 30, 60, 120, and 240 min after administration of 120 mcg (middle column) and 180 mcg dexmedetomidine (right column) in the form of a sublingual film (as described in Example 2) compared with placebo (left column), as measured by the Clinical Global Impression of Improvement (CGI) scale.

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Detailed description of the essence of the invention: abbreviations:

ACES: Agitation and Calmness Evaluation Scale;

AD: Alzheimer's disease;

AE: adverse event;

AUC: area under the curve;

AUClast: area under the curve calculated up to the last observed time point;

AUC0-Inf: Area under the plasma concentration-time curve from time of administration to infinity r/d: twice daily;

BMI: body mass index;

CGI-I: Clinical Global Impression of Improvement scale

CGI-S: Clinical Global Impression Severity Scale

C _max : maximum plasma concentration;

COWS: Opioid Withdrawal Scale;

CMAI: Cohen-Mansfield Agitation Inventory

CMC: carboxymethylcellulose

C-SSRS: Columbia University Suicide Severity Rating Scale

CT: computed tomography;

CTCAE: Common Terminology Criteria for Adverse Events;

DBP: Diastolic Blood Pressure

Dex or DEX: dexmedetomidine

DLB: dementia with Lewy bodies;

DLT: dose-limiting toxicity;

DSM: Diagnostic and Statistical Manual of Mental Disorders;

DT: decay time;

ECG: electrocardiogram;

FTD: Frontotemporal Lobe Disease;

HPC: hydroxypropyl cellulose;

HPMC: hydroxypropyl methylcellulose

HR: Heart rate

ICH: International Conference on Harmonization;

ICU: intensive care unit;

IUD: intrauterine device

IPD: inpatient department;

ITT: Intention-to-treat population

LAR: legal authorized representative;

LSM: least squares method

LS: root mean square;

MedDRA: Medical Dictionary of Regulatory Activity Terminology;

MMRM: mixed effects model for repeated measures;

MMSE: Mini-Mental State Examination;

MRI: magnetic resonance imaging;

Yes: molecular weight;

mm: millimeter;

mcg: microgram;

mg: milligram;

mcg: microgram;

ml: milliliter;

mmHg: millimeters of mercury;

msec: millisecond;

ng: nanogram;

OPD: outpatient department;

PANSS: Positive and Negative Syndrome Scale;

PAS: Pittsburgh Agitation Scale;

PCRS: Placebo Control Reminder Script;

RES: PANSS Emotional Arousal Rating Component;

REO: polyethylene oxide;

PD: pharmacodynamics;

PK: pharmacokinetics

PVA: polyvinyl alcohol;

QTcF: QT interval adjusted for heart rate according to the Fridericia formula;

- 8 047684 p/d: four times a day

RASS: Richmond Sedation-Agitation Scale;

SAE: serious adverse event;SOWS-Gossop: Short Opioid Withdrawal Scale-Gossop;

SAP: statistical analysis plan;

SBP: systolic blood pressure

SD = standard deviation;

SE = standard error

SL: sublingual;

T _1/2 : half-life;

TEAE: treatment-emergent adverse event;

Tmax: time to reach maximum plasma concentration;

Wt%: weight percent ULN: upper limit of normal VAS: visual analogue scale; YMRS: Young Mania Rating Scale DEFINITIONS:

In the context of this document, the term about means plus or minus 10% of the stated numerical value.

The terms composition and composition are used interchangeably except where it is clearly implied that they have different meanings.

In the present description, numerical ranges are specified for certain quantities. It should be understood that these ranges include all internal ranges. Thus, the range from 50 to 80 includes all possible ranges (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). In addition, all values in a given range can be an end point for the range covered by it (e.g., the range 50-80 includes ranges with end points such as 55-80, 50-75, etc.).

Singular terms refer to one or more entities. Accordingly, singular terms, as well as the expressions one or more and at least one, are used interchangeably herein. Furthermore, reference to an agent in the singular does not exclude the possibility of more than one agent unless the context clearly indicates the presence of one and only one agent.

In the context of this document, the verb "comprise" as used in this description and in the claims and its conjugations is used in a non-limiting sense and means that elements following the word are included, but elements not specifically mentioned are not excluded. The present invention may suitably include, consist of, or consist essentially of the steps, elements, and/or reactants described in the claims.

The term pharmaceutically acceptable carrier refers to a pharmacologically inert substance used as a carrier. In the context of this document, the terms carrier and excipient are used interchangeably, except where it is clearly implied that they have different meanings.

In the context of this document, the term agitation means irritability, emotional outburst, impaired thinking or excessive motor and speech activity, which can occur either due to dysfunction of certain areas of the brain, such as the frontal lobes, or due to dysfunction of neurotransmitter systems, such as dopamine and norepinephrine. In the present invention, the term agitation also includes aggression and hyperarousal in post-traumatic stress disorder. Agitation can be acute or chronic.

The term agitation signs includes excessive motor activity (examples include walking, rocking, gesturing, pointing, fidgeting, making repetitive movements), verbal aggression (e.g., yelling, speaking excessively loudly, using foul language, screaming, shouting, threatening others), physical aggression (e.g., grabbing, pushing, shoving, clenching fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, slamming doors, tearing things), and property damage.

The term without significant sedation, etc. means that the patient is sedated to a level of 3 or less on the Ramsay Sedation Scale. Level 3 means sedated but able to respond to commands. In some embodiments, dexmedetomidine may be administered until the patient reaches a score of -1 (mild sedation) on the Richmond Sedation-Agitation Scale (RASS).

The term soluble means that the films described disintegrate easily, for example, at least within about 20 minutes after application to the oral mucosa. Disintegration is achieved by saliva and/or other aqueous substances on the surface of the mucosa.

The term neuropsychiatric conditions includes, but is not limited to, schizophrenia, bipolar condition (bipolar disorder, bipolar mania), depression, delirium, or other related neuropsychiatric conditions.

The term effective amount is interchangeable with therapeutically effective dose or therapeutically effective amount and refers to an amount sufficient to produce the same

- 9 047684 effective amount. The effective amount is sufficient to cause a weakening of the pathological condition (e.g. agitation) in the subject.

In the context of this document, the terms treatment and intervention refer to curative therapy, prophylactic therapy and/or preventive therapy and may be used interchangeably.

The term significantly reduced refers to a reduction of at least 10% or greater, preferably 20% or greater, more preferably 40% or greater, even more preferably 60% or greater, even more preferably 80% or greater, and 90% or greater compared to a control. For example, in the context of agitation, one skilled in the art will readily appreciate that the reduction can be measured using well-known agitation rating scales such as the PEC scale and the CGI-I scale (described in more detail in the examples). As an example, when a patient has a significantly reduced agitation, this reduction can be interpreted as a reduction that achieves at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or greater reduction in the total PEC score compared to baseline (e.g., measured 2 hours after dosing). In some embodiments, a significant reduction in agitation is defined as a reduction in the total PEC score by at least 40% from baseline. Similarly, a significant reduction in agitation can be measured using the CGI-I scale and can refer to a patient who has a score of 1 or 2 on the CGI-I scale (e.g., measured at 1, 2, or 4 hours after dosing) or on the Agitation and Calmness Evaluation Scale (ACES) and can refer to a patient who has, for example, a score of 3 or higher.

The term pharmaceutically acceptable salt refers to a salt that is known to be non-toxic and is commonly used in pharmaceutical literature. Typical inorganic acids used to form such a salt include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, etc. Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxylalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. A preferred salt is the hydrochloride salt.

As used herein, the term film includes thin films, sheets and plates of any shape, including rectangular, square or other desired shape. The film may have any desired thickness and size so that it can be conveniently placed sublingually on a patient. For example, the film may be a relatively thin film having a thickness of about 20 to about 200 microns, or may be a somewhat thicker film having a thickness of about 20 to about 1000 microns. In certain embodiments, the film may be even thicker, such as having a thickness of more than about 30 mm.

In the context of this document, the phrase water-soluble polymer refers to (i) a polymer that is at least partially soluble in water and desirably completely or predominantly soluble in water, and/or (ii) a polymer that absorbs water. Polymers that absorb water are referred to herein as water-swellable polymers.

The term self-supporting means that the films in this document maintain their structural integrity when handled without the need for a protective layer. Some flexibility of the film is assumed and this flexibility may be desirable.

In the context of this document, the phrase "precipitated in a polymer matrix" means that dexmedetomidine or a pharmaceutically acceptable salt thereof is introduced directly into a polymer solution to form a solid polymer matrix film composition.

As used herein, the phrase "precipitated on the surface of a polymer matrix" means that the dexmedetomidine or a pharmaceutically acceptable salt thereof is prepared as a liquid composition separate from the preparation of the solid polymer matrix and is applied to the solid polymer, such as in one or more microprecipitations, where it dries. The dried product is sometimes referred to herein as a microprecipitated matrix film. The liquid formulation of the drug may be in any form, including a solution, emulsion, suspension, or dispersion.

The term intranasal administration refers to the nasal route of administration, in which the drug is administered through the nose. The administration may be local or systemic, i.e., the locally delivered drug may subsequently exhibit either only local or systemic effects.

The term parenteral refers to the administration of a drug by injection under one or more layers of the skin or mucous membrane and may include, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular injection.

The term responder rate is defined as the relative number of subjects who experience a decrease in their RES score of approximately 40% after 2 hours.

The term clinically significant cardiovascular effects means in this document a decrease in blood pressure (hypotension) and/or heart rate (bradycardia) to such an extent that

- 10 047684 degrees that medical intervention is required to eliminate cardiovascular side effects, where the term medical intervention means intervention that is more serious than the introduction of a liquid, such as an energy drink.

I. Active agent

Dexmedetomidine has the IUPAC name (+) 4-((3-)-[1-(2,3-dimethylphenyl)ethyl]-(3-imidazole). As the monohydrochloride salt, this compound is primarily used as a drug for sedation of patients during treatment in intensive care settings or to produce sedation in patients prior to and/or during surgical and other procedures. This drug is currently marketed under the registered trade name PRECEDEX.

Pharmaceutically acceptable salts of dexmedetomidine that may be used in the context of this invention generally include any suitable salt that has been or may be approved by the U.S. FDA or other appropriate foreign or domestic agency for human administration. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydric, phosphoric, monohydric phosphoric, dihydrogen phosphoric, sulfuric, hydrosulfuric and hydroiodic acids. Other examples include salts derived from non-toxic organic acids including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric and methanesulfonic acids or combinations of salts of these acids. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate, or the like. In other embodiments, deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.

II. Dose

In some embodiments, the administered dose of dexmedetomidine or a pharmaceutically acceptable salt thereof may advantageously be in the range of about 0.5 to about 1200 mcg, depending on the route of administration, etc. Examples of suitable doses include: about 0.5 to about 1200 mcg, about 0.5 to about 500 mcg, about 0.5 to about 450 mcg, about 0.5 to about 405 mcg, about 0.5 to about 360 mcg, about 0.5 to about 270 mcg, about 0.5 to about 180 mcg, and about 0.5 to about 120 mcg. The dose may be administered one or more times per day, including two, three, four, five, or six times per day.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered in a dose of about 10 to about 300 mcg, such as about 10 to 270 mcg, about 20 to about 240 mcg, about 30 to about 180 mcg, about 40 to about 140 mcg, about 60 to about 120 mcg, about 70 to about 100 mcg, about 80 to about 100 mcg of the total weight of a unit dose of the pharmaceutical composition. These doses can be provided as one or more units to deliver the total dose. Examples of suitable doses include (in mcg): about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245 and about 250.

In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered through the oral mucosa (e.g., sublingually or buccally) in a dose of about 10 to about 300 mcg, such as about 10 to 270 mcg, about 20 to about 240 mcg, about 30 to about 180 mcg, about 40 to about 140 mcg, about 50 to about 120 mcg, about 60 to about 120 mcg, about 70 to about 100 mcg, about 80 mcg to about 100 mcg of the total weight of a unit dose of the sublingual film composition. These doses can be provided as one or more units for delivering a total dose. Examples of suitable doses include (in mcg): about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245 and about 250.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered in a dose of about 120 to about 405 mcg, such as about 120 to about 270 mcg, including about 120 mcg and about 180 mcg of the total weight of a unit dose of the pharmaceutical composition. These doses can be provided as one or more units to deliver the total dose. Examples of suitable doses include (in mcg): about 120, about 125, about 130, about 135, about

- 11 047684

140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305 , about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400 and about 405.

In another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered through the oral mucosa (e.g., sublingually or buccally) in a dose of about 120 to about 405 mcg, such as about 120 to about 270 mcg, including about 120 mcg and about 180 mcg of the total weight of a unit dose of the sublingual film composition. These doses can be provided as one or more units to deliver the total dose. Examples of suitable doses include (in mcg): about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400 and about 405.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered orally in a dose of about 500 to about 1500 mcg, such as about 900 to about 1200 mcg, based on the total weight of the oral composition. These doses can be provided as one or more units to deliver the total dose. Examples of suitable doses include (in mcg): about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 610, about 620, about 630, about 640, about 650, about 660, about 670, about 680, about 690, about 700, about 710, about 720, about 730, about 740, about 750, about 760, about 770, about 780, about 790, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, about 900, about 910, about 920, about 930, about 940, about 950, about 960, about 970, about 980, about 990, about 1000, about 1010, about 1020, about 1030, about 1040, about 1050, about 1060, about 1 070, about 1080, about 1090, about 1100, about 1110, about 1120, about 1130, about 1140, about 1150, about 1160, about 1170, about 1180, about 1190, about 1200, about 1210, about 1220, about 1230, about 1240, about 1250, about 1260, about 1270, about 1280, about 1290, about 1300, about 1310, about 1320, about 1330, about 1340, about 1350, about 1360, about 1370, about 1380, about 1390, about 1400, about 1410, about 14 10, about 1420, about 1430, about 1440, about 1450, about 1460, about 1470, about 1480, about 1490 and about 1500.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered intramuscularly at a dose of about 100 to about 200 mcg, such as about 120 to about 190 mcg, based on the total weight of the intramuscular injection. Examples of suitable doses include (in mcg) about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, and about 200.

The typical dose of dexmedetomidine or a pharmaceutically acceptable salt thereof to be administered to a particular patient will depend on the type and extent of the pathological condition, the general health of the particular patient, the particular form of dexmedetomidine or a pharmaceutically acceptable salt thereof to be administered, and the particular formulation used to treat the patient.

III. Pharmaceutical compositions

According to the present invention, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered to a human subject by various routes, including oral mucosal administration (e.g., sublingually, buccally), orally, parenterally, etc. Formulations suitable for use in accordance with the present invention are described below. Additional formulations suitable for use in accordance with the present invention are described in US 2020/0000717, which is incorporated herein by reference in its entirety for all purposes.

Formulations for the oral mucosa (sublingual and/or buccal formulations)

Dexmedetomidine or a pharmaceutically acceptable salt thereof may be formulated according to the present disclosure into dosage forms suitable for sublingual or buccal administration. Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, semisolids, suspensions, and the like. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product.

Carriers suitable for inclusion in sublingual or buccal formulations include, but are not limited to, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water, and combinations thereof. There may be

- 12 047684 carriers that dissolve easily in saliva are preferred.

Sublingual or buccal formulations may also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, colorants, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizing agents, suspending agents, and mixtures thereof. Specific excipients that can be used in accordance with the present invention are known in the art, for example, as described in Handbook of Pharmaceutical Excipients, fifth edition, 2005, edited by Rowe et al., Mcgraw Hill.

Films

Suitable films for sublingual or buccal administration (i.e., administration through the oral mucosa) according to the present description comprise dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) located within a polymer matrix or (ii) coated on the surface of a polymer matrix, such as on the surface of a placebo film.

Polymer component of the film

The polymer component consists of one or more water-soluble polymers in a film matrix and/or as part of a drug-containing application (e.g., one or more droplets) on a polymer surface. In some embodiments of the present invention, the polymer component consists of one water-soluble polymer. In some embodiments, the polymer component consists of two or more water-soluble polymers, including two or more identical water-soluble polymers having different molecular weights.

The polymer component in the film matrix has a suitable composition and is present in an amount sufficient to ensure rapid degradation of the film matrix in the oral mucosa. For example, the presence of the polymer component can allow the film matrix to completely degrade on the oral mucosa within about 15 to about 180 s, such as about 30 to about 180 s, including about 120 s. The polymer component in the film matrix also provides sufficient strength to the film (i.e., the film is self-supporting).

When the polymer component is present in one or more droplets of the dexmedetomidine composition deposited on the surface of the polymer matrix/substrate, the polymer component can, for example, consist of a water-soluble polymer of hydroxypropyl cellulose, although various water-soluble polymers are also contemplated, which are described below under the definitions of a first water-soluble polymer and a second water-soluble polymer. For example, the polymer component can consist of one, two or three hydroxypropyl celluloses having different molecular weights. The molecular weights of the various hydroxypropyl celluloses can suitably range from (i) less than about 60,000 Da (e.g., from about 5,000 to about 49,000 Da), (ii) from about 90,000 to about 200,000 Da, and (iii) from about 200,000 to about 500,000 Da. Two or more hydroxypropyl celluloses can be mixed in any suitable ratio to achieve the desired viscosity of the droplets. The viscosity of a solution or suspension of the dexmedetomidine composition can be measured using a Brookfield viscometer with a small sample adapter at a temperature of 25°C, and said viscosity can be from about 5 to about 3700 cP. For example, the viscosity of the solution can be in the range of from about 5 to about 500 cP, from about 6 to about 200 cP, from about 6 to about 100 cP, or from about 6 to about 50 cP. In some embodiments of the present invention, the viscosity of the solution or suspension of the dexmedetomidine composition is from about 6 to about 20 cP at 25°C and a shear rate of about 7 (1/s).

When present in a monolithic (i.e., placebo or drug containing) film, the polymer component may, for example, consist of one water-soluble polymer or two different water-soluble polymers. When two different water-soluble polymers are present, one of the water-soluble polymers may comprise the same polymer but be present in the polymer component as a combination of different molecular weights. For example, the polymer component may consist of one, two or three hydroxypropyl celluloses having different molecular weights, although different water-soluble polymers are also contemplated, as described below under the definitions of a first water-soluble polymer and a second water-soluble polymer, for example, polyethylene oxide. The molecular weights of the various hydroxypropyl celluloses can advantageously vary from (i) less than about 60,000 Da (e.g., about 5,000 to about 49,000 Da) (ii) from about 90,000 to about 200,000 Da, and (iii) from about 200,000 to about 500,000 Da (e.g., about 300,000 to about 450,000 Da). Two or more hydroxypropyl celluloses (e.g., low and high molecular weight hydroxypropyl celluloses) can be mixed in any suitable ratio to achieve the desired film properties. When the polymer component is present in a monolithic (e.g., placebo or drug-containing) film or in a microprecipitated film matrix composition, the polymer component can be comprised of one or more water-soluble

- 13,047,684 polymers having a molecular weight of less than about 60,000 Da (e.g., about 5,000 to about 49,000 Da) and/or about 90,000 to about 200,000 Da and/or about 200,000 to about 500,000 Da (e.g., about 300,000 to about 450,000 Da). When a water-soluble polymer of a different structure is also present, it may conveniently have a higher molecular weight, e.g., a molecular weight greater than about 500,000 Da.

In some embodiments, the present invention provides pharmaceutical film compositions comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component comprising a first water-soluble polymer having a molecular weight of less than about 60,000 Da (e.g., from about 5,000 to about 49,000 Da) and one or more water-soluble polymers having a molecular weight greater than about 60,000 Da; and, optionally (iii) one or more pharmaceutically acceptable carriers.

In some embodiments, the present invention provides pharmaceutical film compositions consisting essentially of: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of a first water-soluble polymer having a molecular weight of less than about 60,000 Da (e.g., from about 5,000 to about 49,000 Da) and one or more water-soluble polymers having a molecular weight greater than about 60,000 Da; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

In some embodiments, the present invention provides pharmaceutical film compositions comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component comprising a first water-soluble polymer having a molecular weight of less than about 60,000 Da (e.g., from about 5,000 to about 49,000 Da) and one or more water-soluble polymers having a molecular weight greater than about 60,000 Da; and, optionally (iii) one or more pharmaceutically acceptable carriers.

Examples of one or more first water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights.

Examples of one or more second water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, methylcellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights. Polyethylene oxide (PEO) may also be present herein as a second water-soluble polymer or may be described separately below in pharmaceutical film compositions as an example of a pharmaceutically acceptable carrier or, more specifically, as a mucoadhesive agent.

In one embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO if present in the film) in the entire film composition is from about 2:1 to about 1:50, such as from about 1:1 to about 1:40, including about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, around 1:26, around 1:27, around 1:28, around 1:29, around 1:30, around 1:31, around 1:32, around 1:33, around 1:34, around 1:35, around 1:36, around 1:37, around 1:38, around 1:39, around 1:40.

In a further embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO, if present in the film) in the overall film composition is from about 1:10 to about 1:30, from about 1:15 to about 1:25, or from about 1:15 to about 1:20. In some embodiments, a ratio of from about 1:15 to about 1:20 provides beneficial functional effects.

Examples of other water-soluble polymers that may be included in the film with the first water-soluble polymer/second water-soluble polymer or replace such polymer(s) include povidone (polyvinylpyrrolidone), copovidone (copolymers of N-vinyl-2-pyrrolidone and vinyl acetate), polyvinyl alcohol, polyethylene glycol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymers, polydextrose, pullulan, carboxymethylcellulose, sodium alginate, chitosan, xanthan gum, tragacanth gum, guar gum, gum senegal, gum acacia, starch, carrageenan, gelatin and mixtures thereof. The water-soluble polymer component, including water-soluble polymeric carriers when present, can advantageously comprise from about 40 to about 99.8%, from about 50 to about 99.7%, from about 60 to about 99.6% of the film composition based on the weight of the film on a dry weight basis.

In some embodiments, the polymer component for the film composition comprises a first water-soluble polymer present in an amount of from about 2 to about 15% based on the dry weight of the polymer component (e.g., from about 3 to about 8% w/w of the total weight of the film). This water-soluble polymer may typically have a molecular weight of from about 5,000 to

- 14 047684 about 49000 Da. Examples of suitable such water-soluble polymers include polymers selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, methylcellulose and mixtures thereof.

In some embodiments, the low molecular weight hydroxypropyl cellulose may be present in the film in an amount of from about 3 to about 8% w/w of the total weight of the film.

In some embodiments, one or more second water-soluble polymers (including water-soluble polymeric carriers such as polyethylene oxide) can, for example, be present in an amount of from about 50 to about 98% by weight based on the dry weight of the polymer component. Each one or more second water-soluble polymers has a molecular weight of greater than 60,000 Da; for example, from about 90,000 to about 1,500,000 Da, especially when the polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof.

In some embodiments, one or more second water-soluble polymers together can be present in the film in an amount of from about 25 to about 40% w/w of the total weight of the film, where each one or more second water-soluble polymers has a molecular weight of from about 90,000 to about 200,000 Da and/or from about 200,000 to about 500,000 Da, and the polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof.

In some embodiments, the polyethylene oxide may be present in the film in an amount of from about 50 to about 60% w/w of the total weight of the film.

In one embodiment, the polymer component for the film composition consists of a water-soluble low molecular weight polymer (e.g., having a molecular weight of less than about 60,000 Da) and one or more high molecular weight polymers (e.g., having a molecular weight of from about 60,000 to about 1,500,000 Da when polyethylene oxide is included in the polymer blend, or up to about 500,000 Da when polyethylene oxide is not included in the polymer blend). This combination of polymers, especially when the polymers are a combination of hydroxypropyl cellulose and polyethylene oxide, imparts certain advantages to the film composition with respect to tensile strength and pharmacokinetics.

In some embodiments of the present invention, a film composition is provided comprising (e.g., consisting essentially of):

(i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymer component consisting of one or more water-soluble polymers; and (iii) one or more pharmaceutically acceptable carriers.

In one embodiment of the present invention, there is provided a film composition comprising (e.g., consisting essentially of):

(i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymer component comprising: (a) one or more first water-soluble polymers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof) having a molecular weight of from about 5,000 to about 49,000 Da, such as from about 2 to about 15% by weight based on the dry weight of the total polymer component; and (b) one or more second water-soluble polymers (e.g., polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof) having a molecular weight greater than 60,000 Da, such as greater than 100,000 Da, such as from about 50 to about 98% by weight based on the dry weight of the total polymer component; and (iii) one or more pharmaceutically acceptable carriers.

The molecular weight of hydroxypropyl cellulose, when present in the film of the present invention, can vary and can be present as both a low molecular weight water-soluble polymer and one or more high molecular weight water-soluble polymers. In some embodiments, the molecular weight can be less than about 60,000 Da (e.g., from about 5,000 to about 49,000 Da). In other embodiments, the molecular weight can be in the range of about 90,000 to about 200,000 Da. In further embodiments, the molecular weight can be in the range of about 200,000 to about 500,000 Da.

Hydroxypropyl cellulose, when part of the film composition comprises polyethylene oxide, may advantageously be present in the range of from about 10 to about 90% by weight based on the dry weight of the polymer component, such as from about 20 to about 80% by weight based on the dry weight of the polymer component, such as from about 20 to about 50% by weight based on the dry weight of the polymer component, such as from about 25 to about 45% by weight based on the dry weight of the poly

- 15 047684 measured component.

The molecular weight of the polyethylene oxide, when present in the film of the present invention, can also vary. In some embodiments, a water-soluble polyethylene oxide with a high molecular weight can be used, for example, to increase the adhesion of the film to the mucous membrane. In certain embodiments, the molecular weight can be in the range of about 100,000 Da to about 1,500,000 Da, including about 100,000, 200,000, 300,000, 600,000, 900,000 or 1,000,000 Da. In some embodiments, it may be desirable to use a combination of polyethylene oxide having a molecular weight of about 600,000 to about 900,000 Da with polyethylene oxide having a molecular weight of about 100,000 to about 300,000 Da in the polymer component.

Polyethylene oxide, when included in the film composition, can advantageously be present in the range of from about 30 to about 90% by weight based on the dry weight of the total polymer component, such as from about 40 to about 85% by weight based on the dry weight of the polymer component, such as from about 55 to about 80% by weight based on the dry weight of the polymer component.

Such film compositions may comprise a drug dispersed within the film or microdeposited on the surface of the film. When microdeposited on the surface of the placebo film, the drug may advantageously be added as part of the dexmedetomidine composition as one or more drops in a liquid carrier such as a solvent (e.g., an alcohol such as ethanol), optionally together with one or more (e.g., two) water-soluble polymers and/or pharmaceutically acceptable carriers. Suitable water-soluble polymers include (1) a low molecular weight water-soluble polymer, such as a low molecular weight water-soluble polymer having a molecular weight of less than about 60,000 Da (e.g., a molecular weight of from about 5,000 to about 49,000 Da, and optionally (2) one or more (e.g., one or two) high molecular weight water-soluble polymers, such as a high molecular weight water-soluble polymer having a molecular weight of greater than about 60,000 Da (e.g., a molecular weight of from about 60,000 to about 150,000 Da, such as hydroxypropyl cellulose (77,000 Da), hydroxypropyl cellulose (80,000 Da), hydroxypropyl cellulose (90,000 Da), or hydroxypropyl cellulose (140,000 Da)) and/or a high molecular weight water-soluble polymer having a molecular weight of greater than about 60,000 Da (e.g., a molecular weight of about 200,000 to about 900,000 Da, such as hydroxypropyl cellulose (340,000 Da), hydroxypropyl cellulose (370,000 Da), polyethylene oxide (200,000 Da), or polyethylene oxide (600,000 Da)). Each water-soluble polymer may be independently selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, polyethylene oxide, and methylcellulose, such as hydroxypropyl cellulose and/or polyethylene oxide.

In some embodiments, the dexmedetomidine composition comprises dexmedetomidine hydrochloride, a low molecular weight polymer that is hydroxypropyl cellulose, and one or two high molecular weight polymers, each of which is hydroxypropyl cellulose, in an ethanol solvent.

In one embodiment, the dexmedetomidine composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), hydroxypropyl cellulose (40,000 Da), and one or both of the following: hydroxypropyl cellulose (140,000 Da) and hydroxypropyl cellulose (370,000 Da).

In another embodiment, the dexmedetomidine composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and only two hydroxypropylcelluloses, namely hydroxypropylcellulose (40,000 Da) and hydroxypropylcellulose (140,000 Da).

In some embodiments, the deposition layer composition may be in any form, including a solution, emulsion, suspension or dispersion. For example, the dexmedetomidine composition may be added as one or more drops to an ethanol-based solution, optionally containing a pH neutralizing agent such as sodium hydroxide. In some embodiments, the surface of the film substrate comprises two or more microprecipitated spots of dexmedetomidine hydrochloride (e.g., two microprecipitated spots) in a polymer matrix. The viscosity of the deposition solution/suspension may be from about 6 to about 3700 cP when measured at 25 °C using a Brookfield viscometer with a small sample adapter. For example, the viscosity of the solution may be in the range of about 5 to about 500 cP, about 6 to about 200 cP, about 6 to about 100 cP, or about 6 to about 50 cP.

In some embodiments of the present invention, the viscosity of the dexmedetomidine composition is from about 6 to about 20 cP at 25°C and a shear rate of about 7 (1/s).

After drying to remove the solvent, the film contains a film backing (e.g., placebo) with a dexmedetomidine composition as described previously, but without the solvent precipitated (e.g., mik

- 16 047684 deposited) on the surface of the film substrate. The dried composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) may cover the entire surface of the film substrate or only a portion of the surface of the film substrate.

In some embodiments, the dried dexmedetomidine composition appears as one or more discrete drug-containing droplets on the surface of the film substrate. Alternatively, a stencil may be used to produce one or more defined and discrete regions of the drug-containing composition on the surface of the film substrate.

In some embodiments of the present invention, there is provided a dry film product comprising a film support with one or more discrete drug-containing droplets on the surface of the film support, wherein each such drug-containing droplet comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose of two molecular weights: hydroxypropyl cellulose (40,000 Da) available as HPC-SSL and hydroxypropyl cellulose (140,000 Da) sold under the trade name KlucelTM Type JF NF, and wherein the film support comprises hydroxypropyl cellulose of three molecular weights:

hydroxypropyl cellulose (40,000 Da), hydroxypropyl cellulose (140,000 Da) and hydroxypropyl cellulose (370,000 Da), sold under the trade name KlucelTM Type GF NF. In some embodiments, the film backing also comprises polyethylene oxide (600,000 Da), available under the name Sentry Polyox WSR 205 LEO NF.

In some embodiments, the dry film product comprises a deposition layer composition (also referred to herein as a dexmedetomidine composition) comprising: (i) dexmedetomidine hydrochloride present in an amount from about 9 to about 50% w/w of the deposition layer composition, such as from about 15 to about 25% w/w of the deposition layer composition; (ii) hydroxypropyl cellulose (40,000 Da) present in an amount from about 5 to about 85% w/w of the deposition layer composition; (iii) hydroxypropyl cellulose (140,000 Da) present in an amount from about 5 to 85% w/w of the deposition layer composition; and (iv) hydroxypropyl cellulose (370,000 Da) present in an amount from about 0 to about 65% w/w of the deposition layer composition. The film also comprises a polymer matrix, wherein said polymer matrix comprises: (i) hydroxypropyl cellulose (40,000 Da) present in an amount of from about 3 to about 40% w/w of the polymer matrix; (ii) hydroxypropyl cellulose (140,000 Da) present in an amount of from about 3 to about 40% w/w of the polymer matrix; (iii) hydroxypropyl cellulose (370,000 Da) present in an amount of from about 0 to about 30% w/w of the polymer matrix, and (iv) polyethylene oxide (600,000 Da) present in an amount of from about 55 to about 75% w/w of the polymer matrix.

In some embodiments, a dry film product (e.g., a microdeposited film product) comprises: (i) dexmedetomidine hydrochloride present in an amount of from about 1 to about 50% w/w of the total film; (ii) hydroxypropyl cellulose (40,000 Da) present in an amount of from about 2 to about 30% w/w of the total film; (iii) hydroxypropyl cellulose (140,000 Da) present in an amount of from about 2 to about 30% w/w of the total film; (iv) hydroxypropyl cellulose (370,000 Da) present in an amount of from about 10 to about 50% w/w of the total film, (v) polyethylene oxide (600,000 Da) present in an amount of from about 40 to about 75% w/w of the total film, and (vi) optionally other pharmaceutically acceptable carriers.

In some embodiments, the films described herein combine several types of hydroxypropyl cellulose (HPC) to produce a film with beneficial properties. For example, a film composition may contain two or three of the following: hydroxypropyl cellulose (40,000 Da), hydroxypropyl cellulose (140,000 Da), and hydroxypropyl cellulose (370,000 Da) in combination. In certain embodiments, polyethylene oxide (600,000 Da) is included in these types of HPC when it is part of a monolithic film.

In certain film compositions of the present invention, low molecular weight hydroxypropyl cellulose (e.g., 40,000 Da) is present in an amount of from about 3% to about 8% (e.g., about 5%) w/w of the total film, high molecular weight hydroxypropyl cellulose (e.g., 140,000 Da) is present in an amount of from about 3 to about 8% (e.g., about 5%) w/w of the total film, high molecular weight hydroxypropyl cellulose (e.g., 370,000 Da) is present in an amount of from about 20 to about 40% w/w of the total film, and polyethylene oxide (e.g., 600,000 Da) is present in an amount of from about 40 to about 70% (e.g., about 50 to about 60%) w/w of the total film. In some embodiments, the two water-soluble high molecular weight polymers are together present in an amount of from about 25 to about 40% w/w of the total weight of the film.

The selection and ratio of water-soluble polymers can be made in such a way as to ensure complete dissolution of the film composition in the fluids of the oral mucosa in

- 17 047684 for a period of seconds to minutes, such as about 0.25 to about 15 minutes, thereby providing delivery of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa. For example, the film compositions can be in the sublingual or buccal region of the mouth for up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes, including for a period of from about 30 seconds to about 15 minutes, from about 1 to about 10 minutes, or from about 1 to about 5 minutes.

A standard basket or paddle apparatus described in any pharmacopoeia can be used for in vitro dissolution testing. The choice of dissolution medium will essentially depend on the immersion conditions and the maximum dose of the drug. The temperature of the dissolution medium should be maintained at 37±0.5°C and 50 rpm (see Bala et al., in Int J Pham Investigation, vol. 3(2), pages 67-76).

The films described herein have several functional advantages that facilitate rapid onset of drug effect. In some embodiments, the thin film compositions of the present invention have a disintegration time (DT) of about 15 to about 180 sec, about 15 to about 160 sec, about 25 to about 150 sec, about 15 to about 140 sec, about 15 to about 120 sec, about 40 to about 120 sec, about 50 to about 120 sec, such as about 120 sec, when administered sublingually or buccally. Disintegration times within these time frames provide optimal onset of drug action.

In some embodiments, the thin film compositions of the present invention have mucoadhesive properties that provide practical advantages of localizing the film in the sublingual region and reducing or preventing effective removal before dissolution. This property is especially useful in clinical settings when the subject is agitated. Thus, in some embodiments, the thin film compositions have a mucoadhesive strength (mucoadhesive strength or mucoadhesive shear strength) of about 50 g or higher, about 100 g or higher, about 200 g or higher, about 300 g or higher, about 400 g or higher, about 500 g or higher, about 600 g or higher, about 700 g or higher, about 800 g or higher, about 900 g or higher, about 1000 g or higher. In some embodiments, the mucoadhesive force is in the range of about 300 to about 4000 g, about 500 to about 3000 g, or about 1000 to about 2000 g.

The film's tensile strength also aids drug delivery. Certain thin film compositions of the present invention have a tensile strength of 50 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900 g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g or higher, 1800 g, 1900 g, 2000 g, 2,500 g, 3,000 g, 3,500 g, 4,000 g, 4,500 g, 5,000 g, 5,500 g, 6,000 g, 6,500 g, 7,000 g, 7,500 g, 8,000 g, 8,500 g, 9000 g, 9500 g, 10,000 g, or 15,000 g. For example, the tensile strength may range from about 200 to about 15,000 g, from about 300 to about 10,000 g, or from 400 to about 5000 g.

Pharmaceutically acceptable carriers

The film compositions may further comprise one or more pharmaceutically acceptable carriers, which include, but are not limited to, liquid carriers, flavoring agents, sweeteners, refreshing agents, antioxidants, pH adjusting agents, permeation enhancers, mucoadhesive agents, plasticizers, fillers, surfactants/nonionic solubilizers, stabilizers, antifoams, colorants, and the like. In some embodiments, the film compositions are substantially free of acid buffer or other acidic agents.

Liquid carriers

According to some embodiments, the pharmaceutically acceptable carrier comprises a liquid carrier. The liquid carrier comprises one or more solvents used in preparing the polymer matrix (containing the drug or placebo) and the composition for application to the polymer matrix. In some embodiments, the solvent may be water. In some embodiments, the solvent may be a polar organic solvent, including, but not limited to, ethanol, isopropanol, acetone, butanol, benzyl alcohol, and mixtures thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride, toluene, ethyl acetate, and mixtures thereof. Certain solvents are alcohols, especially ethanol, water, and mixtures thereof. Desirably, the solvent content of the wet polymer matrix is at least about 30% by weight of the total wet weight of the entire film composition before drying. The subsequent dried film composition will desirably contain less than about 10% by weight solvent, more desirably less than about 8% by weight solvent, even more desirably less than about 6% by weight solvent, and most desirably less than about 2% by weight solvent.

Flavors/Sweeteners/Refreshing Agents

To improve the taste of the film composition, it may be useful to add a sweetener, flavoring agent, refreshing agent, taste masking agent, or a combination thereof to the film compositions. Flavoring agents may be selected from natural and synthetic flavoring liquids. An illustrative list of such agents includes essential oils, synthetic flavor oils, flavors

- 18 047684 aromatic substances, oils, liquids, oleoresins or extracts obtained from plants, leaves, flowers, fruits, stems and combinations thereof. Non-limiting aromatic oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil and bitter almond oil. In one embodiment, the flavoring is peppermint oil flavoring available as peppermint oil, NF.

The amount may be varied to obtain the desired result in the final product. Such variations are within the capabilities of those skilled in the art without the need for further experimentation. Typically, amounts of about 0.1 to about 30% by weight may be used to impart flavor to the films. Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, for example: water-soluble sweeteners such as monosaccharides, disaccharides, and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and dihydrochalcones; water-soluble artificial sweeteners such as soluble saccharin salts, i.e. sodium or calcium saccharin salts, cyclamate salts and water-soluble sweeteners derived from natural water-soluble sweeteners such as known chlorinated derivatives of common sugar (sucrose), such as sucralose. In one embodiment, the sweetener is sucralose.

Flavorings, sweetening agents and refreshing agents may be added in conventional amounts, typically up to a total of from about 0.01 to about 10% by weight of the film on a dry weight basis, such as from about 0.1 to about 7% by weight of the film on a dry weight basis, such as from about 0.1 to about 5% by weight of the film composition on a dry weight basis.

Other taste-masking agents include, for example, polymers, oils or waxes. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is coated with a taste-masking agent prior to formulating the film compositions. In some embodiments, if a taste-masking agent is used to coat the active ingredient, it may be present in an amount of about 5 to about 80% by weight of the particle or granule containing the active ingredient. In another embodiment, the taste-masking agent is present in an amount of about 25 to about 35% by weight of the particle or granule containing the active ingredient.

Antioxidants

Examples of oxygen scavengers or antioxidants that substantially improve the long-term stability of the film composition against oxidative degradation include sulfite salts such as sodium sulfite, sodium bisulfite, sodium metabisulfite, and similar potassium and calcium salts. A suitable amount of sulfite salt (e.g., sodium sulfite) is up to about 5%, such as from about 0.001 to about 2%, based on the weight of the film composition on a dry weight basis.

pH-regulating agents/pH-neutralizing agents

Absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa can be increased in an alkaline microenvironment. For example, this can be achieved when the film compositions are maintained at a pH above 6, from about 6 to about 9, or from about 6.5 to about 8. In some embodiments, the film can include an alkaline substance that increases the pH of the final film. Non-limiting examples of pH-adjusting/pH-neutralizing agents include bicarbonates (e.g., sodium bicarbonate), citrates (e.g., potassium citrate), carbonates (e.g., calcium carbonate), lactates (e.g., sodium lactate), acetates (e.g., calcium acetate), an alkaline buffer (e.g., glycine), sodium hydroxide, sodium chloride, or the like. An alkaline buffer such as glycine is one example of a pH-neutralizing agent. A suitable amount of pH adjusting/neutralizing agent present in the film composition comprises, for example, up to about 10%, such as from about 1 to about 5%, based on the weight of the film composition on a dry weight basis.

Permeation enhancing agents

Certain effective penetration enhancers that promote the absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa include alcohols. An alcohol penetration enhancer, such as butanol, can be advantageously added to the film composition in an amount of up to about 10%, such as from about 0.1 to about 5%, such as from about 1 to about 3%, based on the weight of the film composition on a dry weight basis.

Mucoadhesive agents

Examples of mucoadhesive agents that may be added to the film composition include, but are not limited to, sodium alginate, sodium carboxymethylcellulose, guar gum, polyethylene oxide, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, karaya gum, methylcellulose, retene, tragacanth, and the like. One mucoadhesive agent is

- 19 047684 is polyethylene oxide, which can be successfully added to the film composition in an amount of from about 20 to about 90%, for example from about 40 to about 70%, based on the total weight of the film composition, based on the dry weight.

Plasticizers

Plasticizers that can be effectively used in the present invention include polyethylene glycol, propylene glycol, tributyl citrate, triethyl citrate and glycerol. Depending on the selected film-forming polymer(s) and other components of the film composition, a suitable amount of plasticizer included in the film composition can typically be up to about 10%, such as from about 0.1 to about 5%, such as from about 0.5 to about 5%, based on the weight of the film on a dry weight basis. For some applications, higher molecular weight polyethylene glycols, including polyethylene oxide, can be used.

Fillers:

Suitable fillers that can be added to the film composition include starch, calcium salts such as calcium carbonate, and sugars such as lactose, glucose, sucrose, mannose, sorbitol, mannitol, galactitol, sucralose, trehalose and combinations thereof. The amount of filler that can be successfully added to the film composition is typically up to about 25%, such as from about 0.5 to about 20%, such as from about 1 to about 15%, such as from about 2 to about 10%, based on the weight of the film composition on a dry weight basis.

Surfactants/Nonionic Solubilizers

The film typically includes at least one surfactant/nonionic solubilizer, including, for example, but not limited to, poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol, oxystearates, glyceryl polyglyceryl fatty acid esters, polyglyceryl ethers, and combinations thereof. The amount of surfactant(s) that can be added to the film composition is typically up to about 5%, such as from about 0.5 to about 3%, such as from about 1 to about 3%, based on the weight of the film composition on a dry weight basis.

Antifoaming components

Simethicone is an example of a suitable antifoam and/or foam inhibitor, although other antifoam and/or foam inhibitors may be used. An antifoam and/or foam inhibitor such as simethicone may be added to the film composition in an amount of from about 0.01 to about 5.0%, more desirably from about 0.05 to about 2.5%, and most desirably from about 0.1 to about 1.0%, based on the weight of the film composition on a dry weight basis.

Dyes

Color additives that can be included in the film composition include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C) or external drug and cosmetic colors (Ext. D&C). These agents are dyes, their corresponding lakes, and certain natural and derivative dyes. Specific examples of color additives are inorganic pigments, such as iron or titanium oxides, added at concentrations of from about 0.001 to about 10%, such as from about 0.01 to about 3%, based on the weight of the film composition on a dry weight basis. In one embodiment, the color applied to the dexmedetomidine composition (i.e., the deposited layer composition) is different from the color applied to the film substrate (e.g., the placebo film). One color of the monolithic film and the film substrate of the microdeposited film is emerald green and is available as Fast Emerald Green Shade (06507). One color of the dexmedetomidine composition (i.e., the deposited layer composition) is different from the color of the film substrate and is, for example, blue (available as FD&C Blue No. 1). In some embodiments of the film of the present invention, for example, as described in the aspects and embodiments above, said film is a film comprising about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, comprising two microdeposited spots of dexmedetomidine hydrochloride of blue color on a film substrate of green color.

In some embodiments of the film of the present invention, for example as described in the aspects and embodiments above, said film is a film comprising about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In one embodiment (A), a self-supporting soluble film is provided comprising:

(i) about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt);

(ii) one or more water-soluble polymers;

(iii) polyethylene oxide and optionally (iv) one or more pharmaceutically acceptable carriers.

In another embodiment (B), a self-supporting soluble film is provided,

- 20 047684 containing:

(i) about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt);

(ii) one or more water-soluble polymers;

(iii) polyethylene oxide and optionally (iv) one or more pharmaceutically acceptable carriers.

In a particular embodiment, the one or more water-soluble polymers (ii) of embodiment (A) or (B) above comprise a low molecular weight water-soluble polymer and two high molecular weight water-soluble polymers, such as wherein the low molecular weight water-soluble polymer has a molecular weight of about 5,000 to about 49,000 Da (e.g., about 40,000 Da), and each high molecular weight water-soluble polymer has a molecular weight of greater than about 60,000 Da (e.g., wherein one of the two high molecular weight water-soluble polymers has a molecular weight of about 140,000 Da and the other high molecular weight water-soluble polymer has a molecular weight of about 370,000 Da). In some embodiments, each water-soluble polymer is hydroxypropyl cellulose. Polyethylene oxide, in some embodiments, has a molecular weight of about 600,000 Da.

In some embodiments, a pharmaceutical film composition is provided comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more excipients selected from polyethylene oxide, hydroxypropyl cellulose, sucralose, peppermint oil, emerald green dye, and FD&C blue dye.

In another embodiment (C), a self-supporting soluble film is provided comprising:

(i) about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt);

(ii) a low molecular weight water-soluble polymer having a molecular weight of about 40,000 Da;

(iii) a high molecular weight water-soluble polymer having a molecular weight of about 140,000 Da;

(iv) a high molecular weight water-soluble polymer having a molecular weight of about 370,000 Da; and (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 Da.

In another embodiment (D), a self-supporting soluble film is provided comprising:

(i) about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt);

(ii) a low molecular weight water-soluble polymer having a molecular weight of about 40,000 Da;

(iii) a high molecular weight water-soluble polymer having a molecular weight of about 140,000 Da;

(iv) a high molecular weight water-soluble polymer having a molecular weight of about 370,000 Da; and (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 Da.

In a particular embodiment of the above-mentioned films of embodiments (C) and (D), the film components, except for dexmedetomidine or a pharmaceutically acceptable salt thereof, form a single-layer film substrate, and dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate (e.g., in a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, a low molecular weight water-soluble polymer having a molecular weight of about 40,000 Da, and a high molecular weight water-soluble polymer having a molecular weight of about 140,000 Da). In some embodiments, each water-soluble polymer is hydroxypropyl cellulose.

In another embodiment (E), a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 180 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da); and (iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

- 21 047684 wherein the composition of part (a) is present on the surface of the film substrate (b).

In another embodiment (F), a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 120 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da);

(iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b).

In a particular embodiment of the above-mentioned films of embodiments (E) and (F), dexmedetomidine hydrochloride is present in an amount of from about 0.1 to about 2% w/w of the total weight of the film; hydroxypropyl cellulose (40,000 Da) is present in an amount of from about 4 to about 8% w/w of the total weight of the film; hydroxypropyl cellulose (140,000 Da) is present in an amount of from about 4 to about 8% w/w of the total weight of the film; hydroxypropyl cellulose (370,000 Da) is present in an amount of from about 25 to about 30% w/w of the total weight of the film; polyethylene oxide (600,000 Da) is present in an amount of from about 50 to about 60% w/w of the total weight of the film.

In some embodiments, the pharmaceutical composition of the present invention provides a detectable Cmax of dexmedetomidine in human blood plasma following administration of a single dose and multiple dose administrations of the pharmaceutical composition of the present invention. In some embodiments, the pharmaceutical composition of the present invention provides a _Tmax of dexmedetomidine in human blood plasma following administration of a single dose or multiple dose administrations of the pharmaceutical composition of the present invention. In some embodiments, the pharmaceutical compositions of the present invention provide a detectable area under the curve (AUC) of dexmedetomidine and its metabolites in human blood plasma following administration of a single dose or multiple dose administrations. In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 (time of administration) to 12 hours from time 0 and is expressed as AUC _0-12h . In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 (time of administration) to 24 hours from time 0 and is expressed as AUC _0-24h . In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 to the last measurable concentration and is expressed as AUC _0-last . In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 (time of administration) to time extrapolated to infinity and is expressed as AUC _0-inf . In some embodiments, the ranges and values of AUC _0-last and ^AUC 0-inf for dexmedetomidine (or its metabolites) are similar to the ranges and values of AUC _0-6h for dexmedetomidine (or its metabolites). Thus, in some embodiments, the ranges and values for AUC _0-6h described herein may also serve as ranges and values for AUC _0-last and AUC _0-inf .

In some embodiments, mucosal administration of film (E) (e.g., sublingually or bucally) to subjects with schizophrenia at a dose of about 180 mcg dexmedetomidine hydrochloride resulted in pharmacokinetic parameters of about 80% to about 125% of the following values: C _max of about 100 to about 800 ng/L, T _max of about 1 to about 8 h, and AUC _last of about 500 to about 8900 h*ng/L. In some embodiments, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L and 475 ng/L, about 500 ng/L, about 525 ng/L, about 550 ng/L, about 575 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L. In some embodiments, T _max is about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about

2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about

4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about

6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about

8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, or about 10 h. In some embodiments, the AUC _last is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, about 5500 h*ng/l, about 5750

- 22 047684 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, about 6500 h*ng/l, about 6750 h*ng/l, about 7000 h*ng/l, about 7250 h*ng/l, about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, about 8500 h*ng/l, about 8750 h *ng/l, about 9000 h*ng/l, about 9250 h*ng/l, about 9500 h*ng/l, about 9750 h*ng/l, about 10000 h*ng/l, about 10250 h*ng /l, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about t 11500 h*ng/L, or about 11875 h*ng/L. In some In some embodiments, the film is administered sublingually.

In some embodiments, mucosal administration of film (F) (e.g., sublingually or bucally) to subjects with schizophrenia at a dose of about 120 mcg dexmedetomidine hydrochloride resulted in pharmacokinetic parameters of about 80% to about 125% of the following values: C _max of about 110 to about 400 ng/L, T _max of about 1 to about 4 h, and AUC _last of about 500 to about 4200 h*ng/L. In some embodiments, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, or about 500 ng/L. In some embodiments, the Tmax is about 0.8 hr, about 0.9 hr, about 1 hr, about 1.25 hr, about 1.5 hr, about 1.75 hr, about 2.0 hr, about 2.25 hr, about 2.5 hr, about 2.75 hr, about 3.0 hr, about 3.25 hr, about 3.5 hr, about 3.75 hr, about 4.0 hr, about 4.25 hr, about 4.5 hr, about 4.75 hr, about 5.0 hr. In some embodiments, the _AUClast is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/L, about 4500 h*ng/L, about 4750 h*ng/L, about 5000 h*ng/L, about 5250 h*ng/L, or about 5500 h*ng/L. In a particular embodiment, the film is administered sublingually.

In some embodiments, the present invention provides pharmaceutical compositions for a buccal film comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive polymers, and optional excipients selected from one or more of the following: plasticizers, penetration enhancers, colorants, sweeteners, flavoring agents, taste agents, or salivary stimulants. The mucoadhesive polymers can be selected from hydrophilic polymers and hydrogels. Examples of hydrophilic polymers include polyvinyl alcohol [PVA], sodium carboxymethylcellulose [NaCMC], hydroxylpropyl methylcellulose [HPMC], hydroxylethylcellulose, and hydroxypropylcellulose [HPC]. Examples of hydrogels include anionic polymers such as carbopol, polyacrylates, cationic polymers such as chitosan, and nonionic polymers such as Eudragit analogs.

Sprays, drops or gels

In some embodiments, the present invention provides pharmaceutical spray compositions or drop compositions suitable for sublingual or buccal administration, comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable liquids (from about 1 to about 99.995% by weight). Such liquids can be solvents, co-solvents or non-solvents for dexmedetomidine or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerol, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.) or the like. The pharmaceutically acceptable liquid is selected to dissolve dexmedetomidine or a pharmaceutically acceptable salt thereof, to obtain a stable homogeneous suspension thereof, or to form any combination of a suspension or a solution. In addition to these ingredients, the formulations of dexmedetomidine or a pharmaceutically acceptable salt thereof in the form of sprays or drops may include one or more excipients such as viscosity adjusting agents (e.g., polymers, sugars, sugar alcohols, gums, clays, silicas, etc., such as polyvinylpyrrolidone (PVP)); preservatives (e.g., ethanol, benzyl alcohol, propylparaben and methylparaben); flavoring agents (e.g., peppermint oil), sweeteners (e.g., sugars such as sucrose, glucose, dextrose, maltose, fructose, etc.), artificial sweeteners (e.g., saccharin, aspartame, acesulfame, sucralose) or sugar alcohols (e.g., mannitol, xylitol, lactitol, maltitol syrup); buffers and pH adjusting agent (e.g. sodium hydroxide, citrate and citric acid); colorants; flavors, chelating agents (e.g. EDTA); UV absorbers and antifoaming agents (e.g. low molecular weight alcohols, dimethicone). In addition to one or more of the above ingredients suitable for sublingual or buccal sprays or drops, gel compositions of dexmedetomidine or a pharmaceutically acceptable salt thereof may include one or more excipients such as viscosity modulating materials (e.g. water-soluble or water-swellable polymers such as carbopol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.), or other additives such as hydroxypropyl methylcellulose.

- 23 047684 vine, carboxymethylcellulose).

Sprays, drops and gels may be prepared by mixing appropriate amounts of the above ingredients in accordance with standard good manufacturing practice. Such excipients may be included in the formulation to improve patient or subject acceptance or taste, to improve bioavailability, to increase shelf life, to reduce manufacturing and packaging costs, to meet government regulatory requirements and for other purposes. The relative amounts of each ingredient should not affect the desired pharmacological and pharmacokinetic properties of the resulting product.

In some embodiments, an oromucosal spray composition is provided comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

In one embodiment, the patient may be treated by sublingual or buccally administration of 1 to 2 pump actuations from an irrigation pump. The advantage of spray delivery is the ability to easily titrate the patient with 1 or 2 doses as required per actuation.

Irrigation pumps are characterized by requiring external pressure, such as external manual, mechanical or electrical pressure, to operate. This contrasts with pressure-operated systems, such as propellant aerosol sprayers, in which actuation is typically achieved by a controlled release of pressure, such as by the controlled opening of a valve.

Various formulations of sublingual sprays containing dexmedetomidine hydrochloride in doses of 20, 30, 60, 90, 120 and 180 mcg and excipients are described in Table 1.

Table 1. Embodiments of sublingual spray formulations according to the present invention

Ingredients Variant of the implementation of the composition of sublingual spray No. 1 2 3 4 N-methylpyrrolidone Z Propylene glycol u/ Polyethylene glycol u/ Glycerin z Ethanol u/ u/ u/ u/ Sucralose u/ u/ u/ u/ Peppermint oil u/ u/ u/ u/ Purified water u/ u/ u/ u/ Optional other pharmaceutically acceptable excipients

Various compositions of sublingual drops containing dexmedetomidine hydrochloride in doses of 20, 30, 60, 90, 120 and 180 mcg and excipients are described in Table 2.

- 24 047684

Table 2. Variants of compositions of sublingual drops in accordance with the present invention

20, 30, 60, 90, 120 and 180 mcg and excipients are described in Table 3.

- 25 047684

Table 3. Variants of sublingual gel compositions in accordance with the present invention

Ingredients Variant of the composition of sublingual gel No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Carbopol u/ u/ u/ u/ u/ Hydroxypropyl methylcellulose u/ u/ u/ u/ u/ Hydroxypropyl cellulose Carboxymethylcellulose u/ u/ u/ u/ u/ A'-Methylpyrrolidone u/ u/ u/ Propylene glycol u/ u/ u/ Polyethylene glycol u/ u/ u/ Glycerin u/ u/ u/ Ethanol u/ u/ u/ Sucralose u/ u/ u/ u/ u/ u/ u/ u/ u/ u/ u/ u/ u/ u/ Peppermint oil Purified water Optional other pharmaceutically acceptable excipients u/ ·/ u/ u/ u/ u/ u/ u/ u/ u/ u/ u/ u/ / /

Pills

In some embodiments, the present invention provides tablet formulations suitable for oral mucosal administration (e.g., sublingual or buccal administration) comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers (from about 1 to about 99.995% by weight). Such carriers can be taste-masking agents, diluents, disintegrants, binders, lubricants, glidants, flavorings, or liquid solvents. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerol, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.) or the like. Taste masking agents include, for example, amberlite, Opadry® AMB TAN, polymethacrylates (especially Eudragit® L100), sodium starch glycolate (Primojel), carbopol polymers, PEG-5M, sodium acetate, ethylcellulose, betacyclodextrin. Flavorings can be, for example, mint powder, menthol, vanillin, aspartame, acesulfame potassium, saccharin. Disintegrating agents include, for example, sodium starch glycolate, low-substituted hydroxypropyl cellulose, alginic acid, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium croscarmellose, guar gum, methylcellulose, potassium polacrilin, poloxamer, sodium alginate. Diluents may be, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sucralose, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol. Binders may be, for example, alginic acid, carbomer, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, methylcellulose, polydextrose, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium alginate. At least one lubricant may be advantageously included in the composition to prevent

- 26 047684 sticking of powder to the tablet punch during the pressing procedure. Lubricants may be, for example, talc, magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated castor oil, stearic acid, sodium lauryl sulfate. Glidants are used to accelerate the powder flow by reducing interparticle friction and cohesion. They are used in combination with lubricants, since they do not have the ability to reduce the friction of the matrix walls. Glidants may be, for example, colloidal silicon dioxide, calcium silicate, tribasic calcium phosphate.

Various formulations of buccal tablets containing dexmedetomidine hydrochloride in doses of 20, 30, 60, 90, 120 and 180 mcg and excipients are described in Table 4.

Table 4. Embodiments of buccal tablet formulations according to the present invention

Ingredients Variant of the composition of buccal tablets No. 1 2 3 4 5 Lactose monohydrate u/ u/ u/ u/ u/ Polyethylene oxide u/ Hydroxypropyl cellulose Hydroxypropyl methylcellulose u/ Sodium alginate u/ Xanthan gum u/ Sucralose u/ u/ u/ u/ u/ Magnesium stearate u/ u/ V u/ u/ Talc u/ u/ u/ u/ Optional other pharmaceutically acceptable u/ u/ u/ u/ excipients

Various sublingual tablet formulations containing dexmedetomidine hydrochloride in doses of 20, 30, 60, 90, 120 and 180 mcg and excipients are described in Table 5.

Table 5. Embodiments of the compositions of the sublingual tablet in accordance with _______________________the present invention_______________________

Ingredients Variant of the composition of sublingual tablets No. 1 2 3 4 5 6 7 8 9 10 Lactose monohydrate Z Z Z l/ l/ u/ Z Z Z Hydroxypropyl methylcellulose Z Z Hydroxypropyl cellulose u/ Croscarmellose sodium u/ u/ u/ u/ z Sodium starch glycolate Z Z u/ Z Z Polyethylene oxide u/ u/ Xanthan gum u/ u/ Sodium alginate Z Sucralose u/ Z u/ u/ u/ u/ u/ u/ Magnesium stearate u/ u/ u/ u/ u/ u/ u/ u/ z z Optional other pharmaceutically acceptable excipients ·/ ·/ ·/ ·/ ·/

Compositions for intranasal administration

The compositions according to the present invention can be administered to the nasal cavity in any suitable form. For example, the composition can be administered to the nasal cavity in the form of an aerosol emulsion, suspension or solution, in the form of drops or powder.

The powder mixture of the present invention can be prepared by mixing dexmedetomidine or a pharmaceutically acceptable salt thereof with inert ingredients that

- 27 047 684 are standard in the art. Such inert ingredients include, but are not limited to, diluents such as calcium phosphate, lactose, sugars such as dextrose and sucrose, polyols such as mannitol and sorbitol and microcrystalline cellulose, glidants such as colloidal silicon dioxide and lubricants such as magnesium stearate and hydrogenated vegetable oils and surfactants such as polysorbates; as well as polyethylene glycol. For preparing a homogeneous powder mixture on a small scale, a pestle, mortar and/or sieve may be suitable, whereas for large scale production, mechanical mixers are required. Many types of mixers are available and are widely described in the literature, for example, Chapter 37, Remington: The Science and Practice of Pharmacy, 20th Edition, Lipincott, Williams and Wilkins, Baltimore, 2000.

If the powder composition of the present invention comprises granules, these granules can be prepared by methods well known to those skilled in the art, such as wet granulation, dry granulation (impact compaction), extrusion/spheronization, fluidized bed granulation, and spray crystallization. Further information on granulation processes can be found in the literature, for example, Chapter 6, Pharmaceutical Principles of Solid Dosage Forms, J. T. Carstensen, Technomic, Lancaster, PA, 1993.

In addition to dexmedetomidine or a pharmaceutically acceptable salt thereof, other ingredients may be included in the granules. Such other ingredients include, but are not limited to, diluents such as calcium phosphate, lactose, dextrose, mannitol, and microcrystalline cellulose, binders such as povidone (polyvinylpyrrolidone), methylcellulose, polyethyleneglycol, gelatin, and gum arabic, disintegrants such as starch, crospovidone, and crospovidone, glidants such as colloidal silicon dioxide, and lubricants such as magnesium stearate and hydrogenated vegetable oil. Methods for preparing microspheres are well known to those skilled in the art and include, but are not limited to, spray drying, interfacial polymerization, coarsening/phase separation, and solvent evaporation. Methods for preparing microspheres are described, for example, in Physicochemical Principles of Pharmacy, 3rd Edition, pages 357 to 360, A T Florence and D Attwood, Macmillan, London, 1998 and Physical Pharmacy, 4th Edition, pages 516 to 519, A Martin, Wilkins and Wilkins, Baltimore, 1993. Alternatively, microspheres can be prepared by the methods described in WO 98/30207 and the documents cited therein.

The powder compositions of the present invention can be administered to a subject in aerosol form, whereby the energy from the patient's inhalation (pulling air through the nose) is used to spray the powder in the nasal cavity, or the device itself can generate the aerosolization energy, for example, by means of compressed air. An example of the first device is the device developed by Pfeiffer, and an example of the second device is the Monopowder from Valois. The present invention also provides a device for nasal drug delivery or a metering cartridge for use in a nasal delivery device loaded with a composition as defined above.

In one embodiment of the present invention, a method for preparing solutions of the present invention is also described, comprising mixing the components in a suitable solvent, such as water, ethanol, propylene glycol, polyethylene glycol, glycofurol, benzyl benzoate and polyoxyethylene castor oil derivatives. Said compositions can be prepared using methods known in the art.

The solutions of the present invention may also contain other pharmaceutically acceptable ingredients well known in the art. Such ingredients include, but are not limited to, thickening agents, adhesives, or gelling agents such as, but not limited to, celluloses (e.g., hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, and microcrystalline cellulose), carbomers, polyethylene oxide, poloxamers, or polyethylene glycols, antioxidants (e.g., sodium metabisulfite), chelating agents (such as edetate or one of its salts), preservatives (such as potassium sorbate, parabens, phenylethyl alcohol, or benzalkonium chloride), flavorings, sweetening agents, thickening agents, adhesives, or gelling agents including, but not limited to, celluloses such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, sodium carboxyl cellulose, and microcrystalline cellulose, poloxamers, polyethylene glycols, carbomers, or polyethylene oxide.

The solutions of the present invention may contain a preservative and/or may be sterile. If preservatives are not included in the compositions, microorganisms may be removed by any suitable method known in the art, such as by preparing the compositions under aseptic conditions or by terminally sterilizing them. In some embodiments, the compositions are non-pyrogenic.

In one embodiment, the intranasal compositions of the present invention comprise an aqueous suspension, solution or emulsion containing materials in addition to the active ingredient, such as a suitable dispersant and/or wetting agent, for example propylene glycol.

- 28 047684 or polyethylene glycol, emulsifier, suspending agent, surfactant, solubilizer, carrier, etc.

The pharmaceutical composition can also be prepared in the form of liposomes, microcapsules or centrosomes with one or more suitable pharmaceutically acceptable carriers.

In addition to dexmedetomidine or a pharmaceutically acceptable salt thereof, the microspheres used in the present invention may include ingredients known in the art to be suitable for inclusion in microspheres, such as, but not limited to, starches, dextrans, gelatin, albumin, collagen, hyaluronic acid, chitosan, lactose, sucrose, dextrose, mannitol, methacrylate copolymers such as Eudragit® polymers (Degussa, Germany), celluloses such as methylcellulose, and polyesters such as poly(lactide-co-glycolide).

Any device suitable for intranasal administration can be used. In some embodiments, the device is a metered dose device. The metered dose device can deliver a predetermined dose of the composition. The metered dose device can be a single-dose, dual-dose, or multi-dose device. The pharmaceutically effective amount that can be administered using the metered dose device can be a unit dose device. In some embodiments, the metered dose device can be a device that can deliver the pharmaceutical composition intranasally. Examples of metered dose devices include, but are not limited to, devices that are pump devices, mechanical devices, pressure devices, and/or electromechanical devices. Examples of a metered dose delivery device include, but are not limited to, a spray pump, a pre-compressed nasal spray pump, a metered valve device, an actuated spray device, a side-actuated spray device, a syringe device for nasal spraying (e.g., a syringe with a sprayer for delivering a spray into the nasal cavity), a device for spraying onto the mucous membrane, a device with an electromechanical pump (with or without a counter), and the like. Examples of metered dose delivery devices also include, but are not limited to, devices manufactured by Aptar Pharma (Congers, NY), which are commercially available. Examples of metered dose delivery devices also include, but are not limited to, UDS (Aptar Pharma), BDS (Aptar Pharma), eDevices (Aptar Pharma), Equadel (Aptar Pharma), Latitude (Aptar Pharma), DF30 (Aptar Pharma), VP7 (Aptar Pharma), Classic Nasal Device (Aptar Pharma), MAD Nasal Drug Device (Wolf Tory Medical, Inc.), BD Accuspray SCF™ (Becton Dickinson), etc. Another example includes, but is not limited to, the Aptar Unitdose intranasal system.

Parenteral formulations

Liquid pharmaceutical compositions for parenteral administration may be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion may include, but are not limited to, intravenous, intraperitoneal, intramuscular, intrathecal, and subcutaneous. In some embodiments, parenteral formulations may include prefilled syringes, vials, infusion powder for reconstitution, infusion concentrate for dilution prior to delivery (ready for dilution), or solutions (ready for use).

Pharmaceutical compositions for injections can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fat emulsions or suspensions.

The pharmaceutical compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.

In certain embodiments, the pharmaceutical compositions of the present invention include a biodegradable subcutaneous implant, an osmotically controlled device, a subcutaneous implant, a subcutaneous injection with a delayed release, lipid nanoparticles, liposomes, and the like. Liquid preparations can include, but are not limited to, solutions, suspensions, and emulsions. An example of such preparations are aqueous or aqueous/propylene glycol solutions for parenteral administration. Liquid preparations can also include solutions for intranasal administration.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient(s) are generally used and the pH of the solutions should be appropriately adjusted and buffered. For intravenous solutions, the total concentration of the solute(s) should be controlled to make the preparation isotonic.

The liquid carrier used to prepare the intramuscular injection may be, for example, water, physiological saline solution, another aqueous liquid (aqueous solvent), or a non-aqueous liquid (non-aqueous solvent). Non-aqueous solvents may include organic solvents such as ethanol, isopropyl alcohol, diethylene glycol monoethyl ether,

- 29 047684 cola or other alkyl derivative, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol, etc.) or oily vehicles such as castor oil, peanut oil, sesame oil or other solvents such as carboxymethylcellulose, polysorbate and mixtures thereof. These aqueous and non-aqueous solvents may also act as co-solvents to increase the solubility of drugs or reduce the viscosity of oily vehicles.

The formulation may contain an excipient. Pharmaceutically acceptable excipients that may be included in the formulation are buffers such as citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer; amino acids; urea; alcohols; ascorbic acid; phospholipids; proteins such as serum albumin, collagen and gelatin; salts such as EDTA or EGTA and sodium chloride; liposomes; polyvinylpyrrolidones; sugars such as dextran, mannitol, sorbitol and glycerol; propylene glycol and polyethylene glycol (e.g. PEG-4000, PEG-6000); glycerol; glycine; lipids; preservatives; suspending agents; stabilizers; and colorants. As used herein, the term stabilizer refers to a compound optionally used in the pharmaceutical compositions of the present invention to avoid the need for sulfite salts and to extend shelf life. Non-limiting examples of stabilizers include antioxidants. Buffer systems for use with the formulations include citrate; acetate; bicarbonate; and phosphate buffers.

The formulation may also contain a non-ionic detergent. Examples of non-ionic detergents include, but are not limited to, Polysorbate 20, Polysorbate 80, Triton X-100, Triton X-114, Nonidet P-40, Octyl-α-glucoside, Octyl-β-glucoside, Bridge 35, Pluronic, and Tween 20.

The parenteral formulations of the present invention can be sterilized. Non-limiting examples of sterilization methods include filtration through a bacteria-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heating.

The parenteral formulations described above may be administered by intermittent bolus injections of the drug or may be administered intravenously or intraperitoneally from a reservoir that is external (e.g., an intravenous solution bag) or internal (e.g., a biodegradable implant, bioartificial reservoir, or organ). See, e.g., U.S. Patent Nos. 4,407,957 and 5,798,113, each of which is incorporated herein by reference in its entirety. Methods and apparatus for pulmonary delivery are described, e.g., in U.S. Patent Nos. 5,654,007, 5,780,014, and 5,814,607, each of which is incorporated herein by reference in its entirety. Other suitable parenteral delivery systems include ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, pump delivery, encapsulated cell delivery, liposomal delivery, needle-delivered injection, needle-free injection, nebulizer, aerosolizer, electroporation, and transdermal patch. Needle-free injection devices are described in U.S. Patent Nos. 5,879,327; 5,520,639; and 5,704,911, the disclosures of which are incorporated herein by reference in their entireties. Any of the formulations described herein can be administered by these methods. Other dexmedetomidine injection formulations are described in U.S. Patent No. 8,242,158, U.S. Patent No. 9,649,296, Japanese Patent No. 5,921,928, Japanese Patent Application No. 2016154598, CN Patent Application No. 103284945, CN Patent Application No. 104161760, CN Patent Application No. 105168122, CN Patent Application No. 105534891, CN Patent Application No. 106038538, U.S. Patent Application No. 20170128421, CN Patent Application No. 107028880, CN Patent Application No. 107412152, CN Patent Application No. 108498469, EP Patent No. 2252290, Japanese Patent Application No. 2019048091, and US Patent Application No. 20190183729.

In some non-limiting embodiments, the intramuscular dexmedetomidine composition of the present invention comprises dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.05 to about 15 μg/mL, sodium chloride at a concentration of about 0.01 to about 2.0 wt.%, and a pH in the range of about 1 to about 10.

Formulations for oral administration

The present invention includes oral formulations that can be used to deliver dexmedetomidine. Examples of oral formulations include tablets, orodispersible tablets, orodispersible tablets, wafers, solutions, suspensions, emulsions, and capsules.

The present invention relates to oral orally disintegrating tablets comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one orally disintegrating carrier, wherein the orally disintegrating tablet disintegrates within about 0.5 to about 120 sec and/or a therapeutically effective amount of dexmedetomidine is absorbed into the bloodstream within a time period ranging from 1 to 5 min. In some embodiments, a therapeutically effective amount of dexmedetomidine is absorbed into the bloodstream within about 3 min.

In some embodiments, the at least one orally disintegrating carrier is selected from the group consisting of water-soluble sugars or a sugar alcohol,

- 30 047684 crospovidone, (low substituted) hydroxypropyl cellulose, sodium croscarmellose, microcrystalline cellulose, lactose, pregelatinized starch, sodium starch glycolate, sodium lauryl sulfate, crystalline cellulose and a combination thereof. The water-soluble sugars or sugar alcohol are selected from the group consisting of sucrose, sorbitol, mannitol, xylitol, erythritol, isomalt and fructose. In some embodiments, the orally disintegrating carriers together constitute at least 50 wt.%, such as at least 80 wt.% or at least 85 wt.%, of the orally disintegrating carriers. The aforementioned carriers are in the form of particles, typically with a weight average particle size of 50-300 μm, such as 70-200 μm. FMelt® (Fuji Chemical Industry Co.) is an example of a commercially available particulate material that contains a disintegrant dispersed in a matrix containing a C4-C6 sugar alcohol (mannitol and xylitol). Ludiflash® (BASF) is another example of a commercially available particulate material that contains a disintegrant dispersed in a matrix containing a C4-C6 sugar alcohol (mannitol).

The orally disintegrating tablet of the present invention can be prepared by mixing dexmedetomidine with water-soluble diluents and compressed into a tablet. A suspension containing dexmedetomidine can be prepared with appropriate excipients, and the dexmedetomidine suspension can be filled into blister packs and freeze-dried. A typical platform for preparing a lyophilized preparation that can be used for ODT of dexmedetomidine is ZYDIS® (Catalent, Somerset, NJ, USA). In particular, excipients including water are mixed, and dexmedetomidine is separately sized and mixed with the excipients. The suspension is then lyophilized by flash freezing and freeze-drying. Other methods for producing ODT may be used without limitation, and detailed descriptions of their general methods are described, for example, in U.S. Patent Nos. 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270; 6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978; 6,908,626; 6,908,626; 6,982,251; 7,282,217; 7,425,341; 7,939,105; 7,993,674; 8,048,449; 8,127,516; 8,158,152; 8,221,480; 8256233 and 8313768, each of which is incorporated herein by reference in its entirety.

The liquid pharmaceutical suspension of the present invention for oral administration contains at least one drug in particulate form as an active ingredient, wherein the active ingredient is dexmedetomidine or a pharmaceutically acceptable salt thereof. The particulate dexmedetomidine may be partially dissolved in the liquid phase, but preferably more than 50 percent should be particles. The suspension of the present invention contains at least one suspending polymer exhibiting plastic flowability that imparts a flow value of about 0.2 to about 15 Pa, preferably about 0.5 to about 10 Pa. Preferred are polymers exhibiting Bingham plasticity and shear thinning plastic flowability. Polymers exhibiting thixotropic plastic flow may be used only if the lag time to restore 50% of the flow value is rapid, less than about an hour, preferably less than about five minutes, most preferably less than about a minute. The polymer exhibiting plastic flow may be selected from, among others, xanthan gum, carbomer, microcrystalline cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and combinations thereof. The final flow value of the suspension should be less than about 15 Pa, preferably less than about 10 Pa, so that the product is flowable without shaking.

In addition to the flow value, the rheology of the final suspension should have an apparent viscosity of at least about 50 cP, preferably at least about 100 cP, most preferably at least about 200 cP, at a shear rate of 100 s-1 to retard particle motion when the shear rate exceeds the flow value, such as when shaking or pouring. For a thixotropic plastic fluid, a high viscosity retards particle motion while the flow value is restored after shear is applied. In cases where the suspending polymer(s) added to impart flow value are not adequate to achieve the desired apparent viscosity of at least about 50 cP at a shear rate of 100 s-1, viscosity enhancing agents without a yield point may be added. These viscosity increasing agents can be selected from, among others, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, guar gum, locust bean gum and combinations thereof.

The liquid suspension of the present invention may contain additional ingredients used in the pharmaceutical industry, referred to herein as additives. Additives include well-known components, but are not limited to sweeteners, flavors, colorants, antioxidants, chelating agents, surfactants, wetting agents, antifoaming agents, pH modifiers, acidifiers, preservatives, cosolvents, and mixtures thereof.

The present invention also relates to a homogeneous and stable pharmaceutical solution.

- 31 047684 ru dexmedetomidine suitable for oral administration to a mammal.

The liquid pharmaceutical solution for oral use according to the present invention contains dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from the group consisting of cosolvents, solvents, antioxidants, microbial preservatives, buffering agents, flavoring agents, sweeteners and diluents.

Co-solvents and solvents may include, but are not limited to, glycerin, alcohols, propylene glycol, polyethylene glycol, benzyl alcohol, water, ethanol, isopropyl alcohol, or mixtures thereof.

Suitable antioxidants may include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, sodium ascorbate, gentisic acid, sodium bisulfite, sodium metabisulfite, monothioglycero, cysteine. Sodium thioglycolate, sodium acetone bisulfite, ascorbate (sodium/acid), sodium bisulfite, cysteine/cysteine HCl, sodium dithionite (sodium hydrogen sulfite, sodium sulfoxylate), gentisic acid, gentisic acid ethanolamine, sodium glutamate, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, monothioglycerol (thioglycerol), propyl gallate, sodium sulfite, tocopherol alpha, sodium thioglycolate, EDTA in calcium and sodium compounds or mixtures thereof.

Buffering agents may include, but are not limited to, ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, trisodium citrate dehydrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, carbonated calcium phosphate, magnesium hydroxide, hydrochloric acid, sodium hydroxide, or mixtures thereof.

Diluents may include, but are not limited to, maltitol solution, glucose syrup, glycerin, sorbitol and mannitol solutions, sucrose, sorbitol, xylitol, dextrose, fructose, potassium sucrose, aspartame, saccharin, sodium saccharin, spray-dried or anhydrated lactose, mannitol, starch, or mixtures thereof.

Sweeteners may include, but are not limited to, sucralose, aspartame, acesulfame-K, thaumatin, mogroside, saccharin and their salts, sodium cyclamate, glucose, sucrose, lactose, fructose, mannitol, sorbitol, lactitol, xylitol, erythritol, glycyrrhizin, sodium glycyrrhizinate, monoammonium glycyrrhizinate, isomalt, glycerin, dextrose, or mixtures thereof.

Flavoring agents may include, but are not limited to, fruit flavors such as orange, banana, strawberry, cherry, wild cherry, lemon, etc., and other flavors such as cardamom, anise, mint, menthol, vanillin, or mixtures thereof.

Microbial preservatives may include, but are not limited to, sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts, benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acids and their alkyl esters, methyl and propyl parabens, or mixtures thereof.

In one embodiment of the present invention there is provided a solid pharmaceutical composition for oral use, for example in the form of a tablet, comprising pharmacologically effective amounts of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The compositions of the present invention contain additives customary for the dosage form in question. Tableting additives customary for tablet formulations can be used, and reference is made to an exhaustive list of literature sources on this subject, see in particular Fiedler's Lexikon der Hilfsstoffe, 4th Edition, ECV Aulendorf, 1996, which is incorporated herein by reference. These additives include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizing agents, fillers or diluents, surfactants and the like.

Disintegrants suitable for the compositions of the present invention include, in particular, cross-linked PVP, crospovidone, guar gum, alginic acid, sodium alginate, cross-linked CMC and Ac-Di-Sol®. In some embodiments, the disintegrant is crospovidone.

As binders suitable for the compositions of the present invention, there may be mentioned in particular starches, for example potato starch, wheat starch, corn starch, celluloses such as microcrystalline cellulose, for example the products known under the registered trade marks Avicel®, Filtrak®, Heweten® or Pharmacel®, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, for example hydroxypropyl cellulose having a hydroxypropyl content of from 5 to 16% by weight and a molecular weight of from 80,000 to 1,150,000, more particularly from 140,000 to 850,000.

Suitable glidants for the compositions of the present invention include, in particular, colloidal silicon dioxide, such as Aerosil®, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

As fillers or diluents suitable for the compositions of the present invention, mention may be made of confectioner's sugar, compressed sugar, dextrates, dextrin, dextrose, lacto

- 32 047684 sugar, mannitol, sorbitol, sucrose, microcrystalline cellulose, in particular having a density of about 0.45 g/cm3, such as Avicel® or powdered cellulose and talc.

A preferred filler may be Avicel®.

Suitable lubricants for the compositions of the present invention include, in particular, magnesium, aluminum or calcium stearate, polyethyleneglycol (PEG) having a molecular weight of 4000 to 8000, and talc.

One or more of these additives can be selected and used by a skilled person taking into account the specific desired properties of the solid oral dosage form by routine experimentation and without any undue burden. The amounts of each type of additive used, for example, glidant, binder, disintegrant, filler or diluent and lubricant, can vary within the usual ranges in the art. For example, the amount of glidant can vary in the range of 0.1 to 10% by weight, in particular from 0.1 to 5% by weight, for example from 0.1 to 0.5% by weight; the amount of binder can vary in the range of about 10 to 65.3% by weight, for example from 10 to 45%, for example from 20 to 30% by weight; the amount of disintegrant may vary in the range from 5 to 60% by weight, for example from 13 to 50%, for example from 15 to 40%, for example from 20 to 30%, for example 25%; the amount of filler or extender may vary in the range from 15 to 65% by weight, for example from 20 to 50%, for example from 25 to 40%, for example 30%, while the amount of lubricant may vary in the range from 0.1 to 5.0% by weight.

IV. Methods and introduction

In some embodiments (A) of the present invention, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose of at least about 120 mcg to said subject. In some embodiments, the treatment is effective without causing significant sedation. In some embodiments, the pathological condition is agitation or signs of agitation. In some embodiments, the agitation or signs of agitation are associated with schizophrenia. In some embodiments, the agitation or signs of agitation are associated with a bipolar condition, such as bipolar I disorder. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 to about 405 mcg, such as about 120 to about 270 mcg, or at a dose of about 180 to about 405 mcg, such as about 180 to about 270 mcg, including doses of about 120 or about 180 mcg.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 to about 405 mcg, such as about 120 to about 270 mcg, or at a dose of about 180 to about 405 mcg, such as about 180 to about 270 mcg, including doses of about 120 or about 180 mcg administered to treat agitation or signs of agitation in a human subject.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 to about 405 mcg, such as about 120 to about 270 mcg, or at a dose of about 180 to about 405 mcg, such as about 180 to about 270 mcg, including doses of about 120 or about 180 mcg administered to treat agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder without causing significant sedation.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 to about 405 mcg, such as about 120 to about 270 mcg, or at a dose of about 180 to about 405 mcg, such as about 180 to about 270 mcg, including doses of about 120 or about 180 mcg administered to treat agitation or signs of agitation in a human subject with schizophrenia or bipolar disorder without causing significant sedation or clinically significant cardiovascular effects.

In some embodiments (B) of the present invention, there are provided methods of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) as a single dose of about 120 or about 180 mcg. In some embodiments, the treatment is effective and does not cause clinically significant cardiovascular effects.

In some embodiments, the present invention provides a method of treating acute agitation associated with schizophrenia and bipolar disorder (e.g., bipolar I disorder) in a human subject, comprising oromucosally administering a film composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) as a single dose of 120 or 180 mcg. In some embodiments, an additional dose (e.g., 90 or 60 mcg) may be administered after a suitable period.

- 33 047684 time (e.g. 2 h) in case of persistent or recurrent agitation (e.g. by cutting the 180 or 120 mcg film in half).

In some embodiments, the present invention provides a method of treating acute agitation associated with schizophrenia and bipolar disorder (e.g., bipolar I disorder) in a human subject, comprising oromucosally administering a film composition comprising dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride salt) thereof, wherein said subject simultaneously receives an antipsychotic agent. Suitable antipsychotic agents contemplated by the present invention include, but are not limited to, aripiprazole, benperidol, flupentixol, amisulpride, chlorpromazine, azenapine, risperidone, ziprasidone, lurasidone, clozapine, cariprazine, olanzapine, and quetiapine. In some embodiments, the antipsychotic agent is aripiprazole.

In a specific embodiment (C) of the present invention, there are provided methods of treating agitation or signs of agitation in a human subject suffering from dementia, which do not cause significant sedation and comprise administering from about 30 to about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, 30, 60, or 90 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day. In some embodiments, an additional dose (e.g., 30 mcg) can be taken after an appropriate period of time (e.g., 2, 4, 6, 8, or 12 hours) in case of persistent or recurrent agitation. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally as a unit dose containing from about 30 to about 90 mcg, from 1 to 6 times per day. For example, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered through the oral mucosa 1, 2, 3, 4, 5 or 6 times every 2 hours, every 4 hours, every 6 hours, every 8 hours, every 10 hours or every 12 hours. In some embodiments, each unit dose containing from about 30 to 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof can be taken from one to six times a day at intervals of 2 hours with a maximum of three doses provided within 12 hours after the first dose. In some embodiments, each unit dose containing from about 90 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof can be taken from one to four times a day at intervals of 2 hours with a maximum of two doses provided within 12 hours after the first dose. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally (e.g., sublingually or buccally) as a film. In some embodiments, the desired dose can be achieved by cutting the film in half to deliver half the dose (e.g., a 60 mcg dose can be administered with half of a second 60 mcg dose (30 mcg) to yield a 90 mcg dose).

In a specific embodiment (D), the present invention also provides methods of controlling or treating agitation in delirium in subjects, without inducing significant sedation, comprising administering about 20 to about 240 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is hospitalized. In some embodiments, the subject is hospitalized in an intensive care unit. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) is administered transmucosally in a unit dose containing about 20 or about 60 mcg as a single dose. In some embodiments, each unit dose can be administered one to four times at an appropriate dosing interval (e.g., every 0.5, 1, 2, or 3 hours) over a period of 6 hours after the first dose to obtain the desired effect; for example, 20 mcg is administered four times at 0.5 hour dosing intervals within 6 hours after the first dose to achieve the effect of a dose of 80 mcg, or a dose of 60 mcg is administered four times at 0.5 hour dosing intervals within 6 hours after the first dose to achieve the effect of a dose of 240 mcg. In some embodiments, the treatment is effective and does not cause clinically significant cardiovascular effects. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally (e.g., sublingually or buccally) as a film as described herein.

In a particular embodiment (E) of the present invention there is provided a method of reducing the period of opioid withdrawal in a human subject in need thereof, comprising administering to said subject dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily, wherein the period of withdrawal is up to 14 days. In some embodiments, the period of withdrawal may be 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days. In some embodiments, the human subject is an adult (i.e., at least 18 years of age) suffering from an opioid use disorder and who is physically dependent on opioids. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, orally, intranasally, or parenterally. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) is administered sublingually as a film. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered transmucosally.

- 34 047684 oral mucosa in a dosage range of about 30 to about 200 mcg as a single dose. In some embodiments, dexmedetomidine is administered at a dosage of about 30 mcg, about 60 mcg, or about 90 mcg, about 120 mcg, or about 180 mcg twice daily at about 12 hour intervals for a period of at least 3 days (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, or 13 days). In further embodiments, each unit may be administered at a suitable interval between doses (e.g., about 12 hours between doses) or may be administered simultaneously, such as two units of 30 mcg may be administered simultaneously to produce a 60 mcg dose effect or three units of 60 mcg may be administered simultaneously to produce a 180 mcg dose effect. In one embodiment, withdrawal symptoms following treatment are assessed using the Clinical Opioid Withdrawal Scale (COWS) and/or the Short Opioid Withdrawal Scale-Gossop (SOWS-Gossop) (e.g., over a 10-day period). In some embodiments, the opioid may be selected from the group consisting of, but not limited to, fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanyl carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil, or pentazocine. In some embodiments, the opioid is administered for a period of time exceeding neonatal treatment before withdrawal occurs. Surprisingly, dexmedetomidine has been found to be effective in shortening the period of opioid withdrawal in an adult subject. This finding is surprising because opioids (e.g., fentanyl) are localized in fatty tissue over time, are released intermittently, and have an unpredictable effect on patients during the withdrawal process. Because of the high degree of variability and intermittent release of opioids, clinicians did not expect repeated administration of dexmedetomidine to be effective therapy.

In some embodiments, the present invention provides a method for inducing stage 3 non-REM sleep in a human subject, comprising sublingually administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in a single dose. In some embodiments, the human subject is hospitalized in an intensive care unit with hyperactive delirium.

In some embodiments, the present invention provides a method of treating manifestations of cocaine toxicity and/or symptoms associated with cocaine toxicity, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of an oromucosal film in a dosage range of about 30 to about 200 mcg as a single dose or as a multiple dose therapy.

In another embodiment (F) of the present invention there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) such that the mean total exposure of dexmedetomidine, measured by AUC in plasma from _T0 to T0>, is about 3800 ng*hr/L. In some embodiments, said treatment is effective and does not cause clinically significant effects on the cardiovascular system. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by AUC in plasma from _T0 to Tgo, is from about 80% to about 125% of 3800 ng*hr/L. For example, the AUC is about 3024 ng*hr/L, about 3100 ng*hr/L, about 3200 ng*hr/L, about 3300 ng*hr/L, about 3400 ng*hr/L, about 3500 ng*hr/L, about 3600 ng*hr/L, about 3700 ng*hr/L, about 3800 ng*hr/L, about 3900 ng*hr/L, about 4000 ng*hr/L, about 4100 ng*hr/L, about 4200 ng*hr/L, about 4300 ng*h/L, about 4400 ng*h/L, about 4500 ng*h/L, about 4600 ng*h/L or about 4725 ng*h/L.

In another embodiment (G) of the present invention there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) such that the mean total exposure of dexmedetomidine, measured by AUC in plasma from _T0 to T0>, is about 1800 ng*h/L. In some embodiments, said treatment is effective and does not cause clinically significant effects on the cardiovascular system. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by AUC in plasma from _T0 to T0>, is from about 80% to about 125% of 1800 ng*hr/L. For example, the AUC is about 1440 ng*hr/L, 1500 ng*hr/L, about 1600 ng*hr/L, about 1700 ng*hr/L, about 1800 ng*hr/L, about 1900 ng*hr/L, about 2000 ng*hr/L, about 2100 ng*hr/L, about 2200 ng*hr/L, or about 2250 ng*hr/L.

In a further embodiment (H) of the present invention, there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder.

- 35 047684 a mental disorder, without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T ≥ , of from about 600 to about 9500 ng*h/L. In some embodiments, said treatment is effective and does not cause clinically significant effects on the cardiovascular system. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by AUC in plasma from T ₀ to T 0>, is from about 80% to about 125% of about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h* ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h*ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, up to about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/l, about 9500 h*ng/l, about 9750 h*ng/l, about 10000 h*ng/l, about 10250 h*ng/l, about 10500 h*ng/l, about 10750 h*ng/l, about 110 00 h*ng/l, about 11250 h*ng/l, about 11500 h*ng/l or about 11875 h*ng/l.

In a further embodiment (I) of the present invention there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T ≥ , of from about 590 to about 4400 ng*h/L. In some embodiments, said treatment is effective and does not cause clinically significant effects on the cardiovascular system. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by AUC in plasma from T ₀ to T 0>, is from about 80% to about 125%, from about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, or about 5500 h*ng/l.

In some embodiments of each of embodiments (A) (I), dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered orally, mucosally (e.g., sublingually, buccally), intravenously, intramuscularly, subcutaneously, topically, transdermally, intratracheally, intraperitoneally, intraorbitally, implantation, inhalation, intrathecally, intraventricularly, or intranasally.

In some embodiments of each of embodiments (A) (I), dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject by a sublingual, buccal, oral, intranasal or parenteral route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by a sublingual or buccal route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops, in particular a film. In some embodiments, said film is placed under the tongue, close to the base of the tongue, on the left or right side. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet, in particular a film. In some embodiments, the film is applied to the inner surface of the lip or cheek, close to the jaw line. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject parenterally in the form of an intramuscular injection. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject orally. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets, orally disintegrating tablets (ODT), effervescent tablets, capsules, pellets, pills, lozenges or troches, powders, dispersible granules, wafers, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions, and the like. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject orally in the form of an orally disintegrating tablet.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject sublingually as a single dose containing about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein agitation or signs of agitation are addressed without also causing clinically significant cardiovascular effects. In some embodiments, agitation or signs of agitation are addressed without reducing dia

- 36 047684 blood pressure below about 60 mmHg and/or without a decrease in heart rate below about 50 beats per minute.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject sublingually as a single dose containing about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein agitation or signs of agitation are addressed without also causing clinically significant effects on the cardiovascular system. In some embodiments, agitation or signs of agitation are addressed without decreasing systolic blood pressure below about 80 mmHg and/or without decreasing diastolic blood pressure below about 60 mmHg and/or without decreasing heart rate below about 50 beats per minute.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof, resulting in a cumulative dexmedetomidine exposure, as measured by AUC in plasma from T ₀ to T 0 , of about 600 to about 9,500 ng*hr/L, wherein T _max in plasma is from about 1 to about 8 hours. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the average cumulative dexmedetomidine exposure, as measured by AUC in plasma from T ₀ to T 0 , is from about 80% to about 125% of about 600 to about 9,500 ng*hr/L. For example, about 470 h*ng/l, about 500 h*ng/l, about 600 h*ng/l, about 700 h*ng/l, about 800 h*ng/l, about 900 h*ng/l, about 1000 h*ng/l, about 1250 h*ng/l, about 1500 h*ng/l, about 1750 h*ng/l, about 2000 h *ng/l, about 2250 h*ng/l, about 2500 h*ng/l, about 2750 h*ng/l, about 3000 h*ng/l, about 3250 h*ng/l, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h*ng/l, about 7000 h *ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, up to about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/l, about 9500 h*ng/L, about 9750 h*ng/L, about 10000 h*ng/L, about 10250 h*ng/L, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about 11500 h*ng/L, or about 11875 h*ng/L. In some embodiments, the T _max in plasma from T ₀ to Too is from about 80% to about 125% of from about 1 to about 8 hours. For example, about 0.8 hr, about 0.9 hr, about 1 hr, about 1.25 hr, about 1.5 hr, about 1.75 hr, about 2.0 hr, about 2.25 hr, about 2.5 hr, about

2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about

4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about

6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about

8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours or about 10 hours.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 590 to about 4400 ng*h/L, wherein T _max in plasma is from about 1 to about 4 hours. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the mean total exposure of dexmedetomidine, as measured by AUC in plasma from T ₀ to T 0 , is from about 80% to about 125% of about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l. In some embodiments, the T _max in plasma from T ₀ to T 0 is from about 0.8 hr, about 0.9 hr, about 1 hr, about 1.25 hr, about 1.5 hr, about 1.75 hr, about 2.0 hr, about 2.25 hr, about 2.5 hr, about 2.75 hr, about 3.0 hr, about 3.25 hr, about 3.5 hr, about 3.75 hr, about 4.0 hr, about 4.25 hr, about 4.5 hr, about 4.75 hr, or about 5.0 hr.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually, resulting in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 300 ng/L to about 500 ng/L (e.g., about 400 ng/L) and an AUC from T ₀ to T 0 of about 2300 ng*hr/L to about 3600 ng*hr/L (e.g., about 2900 ng*hr/L). For example, the Cmax is about 240 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L and 475 ng/L, about 500 ng/L, about 600 ng/L or about 625 ng/L, and the AUC _0-inf is about 1840 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L,

- 37 047684 about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/L or about 4500 h*ng/L.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually, resulting in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 150 ng/L to about 350 ng/L (e.g., about 220 ng/L) and an AUC from T ₀ to T 1 of about 1100 ng*hr/L to about 1800 ng*hr/L (e.g., about 1410 ng*hr/L). For example, the Cmax is about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, and the AUC _0-mf is about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, or about 2250 h*ng/L.

In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in an average cumulative exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 1 , of about 3800 ng*hr/L, wherein the average plasma Cmax is about 400 ng/L. In some embodiments, the AUC in plasma from T ₀ to T 1 is from 80 to about 125% of about 3800 ng*hr/L, wherein the average plasma Cmax is from about 80 to about 125% of about 400 ng/L.

In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in an average total exposure of dexmedetomidine, measured by AUC in plasma from _T0 to Tro, of about 1800 ng*hr/L, wherein the average plasma Cmax is about 200 ng/L. In some embodiments, the plasma AUC from _T0 to Tro is from 80% to about 125% of about 1800 ng*hr/L, wherein the average plasma Cmax is from about 80% to about 125% of about 200 ng/L.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a cumulative dexmedetomidine exposure, as measured by AUC in plasma from T ₀ to T , of about 3800 ng*hr/L, wherein T _max in plasma is about 2 hours. In some embodiments, the AUC in plasma from T ₀ to T ro is from 80% to about 125% of about 3800 ng*hr/L, wherein the median T _max in plasma is from about 80% to about 125% of about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a cumulative dexmedetomidine exposure, as measured by plasma AUC from T ₀ to Tro, of about 1800 ng*hr/L, wherein the plasma T _max is about 2 hours. In some embodiments, the plasma AUC from T ₀ to Tro is from 80% to about 125% of about 1800 ng*hr/L, wherein the median plasma T _max is from about 80% to about 125% of about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a cumulative dexmedetomidine exposure, as measured by an AUC in plasma from T ₀ to T , of about 3800 ng*hr/L, a mean plasma Cmax of about 400 ng/L, and a median plasma T _max of about 2 hours. In some embodiments, the plasma AUC from T ₀ to T ro is from 80% to about 125% of about 3800 ng*hr/L, the mean plasma Cmax is from about 80% to about 125% of about 400 ng/L, and the median plasma T _max is from about 80 to about 125% from about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a cumulative dexmedetomidine exposure, as measured by AUC in plasma from T ₀ to T , of about 1800 ng*hr/L, a mean plasma Cmax of about 200 ng/L, and a median plasma T _max of about 2 hours. In some embodiments, the AUC in plasma from T ₀

- 38 047684 to Tmax is from about 80 to about 125% of about 1800 ng*h/L, the mean Cmax in plasma is from about 80 to about 125% of about 200 ng/L, and the median T _max in plasma is from about 80 to about 125% of about 2 h.

In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a cumulative exposure of dexmedetomidine, as measured by AUC in plasma from T ₀ to T 0 , of from about 600 to about 9,500 ng*hr/L, wherein the plasma Cmax is from about 100 to about 800 ng/L. In some embodiments, the plasma AUC from T ₀ to T 0 , of from 80 to about 125%, of about 600 ng*hr/L to about 9,500 ng*hr/L, and the mean plasma Cmax is from about 80 to about 125%, of about 100 to about 800 ng/L.

In some embodiments, there is provided a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of from about 590 to about 4400 ng*hr/L, wherein the plasma Cmax is from about 110 to about 400 ng/L. In some embodiments, the plasma AUC from T ₀ to T 0 , of from 80 to about 125%, of about 590 to about 4400 ng*hr/L, and the mean plasma Cmax is from about 80 to about 125%, of about 110 to about 400 ng/L.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of 180 mcg or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure, measured by AUC in plasma from T ₀ to T 0 , of from about 600 to about 9,500 ng*hr/L, wherein T _max in plasma is from about 1 to about 8 hours. In some embodiments, AUC in plasma from T ₀ to T 0 , of from 80 to about 125% of from about 600 to about 9,500 ng*hr/L, and T _max in plasma is from about 80 to about 125% of from about 1 to about 8 hours.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering dexmedetomidine at a dose of 120 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, as measured by AUC in plasma from T ₀ to T 0 , of from about 590 to about 4,400 ng*hr/L, wherein T _max in plasma is from about 1 to about 4 hours. In some embodiments, AUC in plasma from T ₀ to T 0 , is from 80% to about 125% of from about 5,900 ng*hr/L to about 4,400 ng*hr/L, and T _max in plasma is from about 80 to about 125% of from about 1 to about 4 hours.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually, which results in plasma absorption levels of dexmedetomidine of from about 80 to about 125% of the following values:

Cmax from about 100 to about 800 ng/L and AUC from T ₀ to T0 from about 600 to about 9500 h*ng/L.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually, which results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 to about 400 ng/L and AUC from T ₀ to T 0 of about to about 4400 h*ng/L.

In certain embodiments, a method is provided for treating a pathological condition (e.g., agitation) in a human subject in need thereof without inducing significant sedation, comprising administering a standard dose of 180 or 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject, resulting in rapid absorption with peak concentrations achieved on average within about 2.5 hours after administration.

In some embodiments, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising sublingually administering about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from T ₀ to T 0 of from about 600 to about 9500 h*ng/L. In some embodiments, T _max in plasma is from about 1 to about 8 hours.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising sublingually administering about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in plasma absorption levels of dexmedetomidine from about 80 to about 125% of the following values: Cmax from about 110 to about 400

- 39,047,684 ng/L and AUC from T ₀ to T0 of about 590 to about 4400 h*ng/L. In some embodiments, T _max in plasma is from about 1 to about 4 h.

In some embodiments, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising sublingually administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in average plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following: Cmax from about 300 to about 500 ng/L (e.g., about 400 ng/L) and AUC from T ₀ to T 0 of from about 2300 to about 3600 ng*hr/L (e.g., about 2900 ng*hr/L). In some embodiments, T _max in plasma is about 2 hours.

In some embodiments, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually, which results in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 150 to about 300 ng/L (e.g., about 220 ng/L) and an AUC from T ₀ to T 0 of about 1100 to about 1800 ng*hr/L (e.g., about 1400 ng*hr/L). In some embodiments, the plasma T _max is about 2 hr.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of 180 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of from about 600 to about 9500 ng*h/L, wherein T _max in plasma is from about 1 to about 8 hours.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of 120 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of from about 590 to about 4400 ng*h/L, wherein T _max in plasma is from about 1 to about 4 hours.

In some embodiments, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising buccally administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 300 to about 500 ng/L (e.g., about 400 ng/L) and an AUC from T ₀ to T 0 of about 2300 to about 3600 ng*hr/L (e.g., about 2900 ng*hr/L).

In some embodiments, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising buccally administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 150 to about 300 ng/L (e.g., about 220 ng/L) and an AUC from T ₀ to T 0 of about 1100 to about 1800 ng*hr/L (e.g., about 1400 ng*hr/L).

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T0 to T0, of about 3800 ng*h/L, with an average Cmax in plasma of about 400 ng/L.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 1800 ng*h/L, with an average Cmax in plasma of about 200 ng/L.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T0 to T0, of about 3780 ng*h/L, wherein T _max in plasma is about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of decanoate.

- 40 047684 medetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof to the said subject, resulting in a total exposure to dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 1800 ng*h/L, with T _max in plasma of about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a total dexmedetomidine exposure, measured by AUC in plasma from T ₀ to T 0 , of about 3800 ng*h/L, a mean plasma Cmax of about 400 ng/L, and a median plasma T _max of about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof to said subject, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T0 to T0, of about 1800 ng*h/L, with a mean Cmax in plasma of about 200 ng/L, and a median _Tmax in plasma of about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of from about 600 to about 9500 ng*h/L, wherein the Cmax in plasma is from about 100 to about 800 ng/L.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of from about 590 to about 4400 ng*h/L, and a plasma Cmax of from about 110 to about 400 ng/L.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 180 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 600 to about 9500 ng*h/L, wherein T _max in plasma is from about 1 to about 8 hours.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of dexmedetomidine at a dose of about 120 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of from about 590 to about 4400 ng*h/L, wherein T _max in plasma is from about 1 to about 4 hours.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising buccally administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 ng/L to about 800 ng/L and AUC from T ₀ to T 0 of about 600 to about 9500 h*ng/L.

In some embodiments, a method of treating a pathological condition in a human subject is provided, comprising buccally administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 to about 400 ng/L and AUC from T ₀ to T 0 of about 590 to about 4400 h*ng/L.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising buccal administration of about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 100 to about 800 ng/L and AUC from _T0 to T0 from about 600 to about 9500 h*ng/L, wherein _Tmax in plasma is from about 1 to about 8 hours.

In some embodiments, a method of treating a pathological condition (e.g., agitation) in a human subject is provided, comprising buccal administration of about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in plasma absorption levels of dexmedetomidine from about 80 to about 125% of the following values: Cmax from about 110 to about 400 ng/L

- 41 047684 and AUC from T ₀ to T0 from about 590 to about 4400 h*ng/l, while T _max in plasma is from about 1 to about 4 h.

In some embodiments, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising buccally administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 300 to about 500 ng/L (e.g., about 400 ng/L) and an AUC from T ₀ to T 0 of about 2300 to about 3600 ng*hr/L (e.g., about 2900 ng*hr/L), wherein the median T _max in plasma is about 2 hours.

In some embodiments, there is provided a method of treating a pathological condition (e.g., agitation) in a human subject, comprising administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof buccally, which results in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 150 to about 300 ng/L (e.g., about 200 ng/L) and an AUC from T ₀ to T 0 of about 1100 to about 1800 ng*hr/L (e.g., about 1400 ng*hr/L), wherein the median T _max in plasma is about 2 hours.

In certain embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject parenterally in the form of an intramuscular injection, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of from about 140 mcg to about 190 mcg.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscular administration of dexmedetomidine at a dose of about 120 to about 190 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 600 to about 9500 ng*h/L, wherein T _max in plasma is from about 5 min to about 4 h.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscular administration of dexmedetomidine at a dose of about 120 to about 190 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T0 to T0, of about 600 to about 12,600 ng*h/L, wherein T _max in plasma is from about 5 min to about 4 h.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscular administration of dexmedetomidine at a dose of about 120 to about 190 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 600 to about 12,600 ng*h/L, wherein the Cmax in plasma is from about 200 to about 800 ng/L.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscular administration of dexmedetomidine at a dose of about 120 to about 190 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T0 to T0, of about 600 to about 12,600 ng*h/L, with a median T _max of about 2 hours.

In some embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising intravenous administration of dexmedetomidine at a dose of about 120 to about 190 mcg or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 600 to about 12,600 ng*h/L, wherein T _max in plasma is from about 5 min to about 15 min.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject orally, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 900 to about 1200 mcg.

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising orally administering dexmedetomidine at a dose of from about 900 to about 1200 mcg, or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of from about 600 to about 12,600 ng*h/L, wherein T _max in plasma is from about 1 minute to about 8 hours.

- 42 047684

In certain embodiments, the present invention provides a method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising orally administering dexmedetomidine at a dose of about 900 to about 1200 mcg, or a pharmaceutically acceptable salt thereof, resulting in a total exposure of dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , of about 600 to about 12,600 ng*h/L, with a median T _max of about 2 hours.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose (e.g., as a single unit dose or multiple unit doses administered simultaneously).

In other embodiments of the present invention, a self-sustaining dissolvable film comprising about 180 mcg of dexmedetomidine hydrochloride is provided, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine of about 80 to about 125% of the following values: Cmax of about 100 to about 800 ng/L and AUC from T ₀ to T 0 of about 600 to about 9500 h*ng/L.

In other embodiments of the present invention, a self-sustaining dissolvable film comprising about 120 mcg of dexmedetomidine hydrochloride is provided, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine of about 80 to about 125% of the following values: Cmax of about 110 to about 400 ng/L and AUC from T ₀ to T 0 of about 590 to about 4400 h*ng/L.

In other embodiments, the present invention provides a self-sustaining dissolving film comprising about 180 mcg of dexmedetomidine hydrochloride, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 300 to about 500 ng/L (e.g., about 400 ng/L) and an AUC from T ₀ to T 0 of about 2300 to about 3600 ng*h/L (e.g., about 2900 ng*h/L), with a mean plasma T _max of about 2 hours.

In other embodiments, the present invention provides a self-sustaining dissolvable film comprising about 120 mcg of dexmedetomidine hydrochloride, wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 150 to about 300 ng/L (e.g., about 200 ng/L) and an AUC of _T0 to T0 of about 1100 to about 1800 ng*hr/L (e.g., about 1400 ng*hr/L), with a mean plasma _Tmax of about 2 hours.

In another embodiment of the present invention, there is provided a self-sustaining soluble film comprising from about 180 to about 240 mcg of dexmedetomidine hydrochloride, wherein sublingual application of said film to a subject with schizophrenia or bipolar disorder results in a total exposure to dexmedetomidine, measured by AUC in plasma from T ₀ to T 0 , from about 600 to about 12,600 ng*h/L, wherein T _max in plasma is from about 1 to about 8 hours.

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 180 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da);

(iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b) and wherein sublingual application of said film to a subject suffering from schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine of from about 80% to about 125% of the following values: Cmax of from about 100 to about 800 ng/L and AUC from T ₀ to T 0 of from about 600 to about 9500 h*ng/L. For example, Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L and 475 ng/L, about 500 ng/L, about 525 ng/L, about 550 ng/L, about 575 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, to about 1000 ng/L, and the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/l, about 1750

- 43 047684 h*ng/l, about 2000 h*ng/l, about 2250 h*ng/l, about 2500 h*ng/l, about 2750 h*ng/l, about 3000 h*ng/l, about 3250 h*ng/l, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h *ng/l, about 5000 h*ng/l, about 5250 h*ng/l, about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng /l, up to about 6500 h*ng/l, about 6750 h*ng/l, about 7000 h*ng/l, about 7250 h*ng/l, about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h* ng/l, about 8250 h*ng/l, about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/l, about 9500 h*ng/ l, about 9750 h*ng/l, about 10000 h*ng/l, about 10250 h*ng/l, about 10500 h*ng/l, about 10750 h*ng/l, about 11000 h*ng/l, about 11250 h*ng/l, about 11500 h*ng/l, to about 11875 h*ng/l. In some embodiments, T _max is from about 1 to about 8 h. For example, T _max is about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1 ,75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3, 75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h , about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h before about 10 o'clock

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 120 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da) and (iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b) and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine of from about 80% to about 125% of the following values: Cmax of from about 110 to about 400 ng/L and AUC from T ₀ to T 0> of from about 590 h*ng/L to about 4400 h*ng/L. For example, Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L and 475 ng/L, up to about 500 ng/L, and AUC0 _inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/l, about 900 h*ng/l, about 1000 h*ng/l, about 1250 h*ng/l, about 1500 h*ng/l, about 1750 h*ng/l, about 2000 h*ng/l, about 2250 h*ng/l, about 2500 h*ng/l, about 2750 h*ng/l, about 3000 h*ng/ l, about 3250 h*ng/l, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l. In some embodiments, Tmax is from about 1 to about 4 hours. For example, Tmax is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, up to about 5.0 hours.

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 180 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da);

(iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine of from about 80% to about 125% of the following values: Cmax of from about 100 ng/L to about 800 ng/L and AUC from T ₀ to T 1 of from about 600 h*ng/L to about 9500 h*ng/L, and wherein T _max in plasma is from about 1 to about 8 hours. For example, Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about

- 44 047684

825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, to about 1000 ng/L, and the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/L, about 4500 h*ng/L, about 4750 h*ng/L, about 5000 h*ng/L, about 5250 h*ng/L, to about 5500 h*ng/L, about 5750 h*ng/L, about 6000 h*ng/L, about 6250 h*ng/L, to about 6500 h*ng/L, about 6750 h*ng/L, about 7000 h*ng/L, about 7250 h*ng/L, to about 7500 h*ng/L, about 7750 h*ng/L, about 8000 h*ng/L, about 8250 h*ng/L, up to about 8500 h*ng/L, about 8750 h*ng/L, about 9000 h*ng/L, about 9250 h*ng/L, about 9500 h*ng/L, about 9750 h*ng/L, about 10000 h*ng/L, about 10250 h*ng/L, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about 11500 h*ng/L, up to about 11875 h*ng/L, and T _max is about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5, 5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours to about 10 hours.

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 120 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da) and (iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from _T0 to Tgo from about 590 h*ng/L to about 4400 h*ng/L, and wherein _Tmax in plasma is from about 1 hour to about 4 hours. For example, the Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, and 475 ng/L, to about 500 ng/L, and the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/l, about 900 h*ng/l, about 1000 h*ng/l, about 1250 h*ng/l, about 1500 h*ng/l, about 1750 h*ng/l, about 2000 h*ng/l, about 2250 h*ng/l, about 2500 h*ng/l, about 2750 h*ng/l, about 3000 h*ng/ l, about 3250 h*ng/l, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l and T _max is 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h to about 5.0 h.

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 180 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da) and (iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in mean plasma absorption levels of dexmedetomidine of from about 80% to about 125% of the following values: Cmax of from about 300 to about 474 ng/L (e.g., about 400 ng/L) and an AUC from T ₀ to T 0> of from about 2300 ng*h/L to about 3600 ng*h/L (e.g., about 2900 ng*h/L), wherein the mean plasma T _max is about 2 hours. For example, the Cmax is from about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, up to about 475 ng/L, and AUC _0-inf is about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500

- 45,047,684 h*ng/L, about 3,750 h*ng/L. In some embodiments, T _max is from about 1 to about 4 h. For example, T _max is about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, up to about 5.0 h.

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 120 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da);

(iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in mean plasma absorption levels of dexmedetomidine of from about 80% to about 125% of the following values: Cmax of from about 150 ng/L to about 300 ng/L (e.g., about 200 ng/L) and an AUC of T ₀ to T 0 of from about 1100 ng*h/L to about 1800 ng*h/L (e.g., about 1400 ng*h/L), wherein the median plasma T _max is about 2 hours. For example, the Cmax is about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, or about 300 ng/L, and the AUC _0-inf is about 1100 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, to about 1800 h*ng/L. In some embodiments, the Tmax is from about 1 to about 4 hours. For example, the Tmax is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, to about 5.0 hours

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 180 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da);

(iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b) and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in a cumulative exposure to dexmedetomidine, as measured by AUC in plasma from T ₀ to T 0 , of from about 600 to about 12,600 ng*hr/L, wherein T _max in plasma is from about 1 to about 8 h. For example, the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1,000 h*ng/L, about 1,250 h*ng/L, about 1,500 h*ng/L, about 1,750 h*ng/L, about 2,000 h*ng/l, about 2250 h*ng/l, about 2500 h*ng/l, about 2750 h*ng/l, about 3000 h*ng/l, about 3250 h*ng/l, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng /l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h*ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, up to about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/l, about 9500 h *ng/l, about 9750 h*ng/l, about 10000 h*ng/l, about 10250 h*ng/l, about 10500 h*ng/l, about 10750 h*ng/l, about 11000 h*ng/l, about 11250 h*ng/l, about 11500 h*ng/l, about 11750 h*ng/l, about 12000 h*ng/L, about 12250 h*ng/L or about 12600 h*ng/L, and T _max is about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h or about 8 h.

In another embodiment of the present invention, a self-supporting soluble film is provided comprising:

(a) a composition consisting essentially of:

(i) about 120 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da);

(iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

- 46 047684 (i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b), and wherein application of said film sublingually to a subject with schizophrenia or bipolar disorder results in a cumulative exposure to dexmedetomidine, as measured by AUC in plasma from T ₀ to T o>, of about 590 to about 8750 ng*hr/L, wherein T _max in plasma is from about 1 to about 4 h. For example, the AUC _0-mf is about 590 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h * ng/L, about 2500 h*ng/l, about 2750 h*ng/l, about 3000 h*ng/l, about 3250 h*ng/l, about 3500 h*ng/l, about 3750 h*ng/l, about 4000 h*ng/l, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng /l, about 5000 h*ng/l, about 5250 h*ng/l, about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, about 6500 h*ng/l, about 6750 h*ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/L, about 7750 h*ng/L, about 8000 h*ng/L, about 8250 h*ng/L, about 8500 h*ng/L or about 8750 h*ng/L, and T _max is about 1 h, about 2 h, about 3 h or about 4 h.

In some embodiments, agitation or signs of agitation are significantly reduced within 60 minutes in a patient with schizophrenia or bipolar disorder following administration of a single dose of 120 or 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride, as measured by relative PEC scores immediately before and 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In some embodiments, the relative PEC scores differ by at least six points. In other embodiments, the relative PEC scores differ by at least eight points. In another embodiment, the difference in relative PEC scores is maintained for at least six hours. In a particular embodiment, the difference of at least eight points is maintained for up to about 24 hours upon administration of a single dose of 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

In some embodiments, the reduction in PEC score at 2 hours, as measured by the change in total PEC score from baseline after administration of 180 mcg dexmedetomidine hydrochloride, is -10.8 compared to placebo (-4.5). In some embodiments, the reduction in PEC score at 2 hours after administration of 180 mcg dexmedetomidine hydrochloride is greater (-10.8) compared to administration of 120 mcg (-9.2) or 80 mcg (-7.3) dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately before or immediately after the onset of agitation or signs of agitation in a human subject.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 10 minutes of the onset of agitation or signs of agitation in a human subject. In some embodiments, an additional dose of 90 or 60 mcg may be taken at a suitable time (e.g., two hours) after the first dose.

In some embodiments, after administration of a unit dose of about 30, about 60, about 90, about 120, or about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject experiencing opioid withdrawal symptoms (e.g., agitation or signs of agitation), wherein the opioid withdrawal symptoms are significantly reduced, as determined by relative scores on the COWS and/or the SOWS-Gossop scale immediately before and 2 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In a particular embodiment, each unit dose can be administered twice daily for an appropriate period of withdrawal (e.g., for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days).

In some embodiments, after administration of about 20 to about 240 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to an agitated human subject with delirium who is hospitalized (e.g., in an intensive care unit), agitation or signs of agitation and the severity of delirium are significantly reduced as measured by the RASS and DRS-R-98, respectively. For example, agitation or signs of agitation and the severity of delirium are significantly reduced as measured by the RASS and DRS-R-98 immediately before and after each 30 minutes, 1, 2, 3, 4, 5, or 6 hours after administration of dexmedetomidine. In some embodiments, dexmedetomidine is administered orally (e.g., sublingually or buccally) one to four times daily at appropriate dosing intervals (e.g., every 30 minutes) within 6 hours of the first dose to achieve the desired effect; for example, a standard dose of 20 mcg is administered four times at 30 minute dosing intervals within 6 hours of the first dose to achieve the effect of an 80 mcg dose, or a standard dose of 60 mcg is administered four times at 30 minute dosing intervals within 6 hours of the first dose to achieve the effect of a 240 mcg dose.

In some embodiments, following administration of about 30 to about 90 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to an agitated human subject with delirium, the agitation or signs of agitation and the severity of delirium are significantly

- 47 047 684 are reduced as measured by the PAS and PEC scales. For example, agitation or signs of agitation are significantly reduced as measured by the PAS and PEC scales immediately before and every 2 hours for a period of at least 24 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In one embodiment, dexmedetomidine is administered orally (e.g., sublingually or buccally). In some embodiments, each unit dose contains from about 30 mcg to 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of dexmedetomidine can be taken 1, 2, 3, 4, 5, or 6 times a day every 2 hours, with a maximum of three doses provided within 12 hours after the first dose. In some embodiments, each unit dose containing about 90 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof may be taken 1, 2, 3, or 4 times daily every 2 hours, providing a maximum of two doses within 12 hours of the first dose.

In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally (e.g., sublingually or buccally) as a film. In some embodiments, the desired dose can be achieved by cutting the film in half to deliver half the dose (e.g., a 60 mcg dose can be administered with half the 60 mcg dose (30 mcg) to produce a 90 mcg dose).

In some embodiments, the present invention provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 120 mcg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar I disorder), and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g., bipolar I disorder).

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, the composition can be administered in various ways. For example, in some embodiments, a composition comprising dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, orally, intranasally, or parenterally. In some embodiments, the composition is administered sublingually or buccally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel, or drops. In some embodiments, the composition is administered buccally in the form of a film, patch, or tablet.

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, said method may further comprise administering a second dose of dexmedetomidine after a period of time in the range of about 30 minutes to about 12 hours. For example, said period of time may be about 30 minutes, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, or about 23 hours. In some embodiments, the second dose is administered after a period of time of about 2 hours. In some embodiments, the second dose is from about 10 to about 180 mcg. For example, the additional dose may be about 10 mcg, about 20 mcg, about 30 mcg, about 40 mcg, about 50 mcg, about 60 mcg, about 70 mcg, about 80 mcg, about 90 mcg, about 100 mcg, about 110 mcg, about 120 mcg, about 130 mcg, about 140 mcg, about 150 mcg, about 160 mcg, about 170 mcg, or about 180 mcg. In some embodiments, the additional dose is about 60 or 90 mcg.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, said unit dose composition may be administered to a patient on an empty stomach. In some embodiments, the unit dose composition is administered after a meal.

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Positive and Negative Syndrome Scale (PEC) agitation component score from baseline. In some embodiments, agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, agitation is significantly reduced in less than 45 minutes (e.g., about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient has a decrease in PEC score of >40% compared to baseline. For example, a patient may experience a score reduction of greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from baseline. Treatment efficacy

- 48 047684 changes can also be compared by comparing the PEC score to placebo. In some embodiments, the PEC score is >30% lower than placebo (e.g., in the placebo group, the mean change from baseline in total PEC score is -3, and in the dexmedetomidine-containing composition group, -3.9). For example, compared with placebo, a patient's RES score may be lower or higher by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient has an average change in PEC score of greater than about -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition. For example, at 2 hours, the patient may have an average change in PEC score of greater than about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or about -12. In some embodiments, the decrease in PEC score (e.g., greater than about -4) is maintained for at least 6 hours after administration of the composition. For example, if the patient has an average change in overall PEC score compared to baseline of, for example, -6 at 2 hours, then at 6 hours, the patient's average change in PEC score will be about -6 or lower (e.g., -7, -8, etc.). In some embodiments, the decrease in PEC score (e.g., greater than about -4) is substantially maintained for at least six hours after administration of the composition. For example, if a patient has an average change in total PEC score compared to baseline, such as -6 at 2 hours, then at 6 hours the average change in PEC score of the patient will be about -4, about -5, or about -6 or lower (e.g., -7, -8, etc.). In some embodiments, the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 6 hours after administration of the composition.

According to some embodiments of methods for treating agitation, comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, wherein the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

According to some embodiments of the methods of treating agitation, comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, wherein the single dose administration provides a mean C _max in the range of about 80 to about 125% of about 110 ng/L to about 400 ng/L. For example, a single dose provides a mean _Cmax of about 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500 ng/L, including all whole numbers and ranges between them. In some embodiments, the average C _max is from about 100 ng/L to about 500 ng/L, from about 150 ng/L to about 450 ng/L, from about 150 ng/L to about 400 ng/L, from about 200 ng/L to about 350 ng/L, from about 200 ng/L to about 300 ng/L, from about 200 ng/L to about 250 mg/L, or from about 210 ng/L to about 240 ng/L. In some embodiments, the average C _max is in the range of about 80% to about 125% of about 238 ng/L, the average C _max is in the range of about 80% to about 125% of about 238 ng/L. In some embodiments, the average C _max is about 238 ng/L.

According to some embodiments of methods for treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, single dose administration provides a mean AUC _0-inf in the range of about 80% to about 125% of about 590 h*ng/L to about 4400 h*ng/L. For example, a single dose provides a mean AUC _0-inf of about 475 h*ng/L, about 500 h*ng/L, about 1000 h*ng/L, about 1500 h*ng/L, about 2000 h*ng/L, about 2500 h*ng/L, about 3000 h*ng/L, about 3500 h*ng/L, about 4000 h*ng/L, about 4500 h*ng/L, about 5000 h*ng/L, or about 5500 h*ng/L, including all whole numbers and ranges therebetween. In some embodiments, the mean AUC _0-inf is from about 500 h*ng/L to about 5000 h*ng/L, from about 500 h*ng/L to about 4000 h*ng/L, from about 500 h*ng/L to about 3000 h*ng/L, from about 1000 h*ng/L to about 3000 h*ng/L, from about 1000 h*ng/L to about 2500 h*ng/L, from about 1000 h*ng/L to about 2000 h*ng/L, from about 1000 h*ng/L to about 1500 h*ng/L, or from about 1500 h*ng/L to about 2000 h*ng/L. In some embodiments, the mean AUC _0-inf is between about 80% and about 125% of about 1800 ng*hr/L. In some embodiments, the mean AUC _0-inf is about 1800 ng*hr/L.

According to some embodiments of the methods of treating agitation comprising administering a unit dose of a composition comprising about 120 mcg of dexmedetomidine, administration of a single dose provides an average T _max ranging from about 80 to about 125% of about 1 to about 4 hours. For example, a single dose provides an average T _max of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, to about 5.0 hours. In some embodiments, the T _max is from about 1 to about 4 hours, from about 1 to about 3 hours,

- 49 047684 from about 1.5 to about 3 hours, from about 1.75 to about 2.5 hours, from about 1.75 to about 2.25 hours. In some embodiments, T _max is in the range of from about 80 to about 125% of about 2 hours. In some embodiments, T _max is about 2 hours.

According to some embodiments of the methods of treating agitation, comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, wherein the single dose administration provides a geometric mean C _max in the range of about 80 to about 125% of about 110 to about 400 ng/L. For example, a single dose provides a geometric mean _Cmax of about 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500 ng/L, including all whole numbers and ranges therebetween. In some embodiments, the geometric mean Cmax is from about 100 ng/L to about 500 ng/L, from about 150 ng/L to about 450 ng/L, from about 150 ng/L to about 400 ng/L, from about 200 ng/L to about 350 ng/L, from about 200 ng/L to about 300 ng/L, from about 200 ng/L to about 250 mg/L, or from about 210 ng/L to about 240 ng/L. In some embodiments, the geometric mean _Cmax is in the range of about 80% to about 125% of about 220 ng/L. In some embodiments, the geometric mean _Cmax is about 220 ng/L. In some embodiments, the median _Cmax is about 238 ng/L.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, the single dose administration provides a geometric mean AUC _0-inf in the range of about 80 to about 125%, from about 590 h*ng/L to about 4400 h*ng/L. For example, a single dose provides a geometric mean AUC _0-inf of about 475 h*ng/L, about 500 h*ng/L, about 1000 h*ng/L, about 1500 h*ng/L, about 2000 h*ng/L, about 2500 h*ng/L, about 3000 h*ng/L, about 3500 h*ng/L, about 4000 h*ng/L, about 4500 h*ng/L, about 5000 h*ng/L, or about 5500 h*ng/L, including all whole numbers and ranges therebetween. In some embodiments, the geometric mean AUC _0-inf is from about 500 h*ng/L to about 5,000 h*ng/L, from about 500 h*ng/L to about 4,000 h*ng/L, from about 500 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 2,500 h*ng/L, from about 1,000 h*ng/L to about 2,000 h*ng/L, from about 1,000 h*ng/L to about 1,500 h*ng/L, or from about 1,500 h*ng/L to about 2,000 h*ng/L, from about 1,200 h*ng/L to about 1,500 h*ng/L, from about 1300 h*ng/L to about 1500 h*ng/L, or from about 1350 h*ng/L to about 1450 h*ng/L. In some embodiments, the geometric mean AUC _0-inf is in the range of about 80% to about 125% of about 1410 ng*hr/L. In some embodiments, the geometric mean AUC _0-inf is about 1410 ng*hr/L.

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, administering a single dose provides a geometric mean T _max in the range of about 80 to about 125% of about 1 to about 4 hours. For example, the single dose provides a geometric mean T _max of about 0.8, about 0.9, about 1, about 1.25, about 1.5, about 1.75, about 2.0, about 2.25, about 2.5, about 2.75, about 3.0, about 3.25, about 3.5, about 3.75, about 4.0, about 4.25, about 4.5, about 4.75 to about 5.0 hours. In some embodiments, the geometric mean T _max is from about 1 to about 4 hours, from about 1 to about 3 h, from about 1.5 to about 3 h, from about 1.75 to about 2.5 h, from about 1.75 to about 2.25 h. In some embodiments, T _max is in the range of from about 80 to about 125% of about 2 h. In some embodiments, T _max is about 2 h.

According to some embodiments of the methods of treating agitation, comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, wherein the single dose administration provides a median Cmax in the range of about 80 to about 125% of about 110 to about 400 ng/L. For example, a single dose provides a median Cmax of about 88 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, or about 500 ng/L, including all whole numbers and ranges therebetween. In some embodiments, the mean median C _max is from about 100 ng/L to about 500 ng/L, from about 150 ng/L to about 450 ng/L, from about 150 ng/L to about 400 ng/L, from about 200 ng/L to about 350 ng/L, from about 200 ng/L to about 300 ng/L, from about 200 ng/L to about 250 mg/L, or from about 210 ng/L to about 240 ng/L. In some embodiments, the mean median C _max is in the range of about 80% to about 125% of about 230 ng/L. In some embodiments, the median C _max is about 230 ng/L.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, the single dose administration provides a median AUC _0-inf in the range of about 80 to about 125% from about 590 to about 4400 h*ng/L. For example, a single dose provides a median AUC _0-inf of about 475 h*ng/L, about 500 h*ng/L, about 1000 h*ng/L, about 1500 h*ng/L, about 2000 h*ng/L, about 2500 h*ng/L, about 3000 h*ng/L, about 3500 h*ng/L, about 4000 h*ng/L, about 4500 h*ng/L, about 5000 h*ng/L, or about 5500 h*ng/L.

- 50 047684 including all integers and ranges between them. In some embodiments, the median AUC _0-mf is from about 500 h*ng/L to about 5,000 h*ng/L, from about 500 h*ng/L to about 4,000 h*ng/L, from about 500 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 2,500 h*ng/L, from about 1,000 h*ng/L to about 1,500 h*ng/L, from about 1,500 h*ng/L to about 2,000 h*ng/L, from about 1,000 h*ng/L to about 1,250 h*ng/L, from about 1,000 h*ng/L to about 1200 h*ng/L, from about 1100 h*ng/L to about 1200 h*ng/L, or from about 1150 h*ng/L to about 1250 h*ng/L. In some embodiments, the median AUC _0-mf is in the range of about 80% to about 125% of about 1180 ng*hr/L. In some embodiments, the median AUC _0-mf is about 1180 ng*hr/L.

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 120 mcg of dexmedetomidine, administration of a single dose provides a median T _max ranging from about 80% to about 125% of about 1 to about 4 hours. For example, a single dose provides a median T _max of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, to about 5.0 hours. In some embodiments, the median T _max is from about 1 to about 4 hours, from about 1 to about 3 hours, about 1.5 to about 3 hours, about 1.75 to about 2.5 hours, about 1.75 to about 2.25 hours. In some embodiments, the median T _max is in the range of about 80 to about 125% of about 2 hours. In some embodiments, the median T _max is about 2 hours.

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition containing about 120 mcg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady-state.

In some embodiments, the present invention provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 180 mcg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar I disorder), and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g., bipolar I disorder).

According to some embodiments of the methods of treating agitation, comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, wherein said composition can be administered in various ways. For example, in some embodiments, a composition comprising dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, orally, intranasally, or parenterally. In some embodiments, the composition is administered sublingually or buccally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel, or drops. In some embodiments, the composition is administered buccally in the form of a film, patch, or tablet.

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, the method may further comprise administering a second dose of dexmedetomidine after a period of time in the range of about 30 minutes to about 12 hours. For example, the period of time may be about 30 minutes, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, or about 23 hours. In some embodiments, the second dose is administered after a period of time of about 2 hours. In some embodiments, the second dose is from about 10 to about 180 mcg. For example, the additional dose may be about 10 mcg, about 20 mcg, about 30 mcg, about 40 mcg, about 50 mcg, about 60 mcg, about 70 mcg, about 80 mcg, about 90 mcg, about 100 mcg, about 110 mcg, about 120 mcg, about 130 mcg, about 140 mcg, about 150 mcg, about 160 mcg, about 170 mcg, or about 180 mcg. In some embodiments, the additional dose is about 60 or 90 mcg.

According to some embodiments of the methods for treating agitation, comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, said unit dose composition may be administered to a patient on an empty stomach. In some embodiments, the unit dose composition is administered after a meal.

According to some embodiments of methods for treating agitation comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change from baseline in the agitation component of the Positive and Negative Syndrome Scale (PEC) score. In some embodiments, agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, agitation is significantly reduced in less than

- 51,047,684 minutes (e.g., about 15, about 20, about 25, about 30 minutes). In some embodiments, the patient has a decrease in PEC score of >40% compared to the baseline. For example, the patient may have a decrease in score of greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from the baseline. Treatment efficacy can also be compared by comparing the RES score to placebo. In some embodiments, the RES score is >30% lower than placebo (e.g., in the placebo group, the mean change from baseline in total RES score is -3, and in the dexmedetomidine-containing composition group, -3.9). For example, compared with placebo, a patient's RES score may be lower or higher by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient experiences a mean change in PEC score of greater than about -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition.

For example, after 2 hours, the patient may have an average change in PEC score of more than about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or about -12. In some embodiments, the decrease in PEC score (e.g., more than about -4) is maintained for at least 6 hours after administration of the composition. For example, if the patient has an average change in overall PEC score compared to baseline, such as -6 after 2 hours, then after 6 hours, the average change in the patient's PEC score will be about -6 or lower (e.g., -7, -8, etc.). In some embodiments, the decrease in PEC score (e.g., more than about -4) is substantially maintained for at least six hours after administration of the composition. For example, if a patient has an average change in the overall PEC score compared to the baseline, such as -6 at 2 hours, then at 6 hours the average change in the patient's PEC score will be about -4, about -5, or about -6 or lower (e.g., -7, -8, etc.). In some embodiments, the average change in the PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 24 hours after administration of the composition.

According to some embodiments of methods for treating agitation, comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, wherein the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

According to some embodiments of the methods of treating agitation, comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, wherein the single dose administration provides a mean Cmax in the range of about 80 to about 125% of about 100 to about 800 ng/L. For example, Cmax is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all whole numbers and ranges between them. In some embodiments, the average C _max is from about 100 ng/L to about 1000 ng/L, from about 100 ng/L to about 800 ng/L, from about 200 ng/L to about 600 ng/L, from about 300 ng/L to about 600 ng /L, from about 300 ng/L to about 500 ng/L, from about 350 ng/L to about 500 ng/L, from about 300 ng/L to about 450 ng/L, from about 400 ng/L to about 500 ng/L, or from about 400 ng/L to about 450 ng/L. In some embodiments, the average C _max is in the range of about 80 to about 125% of about 440 ng/L. In some embodiments, the average C _max value is about 440 ng/L.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, the single dose administration provides a mean AUC _0-inf in the range of about 80 to about 125% of about 600 to about 9500 h*ng/L. For example, the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h *ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l,

- 52 047 684 about 8250 h*ng/L, up to about 8500 h*ng/L, about 8750 h*ng/L, about 9000 h*ng/L, about 9250 h*ng/L, about 9500 h*ng/L, about 9750 h*ng/L, about 10000 h*ng/L, about 10250 h*ng/L, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about 11500 h*ng/L, up to about 11875 h*ng/L, including all integers and ranges therebetween. In some embodiments, the AUC _0-inf is from about 500 h*ng/L to about 10,000 h*ng/L, from about 1,000 h*ng/L to about 7,500 h*ng/L, from about 1,000 h*ng/L to about 6,000 h*ng/L, from about 1,500 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 4,000 h*ng /L, from about 2,000 h*ng/L to about 3,000 h*ng/L, from about 2,500 h*ng/L to about 4,000 h*ng/L, from about 3,000 h*ng/L to about 4,000 h*ng/L, from about 3500 h*ng/L to about 4000 h*ng/L or from about 2500 h*ng/L to about 3000 h*ng/L. In some embodiments, the mean AUC _0-inf is in the range of about 80% to about 125% of about 3800 ng*hr/L. In some embodiments, the mean AUC _0-inf is about 3800 ng*hr/L.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, administration of a single dose provides a mean T _max in the range of about 80 to about 125% of about 1 to about 8 hours. For example, a single dose provides a mean T _max of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, up to about 10 h. In some embodiments, T _max is from about 1 to about 8 h, from about 1 to about 6 h, from about 1 to about 4 h, from about 1 to about 3 h, from about 1.5 to about 3 h, from about 1.75 to about 2.5 h, from about 1.75 to about 2.25 h. In some embodiments, T _max is in the range of from about 80 to about 125% from about 2 hours. In some embodiments, T _max is about 2 hours.

According to some embodiments of the methods of treating agitation, comprising administering a unit dose of a composition comprising about 180 mcg of dexmedetomidine, wherein the administration of a single dose provides a geometric mean Cmax value in the range of about 80% to about 125% of about 100 ng/L to about 800 ng/L. For example, C _max is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all whole numbers and ranges between them. In some embodiments, the geometric mean Cmax is from about 100 ng/L to about 1000 ng/L, from about 100 ng/L to about 800 ng/L, from about 200 ng/L to about 600 ng/L, from about 300 ng/L to about 600 ng /L, from about 300 ng/L to about 500 ng/L, from about 350 ng/L to about 500 ng/L, from about 300 ng/L to about 450 ng/L, from about 400 ng/L to about 500 ng/L, from about 400 ng/L to about 450 ng/L, from about 350 ng/L to about 450 ng/L, or from about 350 ng/L to about 400 ng/L. In some embodiments, the geometric mean C _max is between about 80% and about 125% of about 380 ng/L. In some embodiments, the geometric mean C _max is about 380 ng/L.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, the single dose administration provides a geometric mean AUC0-inf in the range of about 80% to about 125% of about 600 h*ng/L to about 9500 h*ng/L. For example, the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h *ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, up to about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/L, about 9500 h*ng/L, about 9750 h*ng/L, about 10000 h*ng/L, about 10250 h*ng/L, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about 11500 h*ng/L, up to about 11875 h*ng/L, including all integers and ranges therebetween. In some embodiments, the AUC _0-inf is from about 500 h*ng/L to about 10,000 h*ng/L, from about 1,000 h*ng/L to about 7,500 h*ng/L, from about 1,000 h*ng/L to about 6,000 h*ng/L, from about 1,500 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 4,000 h*ng /L, from about 2,000 h*ng/L to about 3,000 h*ng/L, from about 2,500 h*ng/L to about 4,000 h*ng/L, from about 3,000 h*ng/L to about 4,000 h*ng/L, from about 3500 h*ng/L to about 4000 h*ng/L, or from about 2500 h*ng/L to about 3000 h*ng/L. In some embodiments, the geometric mean AUC _0-inf is in the range of about 80% to about 125% of about 2880 ng*hr/L. In some embodiments, the geometric mean

- 53 047684 The AUC _0-mf value is approximately 2880 ng*h/L.

According to some embodiments of the methods of treating agitation comprising administering a unit dose of a composition comprising about 180 mcg of dexmedetomidine, administering a single dose provides a geometric mean T _max in the range of about 80 to about 125% of about 1 to about 8 hours. For example, a single dose provides a geometric mean T _max of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hr, about 6.0 hr, about 6.25 hr, about 6.5 hr, about 6.75 hr, about 7.0 hr, about 7.25 hr, about 7.5 hr, about 7.75 hr, about 8.0 hr, about 8.25 hr, about 8.5 hr, about 8.75 hr, about 9.0 hr, about 9.25 hr, about 9.5 hr, about 9.75 hr, to about 10 hr. In some embodiments, T _max is from about 1 to about 8 hr, from about 1 to about 6 hr, from about 1 to about 4 hr, from about 1 to about 3 hr, from about 1.5 to about 3 hr, from about 1.75 to about 2.5 hr, from about 1.75 to about 2.25 hr. In some embodiments, the geometric mean T _max is in the range of from about 80 to about 125% of about 2 h. In some embodiments, the geometric mean is about 2 h.

According to some embodiments of the methods of treating agitation, comprising administering a unit dose of a composition comprising about 180 mcg of dexmedetomidine, wherein the administration of a single dose provides a geometric median C _max value in the range of about 80 to about 125% of about 100 ng/L to about 800 ng/L. For example, C _max is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all whole numbers and ranges between them. In some embodiments, the median C _max value is from about 100 ng/L to about 1000 ng/L, from about 100 ng/L to about 800 ng/L, from about 200 ng/L to about 600 ng/L, from about 300 ng/L to about 600 ng/L, from about 300 ng/L to about 500 ng/L, from about 350 ng/L to about 500 ng/L, from about 300 ng/L to about 450 ng/L, from about 400 ng/L to about 500 ng/L, from about 400 ng/L to about 450 ng/L, from about 450 ng/L to about 500 ng/L, from about 470 ng/L to about 490 ng/L. In some embodiments, the median C _max is between about 80% and about 125% of about 485 ng/L. In some embodiments, the median C _max is about 485 ng/L.

According to some embodiments of methods for treating agitation comprising administering a unit dose composition comprising about 180 mcg of dexmedetomidine, the single dose administration provides a median AUC _0-mf in the range of about 80% to about 125% of about 600 h*ng/L to about 9500 h*ng/L. For example, the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h *ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, up to about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/L, about 9500 h*ng/L, about 9750 h*ng/L, about 10000 h*ng/L, about 10250 h*ng/L, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about 11500 h*ng/L, up to about 11875 h*ng/L, including all integers and ranges therebetween. In some embodiments, the AUC _0-inf is from about 500 h*ng/L to about 10,000 h*ng/L, from about 1,000 h*ng/L to about 7,500 h*ng/L, from about 1,000 h*ng/L to about 6,000 h*ng/L, from about 1,500 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 4,000 h*ng /L, from about 2,000 h*ng/L to about 3,000 h*ng/L, from about 2,500 h*ng/L to about 4,000 h*ng/L, from about 3,000 h*ng/L to about 4,000 h*ng/L, from about 3500 h*ng/L to about 4000 h*ng/L or from about 2500 h*ng/L to about 3000 h*ng/L. In some embodiments, the median AUC _0-inf is in the range of about 80% to about 125% of about 2900 ng*hr/L. In some embodiments, the median AUC _0-inf is about 2900 ng*hr/L.

According to some embodiments of the methods for treating agitation comprising administering a unit dose of a composition comprising about 180 mcg of dexmedetomidine, administration of a single dose provides a median T _max in the range of about 80 to about 125% of about 1 to about 8 hours. For example, a single dose provides a median T _max of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours,

- 54 047684 about 9.25 h, about 9.5 h, about 9.75 h, up to about 10 h. In some embodiments, T _max is from about 1 to about 8 h, from about 1 to about 6 h, from about 1 to about 4 h, from about 1 to about 3 h, from about 1.5 to about 3 h, from about 1.75 to about 2.5 h, from about 1.75 to about 2.25 h. In some embodiments, T _max is in the range from about 80 to about 125% of about 2 h. In some embodiments, T _max is about 2 h.

According to some embodiments of the methods of treating agitation comprising administering a unit dose of a composition comprising about 180 mcg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady-state.

In some embodiments, the present invention provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose of a composition comprising about 120 to about 180 mcg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar I disorder), and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g., bipolar I disorder).

According to some embodiments of the methods of treating agitation, comprising administering a unit dose composition comprising about 120 to about 180 mcg of dexmedetomidine, wherein said composition can be administered in various ways. For example, in some embodiments, a composition comprising dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, orally, intranasally, or parenterally. In some embodiments, the composition is administered sublingually or buccally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel, or drops. In some embodiments, the composition is administered buccally in the form of a film, patch, or tablet.

According to some embodiments of the methods of treating agitation comprising administering a unit dose composition comprising from about 120 to about 180 mcg of dexmedetomidine, the method may further comprise administering a second dose of dexmedetomidine after a period of time in the range of from about 30 minutes to about 12 hours. For example, the period of time may be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered after a period of time of about 2 hours. In some embodiments, the second dose is from about 10 to about 180 mcg. For example, the additional dose can be about 10 mcg, about 20 mcg, about 30 mcg, about 40 mcg, about 50 mcg, about 60 mcg, about 70 mcg, about 80 mcg, about 90 mcg, about 100 mcg, about 110 mcg, about 120 mcg, about 130 mcg, about 140 mcg, about 150 mcg, about 160 mcg, about 170 mcg, or about 180 mcg. In some embodiments, the additional dose is about 60 or 90 mcg.

According to some embodiments of the methods for treating agitation, comprising administering a unit dose composition comprising about 120 to about 180 mcg of dexmedetomidine, said unit dose composition may be administered to a patient on an empty stomach. In some embodiments, the unit dose composition is administered after a meal.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising about 120 mcg to about 180 mcg of dexmedetomidine, agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Positive and Negative Syndrome Scale (PEC) agitation component score from baseline. In some embodiments, agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, agitation is significantly reduced in less than 45 minutes (e.g., about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient has a decrease in PEC score of > 40% compared to baseline. For example, a patient may experience a score reduction of greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from baseline. Treatment effectiveness can also be compared by comparing the RES score to placebo. In some embodiments, the PEC score is >30% lower than placebo (e.g., the placebo group had an average change from baseline in total PEC score of -3 and the dexmedetomidine-containing composition group had an average change from baseline in total PEC score of -3.9). For example, compared to placebo, a patient's PEC score can be lower or greater by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%,

- 55 047684 about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient has a mean change in PEC score of greater than about -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition. For example, after 2 hours, the patient may have a mean change in PEC score of greater than about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or about -12. In some embodiments, the decrease in PEC score (e.g., greater than about -4) is maintained for at least 6 hours after administration of the composition. For example, if a patient has an average change in the total PEC score compared to the baseline, for example, -6 after 2 hours, then after 6 hours the average change in the PEC score of the patient will be about -6 or lower (e.g., -7, -8, etc.). In some embodiments, the decrease in the PEC score (e.g., by more than about -4) is substantially maintained for at least 6 hours after administration of the composition. For example, if a patient has an average change in the total PEC score compared to the baseline, for example, -6 after 2 hours, then after 6 hours the average change in the PEC score of the patient will be about -4, about -5, or about -6 or lower (e.g., -7, -8, etc.). In some embodiments, the average change in the PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 24 hours after administration of the composition.

According to some embodiments of methods for treating agitation, comprising administering a unit dose composition comprising about 120 to about 180 mcg of dexmedetomidine, wherein the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

According to some embodiments of the methods of treating agitation, comprising administering a unit dose of a composition comprising from about 120 to about 180 mcg of dexmedetomidine, wherein the administration of a single dose provides an average _Cmax value in the range of from about 80 to about 125% of from about 100 to about 800 ng/L. For example, C _max is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all whole numbers and ranges between them. In some embodiments, the average C _max is from about 100 ng/L to about 1000 ng/L, from about 100 ng/L to about 800 ng/L, from about 200 ng/L to about 600 ng/L, from about 300 ng/L to about 600 ng/L, from about 300 ng/L to about 500 ng/L, from about 350 ng/L to about 500 ng/L, from about 300 ng/L to about 450 ng/L, from about 400 ng/L to about 500 ng/L, or from about 400 ng/L to about 450 ng/L, from about 100 ng/L to about 500 ng/L, from about 150 ng/L to about 450 ng/L, from about 150 ng/L to about 400 ng/L, from about 200 ng /L to about 350 ng/L, from about 200 ng/L to about 300 ng/L, from about 200 ng/L to about 250 mg/L, or from about 210 ng/L to about 240 ng/L. In some embodiments, the average Cmax is in the range of about 80 to about 125% of 200 to about 500 ng/L. In some embodiments, the average Cmax is from about 230 to about 440 ng/L.

According to some embodiments of the methods for treating agitation, comprising administering a unit dose composition comprising from about 120 mcg to about 180 mcg of dexmedetomidine, the single dose administration provides a mean AUC _0-inf in the range of from about 80% to about 125% of from about 600 h*ng/L to about 9500 h*ng/L. For example, the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h *ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, up to about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/L, about 9500 h*ng/L, about 9750 h*ng/L, about 10000 h*ng/L, about 10250 h*ng/L, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about 11500 h*ng/L, up to about 11875 h*ng/L, including all integers and ranges therebetween. In some embodiments, the AUC _0-inf is from about 500 h*ng/L to about 10,000 h*ng/L, from about 1,000 h*ng/L to about 7,500 h*ng/L, from about 1,000 h*ng/L to about 6,000 h*ng/L, from about 1,500 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 4,000 h*ng/L, from about 2,000 h*ng/L to about 3,000 h*ng/L, from about 2,500 h*ng/L to about 4,000 h*ng/L, from about 3,000 h*ng/L to about 4,000 h*ng/L, from about 500 h*ng/L to about 5,000 h*ng/L, from about 500 h*ng/L to about 4,000 h*ng/L, from about 500 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 2,500 h*ng/L, from about 1,000 h*ng/L to about 2,000 h*ng/L, from about 1,000 h*ng/L to about 1,500 h*ng/L, or from about 1,500 h*ng/L to about 2,000 h*ng/L, from about 3,500 h*ng/L to about 4,000 h*ng/L

- 56 047 684 or from about 2500 h*ng/L to about 3000 h*ng/L. In some embodiments, the mean AUCo-mf is in the range of from about 80% to about 125% of about 1400 ng*h/L to about 4000 ng*h/L. In some embodiments, the mean AUC _0-inf is about 3800 ng*h/L. In some embodiments, the mean AUC _0-in f is in the range of from about 80 to about 125% of 1800 to about 3800 ng*h/L.

According to some embodiments of the methods for treating agitation comprising administering a unit dose composition comprising from about 120 to about 180 mcg of dexmedetomidine, administration of a single dose provides a mean T _max in the range of from about 80 to about 125% of from about 1 to about 8 hours. For example, a single dose provides a mean T _max of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, to about 10 h. In some embodiments, T _max is from about 1 to about 8 h, from about 1 to about 6 h, from about 1 to about 4 h, from about 1 to about 3 h, from about 1.5 to about 3 h, from about 1.75 to about 2.5 h, from about 1.75 to about 2.25 h. In some embodiments, T _max is in the range of from about 80 to about 125% of about 2 hours. In some embodiments, T _max is about 2 hours.

According to some embodiments of the methods for treating agitation comprising administering a unit dose of a composition comprising from about 120 to about 180 mcg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady-state.

In some embodiments, the present invention also provides methods for treating or alleviating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a human patient in need thereof, wherein the patient is at least 18 years of age and wherein the withdrawal period is up to 14 days. The term opioid withdrawal syndrome refers to a variety of symptoms and complaints that occur upon abrupt cessation or rapid reduction of a usual dose of opioids. Physical manifestations may include sweating, nausea, yawning, chills, diarrhea, dilated pupils, piloerection, tachycardia, increased blood pressure, hypersensitivity to pain, stomach cramps, and muscle spasms. Observed psychological manifestations of opioid withdrawal syndrome may include agitation, dysphoria, restlessness, irritability, anxiety, and depression. In some embodiments, the opioid withdrawal symptom is agitation. The first manifestations often begin within 6-24 hours after the last opioid use. In some embodiments, treating or alleviating opioid withdrawal refers to treating or reducing one or more of the aforementioned symptoms. Treatment or improvement can be measured using a variety of methods well known in the art, including, but not limited to, the Clinical Opioid Withdrawal Scale (COWS) and/or the Short Opioid Withdrawal Scale (SOWSGossop).

Thus, in some embodiments of the present invention, there are provided methods for treating or ameliorating agitation associated with opioid withdrawal symptoms. In some embodiments, treating or ameliorating the condition includes shortening the period of opioid withdrawal. For example, a patient receiving treatment in accordance with embodiments of the present invention may have an opioid withdrawal period of about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, or about 14 days, while a similar patient who did not receive treatment in accordance with embodiments of the present invention would have a longer period of opioid withdrawal treatment.

In some embodiments, the composition is administered twice daily. In some embodiments, the composition comprises a dosage range of dexmedetomidine or a pharmaceutically acceptable salt thereof from about 30 to about 200 mcg. For example, the composition comprises a unit dose of about 30 mcg, about 60 mcg, about 90 mcg, about 120 mcg, or 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, a single dose of a composition comprising about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for at least about 24 hours. In some embodiments, the composition is administered twice daily for 7 days.

In some embodiments, the patient suffers from opioid withdrawal syndrome, wherein the opioid is one or more of the following agents: fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanylcarfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil, or pentazocine. In some embodiments, the opioid is fentanyl. In some embodiments, the opioid has been administered for a time exceeding neonatal treatment prior to withdrawal.

- 57 047684

In some embodiments, the composition is administered sublingually, buccally, orally, intranasally, or parenterally. In some embodiments, the composition is administered buccally in the form of a tablet, film, spray, gel, or drops. In some embodiments, the composition is administered sublingually in the form of a film. In some embodiments, the composition is administered buccally in the form of a film, patch, or tablet. In some embodiments, the composition is administered buccally in the form of a film. In some embodiments, the patient receives treatment without experiencing clinically significant cardiovascular effects.

In some embodiments, the present invention also provides a pharmaceutical composition comprising about 20 to about 240 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In some embodiments, the dose of dexmedetomidine is about 120 mcg. In some embodiments, the dose of dexmedetomidine is about 180 mcg.

In some embodiments, said composition is formulated for sublingual or buccal administration. In some embodiments, said composition is formulated for sublingual administration in the form of a tablet, film, spray, gel, or drops. In some embodiments, said composition is formulated for buccal administration in the form of a film, patch, or tablet.

In some embodiments, a pharmaceutical composition comprising about 20 to about 240 mcg of dexmedetomidine is administered to a patient with agitation associated with schizophrenia or bipolar disorder, wherein agitation is significantly reduced within about 2 hours after administration of said composition, as measured by the mean change in the agitation component score of the Positive and Negative Syndrome Scale (PEC) from baseline. For example, agitation is significantly reduced at 30, 45, 1 hour, 90 minutes, or about 2 hours. In some embodiments, the patient has a decrease in PEC score of >40% compared to baseline. For example, a patient may experience a score reduction of greater than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% from baseline. Treatment effectiveness can also be compared by comparing the RES score to placebo. In some embodiments, the RES score is >30% lower than placebo (e.g., in the placebo group, the mean change in total RES score from baseline is -3, and in the dexmedetomidine-containing composition group, -3.9). For example, compared with placebo, a patient's RES score may be lower or higher by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200%. In some embodiments, the patient has an average change in PEC score of greater than about -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition. For example, at 2 hours, the patient may have an average change in PEC score of greater than about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or about -12. In some embodiments, the decrease in PEC score (e.g., greater than about -4) is maintained for at least 6 hours after administration of the composition. For example, if the patient has an average change in overall PEC score compared to baseline of, for example, -6 at 2 hours, then at 6 hours the patient's average change in PEC score will be about -6 or lower (e.g., -7, -8, etc.). In some embodiments, the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 24 hours after administration of the composition.

According to some embodiments of a pharmaceutical composition comprising from about 20 to about 240 mcg of dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

Administration of a single dose of a pharmaceutical composition containing from about 20 to about 240 mcg of dexmedetomidine provides an average C _max value in the range from about 80 to about 125% of about 100 to about 800 ng/L. For example, C _max is about 80 ng/L, about 100 ng/L, about 125 ng/L, about 150 ng/L, about 175 ng/L, about 200 ng/L, about 225 ng/L, about 250 ng/L, about 275 ng/L, about 300 ng/L, about 325 ng/L, about 350 ng/L, about 375 ng/L, about 400 ng/L, about 425 ng/L, about 450 ng/L, about 475 ng/L, about 500 ng/L, about 600 ng/L, about 625 ng/L, about 650 ng/L, about 675 ng/L, about 700 ng/L, about 725 ng/L, about 750 ng/L, about 775 ng/L, about 800 ng/L, about 825 ng/L, about 850 ng/L, about 875 ng/L, about 900 ng/L, about 925 ng/L, about 950 ng/L, about 975 ng/L, or about 1000 ng/L, including all whole numbers and ranges between them. In some embodiments, the average Cmax is from about 100 ng/L to about 1000 ng/L, from about 100 ng/L to about 800 ng/L, from about 200 ng/L to about 600 ng/L, from about 300 ng/L to about 600 ng/L, from about 300 ng/L to about 500 ng/L, from about 350 ng/L to about 500

- 58 047684 ng/L, from about 300 ng/L to about 450 ng/L, from about 400 ng/L to about 500 ng/L or from about 400 ng/L to about 450 ng/L, from about 100 ng/L to about 500 ng/L, from about 150 ng/L to about 450 ng/L, from about 150 ng/L to about 400 ng/L, from about 200 ng /L to about 350 ng/L, from about 200 ng/L to about 300 ng/L, from about 200 ng/L to about 250 mg/L or from about 210 ng/L to about 240 ng/L. In some embodiments, the average Cmax value is in the range of about 80 to about 125% of 200 to about 500 ng/L. In some embodiments, the average _Cmax value is in the range of about 230 to about 440 ng/L.

Administration of a single dose of a pharmaceutical composition containing from about 20 mcg to about 240 mcg of dexmedetomidine provides a mean AUC _0-inf value in the range of from about 80% to about 125% from about 600 h*ng/L to about 9500 h*ng/L. For example, the AUC _0-inf is about 470 h*ng/L, about 500 h*ng/L, about 600 h*ng/L, about 700 h*ng/L, about 800 h*ng/L, about 900 h*ng/L, about 1000 h*ng/L, about 1250 h*ng/L, about 1500 h*ng/L, about 1750 h*ng/L, about 2000 h*ng/L, about 2250 h*ng/L, about 2500 h*ng/L, about 2750 h*ng/L, about 3000 h*ng/L, about 3250 h*ng/L, about 3500 h*ng/L, about 3750 h*ng/L, about 4000 h*ng/L, about 4250 h*ng/l, about 4500 h*ng/l, about 4750 h*ng/l, about 5000 h*ng/l, about 5250 h*ng/l, up to about 5500 h*ng/l, about 5750 h*ng/l, about 6000 h*ng/l, about 6250 h*ng/l, up to about 6500 h*ng/l, about 6750 h *ng/l, about 7000 h*ng/l, about 7250 h*ng/l, up to about 7500 h*ng/l, about 7750 h*ng/l, about 8000 h*ng/l, about 8250 h*ng/l, up to about 8500 h*ng/l, about 8750 h*ng/l, about 9000 h*ng/l, about 9250 h*ng/L, about 9500 h*ng/L, about 9750 h*ng/L, about 10000 h*ng/L, about 10250 h*ng/L, about 10500 h*ng/L, about 10750 h*ng/L, about 11000 h*ng/L, about 11250 h*ng/L, about 11500 h*ng/L, up to about 11875 h*ng/L, including all integers and ranges therebetween. In some embodiments, the AUC _0-inf is from about 500 h*ng/L to about 10,000 h*ng/L, from about 1,000 h*ng/L to about 7,500 h*ng/L, from about 1,000 h*ng/L to about 6,000 h*ng/L, from about 1,500 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 5,000 h*ng/L, from about 2,000 h*ng/L to about 4,000 h*ng/L, from about 2,000 h*ng/L to about 3,000 h*ng/L, from about 2,500 h*ng/L to about 4,000 h*ng/L, from about 3,000 h*ng/L to about 4,000 h*ng/L, from about 500 h*ng/L to about 5,000 h*ng/L, from about 500 h*ng/L to about 4,000 h*ng/L, from about 500 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 3,000 h*ng/L, from about 1,000 h*ng/L to about 2,500 h*ng/L, from about 1,000 h*ng/L to about 2,000 h*ng/L, from about 1,000 h*ng/L to about 1,500 h*ng/L, or from about 1,500 h*ng/L to about 2,000 h*ng/L, from about 1,3,500 h*ng/L to about 4,000 h*ng/L, or from about 2,500 h*ng/L to about 3,000 h*ng/L. In some embodiments, the mean AUC _0-inf is in the range of about 80 to about 125% of about 1400 to about 4000 ng*hr/L. In some embodiments, the mean AUC _0-inf is about 3800 ng*hr/L. In some embodiments, the mean AUC _0-inf is in the range of about 80 to about 125% of 1800 to about 3800 ng*hr/L.

Administration of a single dose of a pharmaceutical composition containing from about 20 to about 240 mcg of dexmedetomidine provides an average T _max in the range of from about 80 to about 125% of about 1 to about 8 h. For example, a single dose provides an average T _{max of} about 0.8 h, about 0.9 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2.0 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3.0 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4.0 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5.0 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6.0 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7.0 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8.0 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9.0 h, about 9.25 h, about 9.5 h, about 9.75 h, up to about 10 h. In some embodiments, T _max is from about 1 to about 8 h, from about 1 to about 6 h, from about 1 to about 4 h, from about 1 to about 3 h, from about 1.5 to about 3 h, from about 1.75 to about 2.5 h, from about 1.75 to about 2.25 h. In some embodiments, T _max is in the range of from about 80 to about 125% of about 2 h. In some embodiments, T _max is about 2 h.

In some embodiments, the above pharmacokinetic parameters are non-steady-state.

In some embodiments, the present invention provides methods for reducing agitation to 1 (very much improved) or 2 (much improved) within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), as measured by the Clinical Global Impression of Improvement scale. In some embodiments, agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation lasts for more than about 2 hours. For example, the reduction in agitation lasts for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 mcg of dexmedetomidine. In some embodiments, the composition comprises about 180 mcg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

In some embodiments, the present invention provides methods for reducing agitation to 3 (mild agitation) or 4 (normal behavior) within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof on the Agitation Rating Scale.

- 59 047684 agitation and calmness (ACES). In some embodiments, agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, agitation is reduced to 4 (normal behavior). In some embodiments, the reduction in agitation persists for more than about 2 hours. For example, the reduction in agitation persists for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 mcg of dexmedetomidine. In some embodiments, the composition comprises about 180 mcg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

In some embodiments, the present invention also provides methods for achieving a >40% reduction in agitation within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the PEC scale. In some embodiments, agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation is >40%, >50%, >60%, >70%, >80%, >90%, or >100%. In some embodiments, the reduction in agitation lasts for more than about 2 hours. For example, the reduction in agitation lasts for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 mcg of dexmedetomidine. In some embodiments, the composition comprises about 180 mcg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

In some embodiments, the present invention provides a method of achieving a reduction in the PEC score for agitation over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the reduction in the PEC score is from about -8 to about -10, and wherein said extended period is from about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the long period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the decrease in PEC score is about -8, about -9, or about -10.

In some embodiments, the present invention provides a method of achieving an improvement in ACES score for agitation over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the improvement in ACES score is from about 3 to about 4, and wherein said extended period is from about 2 to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the long period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the ACES score is about 4.

In some embodiments, the present invention provides a method of achieving an improvement in the CGI-I agitation score over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the improvement in the CGI-I score is to about 1 (very strong improvement) or to about 2 (strong improvement), and wherein said extended period is from about 2 to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments

- 60 047684 in which the said prolonged period is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the CGI-I score is about 1.

Specific embodiments

Embodiment 1. A method for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in an average total exposure of dexmedetomidine, measured by AUC in plasma from _T0 to Tx, of about 3800 ng*h/L.

Embodiment 2. A method for treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in an average total exposure of dexmedetomidine, measured by AUC in plasma from T0 to Tx, of about 600 to about 12,600 ng*h/L.

Embodiment 3. Methods of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in an average total exposure of dexmedetomidine, measured by AUC in plasma from _T0 to Tx, of about 1800 ng*h/L.

Embodiment 4. A method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in an average total exposure of dexmedetomidine, measured by AUC in plasma from _T0 to Tx, of about 590 to about 8750 ng*hr/L.

Embodiment 5. The method according to embodiments 1-4, characterized in that said agitation or signs of agitation are associated with schizophrenia.

Embodiment 6. The method according to embodiments 1-4, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, orally, intranasally, or parenterally.

Embodiment 7. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally.

Embodiment 8. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually.

Embodiment 9. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 10. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film.

Embodiment 11. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally.

Embodiment 12. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet.

Embodiment 13. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally.

Embodiment 14. The method according to embodiment 13, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally in the form of an intramuscular injection.

Embodiment 15. The method according to embodiment 6, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally.

Embodiment 16. The method according to any one of embodiments 1-15, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose.

Embodiment 17. The method according to any one of embodiments 1-15, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose containing about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 18. The method according to any one of embodiments 1-15, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose containing about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 19. The method of embodiment 14, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 140 to 190 mcg.

- 61 047684

Embodiment 20. The method of embodiment 15, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 900 to 1200 mcg.

Embodiment 21. The method according to any of embodiments 1-20, characterized in that agitation or signs of agitation are also treated without inducing clinically significant effects on the cardiovascular system.

Embodiment 22. The method according to any one of embodiments 1-21, characterized in that agitation or signs of agitation are significantly reduced within 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 23. The method according to any one of embodiments 1-21, characterized in that agitation or signs of agitation are significantly reduced within 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by a significant relative change in the PEC score immediately before and 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 24. The method according to embodiment 23, characterized in that the relative PEC scores differ by at least six points.

Embodiment 25. The method according to embodiment 23, characterized in that the relative PEC scores differ by at least eight points.

Embodiment 26. The method according to embodiment 24 or 25, characterized in that the difference in relative PEC scores is maintained for at least 6 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 27. The method of embodiment 23, wherein said relative PEC scores differ by at least eight points, and wherein said difference of at least eight points is maintained for at least about 24 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 28. The method according to any one of embodiments 1-27, characterized in that the average Cmax value in plasma is about 400 ng/L.

Embodiment 29. The method according to any one of embodiments 1-28, characterized in that the median T _max value in plasma is about 2.0 h.

Embodiment 30. The method according to any one of embodiments 1-29, characterized in that the mean Cmax value in plasma is about 400 ng/L and the median _Tmax value in plasma is about 2.0 h.

Embodiment 31. The method according to any one of embodiments 28-30, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually.

Embodiment 32. The method of any of embodiments 28-30, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film.

Embodiment 33. The method according to any one of embodiments 1-27, characterized in that the Cmax value in plasma is from about 100 to about 1100 ng/L.

Embodiment 34. The method according to any one of embodiments 1-27, characterized in that the Cmax value in plasma is from about 200 to about 800 ng/L.

Embodiment 35. The method according to any one of embodiments 1-27, characterized in that the Cmax value in plasma is from about 3000 to about 5000 ng/L.

Embodiment 36. The method according to any one of embodiments 33-35, characterized in that the T _max value in plasma is from about 1 to about 8 hours.

Embodiment 37. The method according to any one of embodiments 33-35, characterized in that the T _max value in plasma is from about 5 min to about 4 h.

Embodiment 38. The method according to any one of embodiments 33-35, characterized in that the T _max value in plasma is from about 5 to about 15 min.

Embodiment 39. A method of treating a pathological condition (e.g., agitation) in a human subject, comprising sublingually or buccally administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in mean plasma absorption levels of dexmedetomidine of about 80% to about 125% of the following: a Cmax of about 300 to about 500 ng/L (e.g., about 400 ng/L) and an AUC from T ₀ to T 1 of about 2300 to about 3600 ng*hr/L (e.g., about 2900 ng*hr/L).

Embodiment 40. A method of treating a pathological condition (e.g., agitation) in a human subject comprising sublingually or buccally administering to said subject about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following: Cmax from about 100 ng/L to about 800 ng/L and AUC from _T0 to Tgo from about 600 to about 9500 h*ng/L.

Embodiment 41. A method of treating a pathological condition (e.g., agitation) in a human subject comprising sublingually or buccally administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in average levels

- 62 047684 absorption in plasma of dexmedetomidine is from about 80 to about 125% of the following values: Cmax from about 150 to about 300 ng/L (eg, about 220 ng/L) and AUC from T ₀ to Tgo is from about 1100 to about 1800 ng*h/L (eg, about 1420 ng*h/L).

Embodiment 42. A method of treating a pathological condition (e.g., agitation) in a human subject comprising sublingually or buccally administering to said subject about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in plasma absorption levels of dexmedetomidine from about 80% to about 125% of the following values: Cmax from about 110 ng/L to about 400 ng/L and AUC from T ₀ to Tro from about 590 to about 4400 h*ng/L.

Embodiment 43. The method according to embodiments 39-42, characterized in that the pathological condition is agitation or signs of agitation.

Embodiment 44. The method of embodiments 39-43, wherein said agitation or signs of agitation are associated with schizophrenia or bipolar disorder.

Embodiment 45. The method according to any one of embodiments 39-44, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered through the oral mucosa (e.g. sublingually or buccally).

Embodiment 46. The method according to embodiment 45, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 47. The method according to embodiment 46, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film.

Embodiment 48. The method according to embodiment 45, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally.

Embodiment 49. The method according to embodiment 48, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet.

Embodiment 50. The method according to embodiment 49, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film.

Embodiment 51. The method according to any one of embodiments 39-50, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose.

Embodiment 52. The method according to any one of embodiments 39-51, characterized in that the subject is treated also without inducing a clinically significant sedative effect.

Embodiment 53. The method according to any one of embodiments 39-52, characterized in that the subject is treated also without inducing clinically significant effects on the cardiovascular system.

Embodiment 54. The method according to any one of embodiments 43-53, characterized in that agitation or signs of agitation are significantly reduced within 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 55. The method according to any one of embodiments 43-54, characterized in that agitation or signs of agitation are significantly reduced within 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by relative PEC scores immediately before and 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 56. The method according to embodiment 55, characterized in that the relative PEC scores differ by at least six points.

Embodiment 57. The method according to embodiment 55, characterized in that the relative PEC scores differ by at least eight points.

Embodiment 58. The method of embodiment 56 or 57, wherein the difference in relative PEC scores is maintained for at least six hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 59. The method of embodiment 55, wherein said relative PEC scores differ by at least eight points and wherein said difference of at least eight points is maintained for at least about 24 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 60. The method according to any one of embodiments 39-59, characterized in that the median T _max value in plasma is about 2 hours.

Embodiment 61. The method according to any one of embodiments 39-59, characterized in that the T _max value in plasma is from about 1 to about 8 hours.

Embodiment 62. A method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering 180 mcg of dexmedetomidine or a pharmaceutically acceptable

- 63 047684 my salt in a single dose.

Embodiment 63. A method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose.

Embodiment 64. A method of alleviating or preventing the occurrence of a new episode of agitation in a human subject with schizophrenia or bipolar disorder for about 24 hours after a previous episode of agitation, comprising administering about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof in a single dose immediately after said previous episode of agitation.

Embodiment 65. A method of alleviating or preventing the occurrence of a new episode of agitation in a human subject with schizophrenia or bipolar disorder for about 24 hours after a previous episode of agitation, comprising administering about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof in a single dose immediately after said previous episode of agitation.

Embodiment 66. The method according to embodiment 62 or 63, characterized in that said agitation or signs of agitation are associated with schizophrenia.

Embodiment 67. A method for treating agitation or signs of agitation in a human subject suffering from dementia without inducing significant sedation, comprising administering through the oral mucosa about 30 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to six times per day with an interval between doses of at least 2 hours.

Embodiment 68. A method for treating agitation or signs of agitation in a human subject suffering from dementia without inducing significant sedation, comprising administering through the oral mucosa about 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof from one to six times per day with an interval between doses of at least 2 hours.

Embodiment 69. A method for treating agitation or signs of agitation in a human subject suffering from dementia without inducing significant sedation, comprising administering through the oral mucosa about 90 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to four times a day with an interval between doses of at least 2 hours.

Embodiment 70. A method for treating agitation or signs of agitation in a human subject with delirium hospitalized in an intensive care unit without inducing significant sedation, comprising oromucosal administration of about 20 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to four times daily for 6 hours after a first dose with an interval of at least 30 minutes between doses.

Embodiment 71. A method for treating agitation or signs of agitation in a human subject with delirium hospitalized in an intensive care unit without inducing significant sedation, comprising oromucosal administration of about 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof one to four times daily for 6 hours after a first dose with an interval of at least 30 minutes between doses.

Embodiment 72. A method for shortening the period of opioid withdrawal syndrome by administering to a human subject in need thereof, at least 18 years of age, dexmedetomidine twice daily during the withdrawal period, wherein the withdrawal period is up to 14 days.

Embodiment 73. The method of embodiment 72, wherein dexmedetomidine is administered in a dosage range of 30 to about 200 mcg.

Embodiment 74. The method of embodiment 73, wherein dexmedetomidine is administered in a single dose of about 30, 60, 90, 120, and 180 mcg.

Embodiment 75. The method of embodiment 72, wherein the cancellation period is up to 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days.

Embodiment 76. The method of embodiment 72, wherein the opioid is selected from the group consisting of, but not limited to, fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanylcarfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil, or pentazocine.

Embodiment 77. The method of embodiment 72, wherein the opioid is administered for a period of time exceeding the neonatal treatment before withdrawal occurs.

Embodiment 78. A method of treating agitation or signs of agitation in a human subject suffering from schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an oromucosal film containing about 120 mcg or about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose.

Embodiment 79. The method of embodiment 78, wherein the subject has previously been administered a liquid formulation of dexmedetomidine or a pharmaceutically acceptable salt thereof parenterally.

- 64 047684 by oral route (by intravenous, intramuscular, subcutaneous injection or intravenous infusion).

Embodiment 80. The method according to any of embodiments 78 and 79, characterized in that the administration through the oral mucosa is carried out within 3-5 days after the previous administration of the liquid composition of dexmedetomidine by parenteral route.

Embodiment 81. The method according to embodiment 78, characterized in that parenteral administration is carried out within 3-5 hours after the previous administration of the film for the oral mucosa.

Embodiment 82. The method according to embodiment 79, characterized in that the liquid composition is pre-filled into disposable syringes for self-administration by patients using an autoinjector.

Embodiment 83. The method of embodiment 78, wherein the subject is currently undergoing concomitant treatment with an antipsychotic agent.

Embodiment 84. The method of embodiment 83, wherein the antipsychotic agent is selected from, but not limited to, aripiprazole, benperidol, flupentixol, amisulpride, chlorpromazine, asenapine, risperidone, ziprasidone, lurasidone, clozapine, cariprazine, olanzapine, and quetiapine. In a preferred embodiment, the antipsychotic agent is aripiprazole.

Embodiment 85. The method of embodiment 72, wherein the improvement in the subject's condition is assessed after treatment using the Clinical Opioid Withdrawal Scale (COWS) and/or the Brief Opioid Withdrawal Scale-Gossop (SOWS-Gossop) (e.g., over a 10-day period).

Embodiment 86. The method of embodiment 70 or 71, characterized in that changes in the severity of delirium are measured using the DRS-R-98 scale.

Embodiment 87. The method of embodiment 70 or 71, characterized in that changes in agitation are monitored using the RASS scale.

Embodiment 88. The method according to any of embodiments 62, 63, 64, 65, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered through the oral mucosa (for example, sublingually, buccally), orally, intranasally or parenterally.

Embodiment 89. The method according to any of embodiments 67, 68, 69, 70, 71 and 72, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered through the oral mucosa (e.g. sublingually, buccally) in the form of a tablet, film, spray, gel or drops.

Embodiment 90. The method according to embodiment 89, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 91. The method according to embodiment 90, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film.

Embodiment 92. The method according to embodiment 89, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet.

Embodiment 93. The method according to embodiment 92, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film.

Embodiment 94. The method according to embodiments 62-65, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally in the form of an intravenous or intramuscular injection or an intravenous infusion.

Embodiment 95. The method of embodiments 62-65, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by intramuscular injection.

Embodiment 96. The method of embodiments 62-65, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once daily.

Embodiment 97. The method according to paragraphs 62-65, 67, 68, 69, 70, 71 and 72, characterized in that agitation or signs of agitation are also treated without inducing clinically significant effects on the cardiovascular system.

Embodiment 98. The method of claim 62 or claim 64, wherein a single dose of about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for at least about 24 hours.

Embodiment 99. The method according to any one of embodiments 62-65, characterized in that agitation or signs of agitation are significantly reduced within 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by a significant relative change in the PEC score immediately before and 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

- 65 047684

Embodiment 100. The method of embodiment 99, wherein the relative PEC scores differ by at least six points or by eight points.

Embodiment 101. The method of embodiment 99 or embodiment 100, wherein the difference in relative PEC scores is maintained for at least six hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 102. The method of embodiment 99 or embodiment 100, wherein said relative PEC scores differ by at least eight points, and wherein the difference of at least eight points is maintained for at least about 24 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 103. The method according to any one of the corresponding preceding embodiments, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, wherein said film is a self-supporting soluble film comprising:

(i) dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) one or more water-soluble polymers and, optionally, (iii) one or more pharmaceutically acceptable carriers.

Embodiment 104. The method of embodiment 103, wherein (ii) comprises a low molecular weight water-soluble polymer and two high molecular weight water-soluble polymers.

Embodiment 105. The method of embodiment 104, wherein the low molecular weight water-soluble polymer has a molecular weight of from about 5,000 Da to about 49,000 Da, and each high molecular weight water-soluble polymer has a molecular weight of greater than about 60,000 Da.

Embodiment 106. The method of embodiment 104, wherein the low molecular weight water-soluble polymer has a molecular weight of about 40,000 Da, one of the two high molecular weight water-soluble polymers has a molecular weight of about 140,000 Da, and the other high molecular weight water-soluble polymer has a molecular weight of about 370,000 Da.

Embodiment 107. The method according to any one of embodiments 103-106, characterized in that each water-soluble polymer is hydroxypropyl cellulose.

Embodiment 108. The method according to any of embodiments 103-106, characterized in that the film also contains polyethylene oxide.

Embodiment 109. The method according to embodiment 108, characterized in that the polyethylene oxide has a molecular weight of about 600,000 Da.

Embodiment 110. The method according to any of the corresponding preceding embodiments, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, wherein said film is a self-supporting soluble film comprising:

(i) dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a low molecular weight water-soluble polymer having a molecular weight of about 40,000 Da;

(iii) a high molecular weight water-soluble polymer having a molecular weight of about 140,000 Da;

(iv) a high molecular weight water-soluble polymer having a molecular weight of about 370,000 Da; and (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 Da.

Embodiment 111. The method of embodiment 110, wherein the film components, except for dexmedetomidine or a pharmaceutically acceptable salt thereof, form a single-layer film substrate, and dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of said film substrate.

Embodiment 112. The method of embodiment 111, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate in a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, a low molecular weight water-soluble polymer having a molecular weight of about 40,000 Da, and a high molecular weight water-soluble polymer having a molecular weight of about 140,000 Da.

Embodiment 113. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a standard dose of a composition comprising about 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 114. The method according to embodiment 113, characterized in that the patient has schizophrenia.

Embodiment 115. The method of embodiment 113 or embodiment 114, wherein the patient has bipolar disorder type I.

Embodiment 116. The method according to any one of embodiments 113-115, characterized

- 66 047684 characterized in that the said composition contains dexmedetomidine hydrochloride.

Embodiment 117. The method according to any of embodiments 113-116, characterized in that said composition is administered sublingually or buccally.

Embodiment 118. The method according to embodiment 117, characterized in that said composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 119. The method according to embodiment 117, characterized in that said composition is administered buccally in the form of a film, patch or tablet.

Embodiment 120. The method of any one of embodiments 113-119, further comprising administering a second dose after a period of time in the range of about 30 minutes to about 12 hours.

Embodiment 121. The method of embodiment 120, wherein said additional dose is about 60 or 90 mcg.

Embodiment 122. The method of embodiment 120 or embodiment 121, wherein the second dose is administered after a period of about 2 hours.

Embodiment 123. The method according to any of embodiments 113-122, characterized in that the patient is in a post-meal state.

Embodiment 124. The method according to any of embodiments 113-122, characterized in that the patient is in a fasting state.

Embodiment 125. The method according to any one of embodiments 113-124, characterized in that agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the agitation component score of the Positive and Negative Syndrome Scale (PEC) relative to the baseline level.

Embodiment 126. The method of embodiment 125, wherein agitation is significantly reduced within about 30 minutes to about 1 hour.

Embodiment 127. The method of embodiment 125 or embodiment 126, wherein the patient experiences a decrease in PEC score of >40% compared to baseline.

Embodiment 128. The method of embodiment 127, wherein the patient experiences a decrease in RES score by >60% compared to baseline.

Embodiment 129. The method according to any one of embodiments 125-128, characterized in that the PEC score is >30% lower than with placebo.

Embodiment 130. The method of embodiment 129, wherein the RES score is >60% lower than when using placebo.

Embodiment 131. The method of any one of embodiments 125-130, wherein the average change in PEC score is greater than -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition.

Embodiment 132. The method of embodiment 131, wherein the average change in PEC score is greater than -6 compared to baseline within 2 hours after administration of the composition.

Embodiment 133. The method of embodiment 131, wherein the average change in PEC score is greater than -8 compared to baseline within 2 hours after administration of the composition.

Embodiment 134. The method according to any one of embodiments 125-133, characterized in that the reduction in the PEC score is maintained for at least 6 hours after administration of the composition.

Embodiment 135. The method according to any one of embodiments 125-134, characterized in that the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 6 hours after administration of the composition.

Embodiment 136. The method according to any one of embodiments 113-135, characterized in that the subject is treated without experiencing a clinically significant sedative effect.

Embodiment 137. The method according to any one of embodiments 113-136, characterized in that the subject is treated without experiencing clinically significant cardiovascular effects.

Embodiment 138. The method of any one of embodiments 113-137, wherein the single dose administration provides an average C _max value in the range of about 80 to about 125% of about 110 to about 400 ng/L.

Embodiment 139. The method of embodiment 138, wherein the average C _max value is in the range of about 80 to about 125% of about 238 ng/L.

Embodiment 140. The method of embodiment 138, wherein the average C _max value is about 238 ng/L.

Embodiment 141. The method according to any one of embodiments 113-140, characterized

- 67 047684 characterized by the fact that administration of a single dose provides a mean AUC _0-inf value in the range from about 80 to about 125% from about 590 to about 4400 ng/L.

Embodiment 142. The method of embodiment 141, wherein the mean AUC _0-inf is in the range of about 80% to about 125% of about 1810 ng*h/L.

Embodiment 143. The method of embodiment 141, wherein the mean AUC _0-inf value is about 1810 ng*h/L.

Embodiment 144. The method of any one of embodiments 113-143, wherein the single dose administration provides an average T _max in the range of about 80 to about 125% from about 1 to about 4 hours.

Embodiment 145. The method of embodiment 144, wherein the average T _max value is in the range of about 80 to about 125% of about 2 hours.

Embodiment 146. The method according to embodiment 144, characterized in that the average value of T _max is about 2 hours.

Embodiment 147. The method of any one of embodiments 113-146, wherein the single dose administration provides a geometric mean C _max in the range of about 80 to about 125% of about 110 to about 400 ng/L.

Embodiment 148. The method of embodiment 147, wherein the geometric mean C _max value is in the range of about 80 to about 125% of about 220 ng/L.

Embodiment 149. The method of embodiment 147, wherein the geometric mean Cmax value is about 220 ng/L.

Embodiment 150. The method of any one of embodiments 113-149, wherein the single dose administration provides a geometric mean AUC _0-inf in the range of about 80 to about 125% of about 590 to about 4400 ng/L.

Embodiment 151. The method of embodiment 150, wherein the geometric mean AUC _0-inf is in the range of about 80% to about 125% of about 1410 ng*h/L.

Embodiment 152. The method of embodiment 150, wherein the geometric mean AUC _0-inf is about 1410 ng*h/L.

Embodiment 153. The method of any one of embodiments 113-152, wherein the single dose administration provides a geometric mean T _max in the range of about 80 to about 125% from about 1 to about 4 hours.

Embodiment 154. The method of embodiment 153, wherein the geometric mean value of Tmax is in the range of from about 80 to about 125% of about 2 hours.

Embodiment 155. The method of embodiment 153, wherein the geometric mean value of Tmax is about 2 hours.

Embodiment 156. The method of any one of embodiments 113-155, wherein the single dose administration provides a median Cmax in the range of about 80 to about 125% of about 110 to about 400 ng/L.

Embodiment 157. The method of embodiment 156, wherein the median Cmax value is in the range of about 80 to about 125% of about 230 ng/L.

Embodiment 158. The method of embodiment 156, wherein the median C _max value is about 230 ng/L.

Embodiment 159. The method of any one of embodiments 113-158, wherein the single dose administration provides a median AUC0-inf in the range of about 80 to about 125% of about 590 to about 4400 ng/L.

Embodiment 160. The method of embodiment 159, wherein the median AUC _0-inf value is in the range of about 80% to about 125% of about 1180 ng*h/L.

Embodiment 161. The method of embodiment 141, wherein the median AUC _0-inf value is about 1810 ng*h/L.

Embodiment 162. The method of any one of embodiments 113-161, wherein the single dose administration provides a median T _max in the range of about 80 to about 125% from about 1 to about 4 hours.

Embodiment 163. The method of embodiment 162, wherein the median T _max value is in the range of about 80 to about 125% of about 2 hours.

Embodiment 164. The method of embodiment 162, wherein the median Tmax value is about 2 hours.

Embodiment 165. The method according to any one of embodiments 138-164, characterized in that the pharmacokinetic parameters are non-steady-state.

Embodiment 166. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a standard dose of a composition comprising about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 167. The method according to embodiment 166, characterized in that the patient

- 68 047684 ent has schizophrenia.

Embodiment 168. The method of embodiment 166 or embodiment 167, wherein the patient has bipolar disorder type I.

Embodiment 169. The method according to any one of embodiments 166-168, characterized in that said composition comprises dexmedetomidine hydrochloride.

Embodiment 170. The method according to any of embodiments 166-169, characterized in that said composition is administered sublingually or buccally.

Embodiment 171. The method according to embodiment 170, characterized in that said composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 172. The method according to embodiment 170, characterized in that said composition is administered buccally in the form of a film, patch or tablet.

Embodiment 173. The method of any one of embodiments 166-172, further comprising administering a second dose after a period of time in the range of about 30 minutes to about 12 hours.

Embodiment 174. The method of embodiment 173, wherein said additional dose is about 60 or 90 mcg.

Embodiment 175. The method of embodiment 8 or embodiment 174, wherein the second dose is administered after a period of about 2 hours.

Embodiment 176. The method according to any of embodiments 166-175, characterized in that the patient is in a post-meal state.

Embodiment 177. The method according to any of embodiments 166-175, characterized in that the patient is in a fasting state.

Embodiment 178. The method according to any one of embodiments 166-177, characterized in that agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the agitation component score of the Positive and Negative Syndrome Scale (PEC) relative to the baseline level.

Embodiment 179. The method of embodiment 178, wherein agitation is significantly reduced within about 30 minutes to about 1 hour.

Embodiment 180. The method of embodiment 178 or embodiment 179, wherein the patient experiences a decrease in PEC score by >40% compared to baseline.

Embodiment 181. The method of embodiment 180, wherein the patient experiences a decrease in RES score by >60% compared to baseline.

Embodiment 182. The method according to any one of embodiments 178-181, characterized in that the PEC score is >30% lower than with placebo.

Embodiment 183. The method of embodiment 182, wherein the RES score is >60% lower than when using placebo.

Embodiment 184. The method of any one of embodiments 178-183, wherein the mean change in PEC score is greater than -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition.

Embodiment 185. The method of embodiment 184, wherein the average change in PEC score is greater than -6 compared to baseline within 2 hours after administration of the composition.

Embodiment 186. The method of embodiment 184, wherein the average change in PEC score is greater than -8 compared to baseline within 2 hours after administration of the composition.

Embodiment 187. The method according to any one of embodiments 178-186, characterized in that the reduction in the PEC score is maintained for at least 6 hours after administration of the composition.

Embodiment 188. The method according to any one of embodiments 178-187, characterized in that the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 24 hours after administration of the composition.

Embodiment 189. The method according to any one of embodiments 166-188, characterized in that the subject is treated without experiencing a clinically significant sedative effect.

Embodiment 190. The method according to any one of embodiments 166-189, characterized in that the subject is treated without experiencing clinically significant cardiovascular effects.

Embodiment 191. The method of any one of embodiments 166-190, wherein the single dose administration provides an average C _max value in the range of about 80 to about 125% of about 100 to about 800 ng/L.

Embodiment 192. The method according to embodiment 191, characterized in that the medium

- 69 047684 its Cmax value is in the range from about 80 to about 125% of about 440 ng/L

Embodiment 193. The method of embodiment 191, wherein the average C _max value is about 440 ng/L.

Embodiment 194. The method of any one of embodiments 166-193, wherein the single dose administration provides a mean AUC _0-inf in the range of about 80 to about 125% of about 600 to about 9500 h*ng/L.

Embodiment 195. The method of embodiment 194, wherein the mean AUC _0-inf is in the range of about 80% to about 125% of about 3800 ng*h/L.

Embodiment 196. The method of embodiment 194, wherein the mean AUC _0-inf is about 3800 ng*h/L.

Embodiment 197. The method of any one of embodiments 166-196, wherein the administration of a single dose provides an average T _max in the range of about 80 to about 125% from about 1 to about 8 hours.

Embodiment 198. The method of embodiment 197, wherein the average T _max value is in the range of about 80 to about 125% of about 2 hours.

Embodiment 199. The method according to embodiment 197, characterized in that the average value of T _max is about 2 hours.

Embodiment 200. The method of any one of embodiments 166-199, wherein the single dose administration provides a geometric mean C _max in the range of about 80 to about 125% of about 100 to about 800 ng/L.

Embodiment 201. The method of embodiment 200, wherein the geometric mean Cmax is in the range of about 80 to about 125% of about 380 ng/L.

Embodiment 202. The method of embodiment 200, wherein the geometric mean Cmax is about 380 ng/L.

Embodiment 203. The method of any one of embodiments 166-202, wherein the single dose administration provides a geometric mean AUC _0-inf in the range of about 80 to about 125% of about 600 to about 9500 h*ng/L.

Embodiment 204. The method of embodiment 203, wherein the geometric mean AUC _0-inf is in the range of about 80% to about 125% of about 2880 ng*h/L.

Embodiment 205. The method of embodiment 203, wherein the geometric mean AUC _0-inf is about 2880 ng*h/L.

Embodiment 206. The method of any one of embodiments 166-205, wherein the single dose administration provides a geometric mean Tmax in the range of about 80 to about 125% from about 1 to about 8 hours.

Embodiment 207. The method of embodiment 206, wherein the geometric mean value of Tmax is in the range of from about 80 to about 125% of about 2 hours.

Embodiment 208. The method of embodiment 206, wherein the geometric mean value of T _max is about 2 hours.

Embodiment 209. The method of any one of embodiments 166-208, wherein the single dose administration provides a median C _max value in the range of about 80 to about 125% of about 110 to about 800 ng/L.

Embodiment 210. The method of embodiment 209, wherein the median Cmax value is in the range of about 80 to about 125% of about 485 ng/L.

Embodiment 211. The method of embodiment 209, wherein the median Cmax value is about 485 ng/L.

Embodiment 212. The method of any one of embodiments 166-211, wherein the single dose administration provides a median AUC0-inf in the range of about 80 to about 125% of about 600 to about 9500 h*ng/L.

Embodiment 213. The method of embodiment 212, wherein the median AUC _0-inf is in the range of about 80% to about 125% of about 2900 ng*h/L.

Embodiment 214. The method of embodiment 194, wherein the median AUC _0-inf value is about 2900 ng*h/L.

Embodiment 215. The method of any one of embodiments 166-214, wherein the single dose administration provides a median Tmax in the range of about 80 to about 125% from about 1 to about 8 hours.

Embodiment 216. The method of embodiment 215, wherein the median Tmax value is in the range of about 80% to about 125% of about 2 hours.

Embodiment 217. The method of embodiment 215, wherein the median Tmax value is about 2 hours.

Embodiment 218. The method according to any one of embodiments 191-217, characterized in that the pharmacokinetic parameters are non-steady-state.

- 70 047684

Embodiment 219. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose of a composition comprising from about 120 mcg to about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 220. The method according to embodiment 219, characterized in that the patient has schizophrenia.

Embodiment 221. The method of embodiment 219 or embodiment 220, wherein the patient has bipolar I disorder.

Embodiment 222. The method according to any one of embodiments 219-221, characterized in that said composition comprises dexmedetomidine hydrochloride.

Embodiment 223. The method according to any one of embodiments 219-222, characterized in that the standard dose of dexmedetomidine is about 120 mcg.

Embodiment 224. The method according to any one of embodiments 219-222, characterized in that the standard dose of dexmedetomidine is about 180 mcg.

Embodiment 225. The method according to any of embodiments 219-224, characterized in that said composition is administered sublingually or buccally.

Embodiment 226. The method according to embodiment 225, characterized in that said composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 227. The method according to embodiment 225, characterized in that said composition is administered buccally in the form of a film, patch or tablet.

Embodiment 228. The method of any one of embodiments 219-227, further comprising administering a second dose after a period of time in the range of about 30 minutes to about 12 hours.

Embodiment 229. The method of embodiment 228, wherein said additional dose is about 60 or 90 mcg.

Embodiment 230. The method of embodiment 228 or embodiment 229, wherein the second dose is administered after a period of about 2 hours.

Embodiment 231. The method according to any one of embodiments 219-230, characterized in that agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the agitation component score of the Positive and Negative Syndrome Scale (PEC) relative to the baseline level.

Embodiment 232. The method of embodiment 231, wherein agitation is significantly reduced within about 30 minutes to about 1 hour.

Embodiment 233. The method of embodiment 231 or embodiment 232, wherein the patient experiences a decrease in PEC score of >40% compared to baseline.

234. The method according to embodiment 233, characterized in that the patient experiences a decrease in the RES score by >60% compared to the baseline level.

Embodiment 235. The method according to any one of embodiments 231-234, characterized in that the PEC score is >30% lower than with placebo.

Embodiment 236. The method of embodiment 235, wherein the RES score is >60% lower than when using placebo.

Embodiment 237. The method of any one of embodiments 231-236, wherein the mean change in PEC score is greater than -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of dexmedetomidine.

Embodiment 238. The method of embodiment 237, wherein the average change in PEC score is greater than -6 compared to baseline within 2 hours after administration of the composition.

Embodiment 239. The method of embodiment 237, wherein the average change in PEC score is greater than -8 compared to baseline within 2 hours after administration of the composition.

Embodiment 240. The method according to any one of embodiments 231-239, characterized in that the reduction in the PEC score is maintained for at least 6 hours after administration of the composition.

Embodiment 241. The method of any one of embodiments 231-240, wherein the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 24 hours after administration of the composition.

Embodiment 242. The method of any one of embodiments 219-241, wherein the subject is treated without experiencing a clinically significant sedative effect.

Embodiment 243. The method according to any one of embodiments 219-242, wherein the subject is treated without experiencing clinically significant effects from the serum

- 71 047684 cerebrovascular system.

Embodiment 244. The method of any one of embodiments 219-243, wherein administration of a single dose provides a mean peak plasma concentration (C _max ) in the range of about 80 to about 125% of about 100 to about 800 ng/L.

Embodiment 245. The method of embodiment 244, wherein the average C _max value is in the range of about 80 to about 125% of about 200 to about 500 ng/L.

Embodiment 246. The method of embodiment 244, wherein the average C _max value is in the range of about 80 to about 125% of about 230 to about 440 ng/L.

Embodiment 247. The method of any one of embodiments 219-246, wherein the single dose administration provides an average area under the curve (AUC) of _0-mf in the range of about 80 to about 125% of about 590 to about 9500 h*ng/L.

Embodiment 248. The method of embodiment 247, wherein the mean AUC _0-mf is in the range of about 80 to about 125% of about 1400 to about 4000 ng*h/L.

Embodiment 249. The method of embodiment 247, wherein the mean AUC _0-mf is in the range of about 80% to about 125% of about 1800 ng*hr/L to about 3800 ng*hr/L.

Embodiment 250. The method of any one of embodiments 219-249, wherein the administration of a single dose provides a mean time to reach maximum plasma concentration (T _max ) in the range of about 80 to about 125% from about 1 to about 8 hours.

Embodiment 251. The method of embodiment 250, wherein the average value of T _max is in the range of from about 80 to about 125% of several hours.

Embodiment 252. The method according to embodiment 250, characterized in that the average value of T _max is about 2 hours.

Embodiment 253. The method according to any one of embodiments 244-252, characterized in that the pharmacokinetic parameters are non-steady-state.

Embodiment 254. The method according to any of embodiments 219-253, characterized in that the patient is in a post-meal state.

Embodiment 255. The method according to any of embodiments 219-253, characterized in that the patient is in a fasting state.

Embodiment 256. A method for treating or alleviating opioid withdrawal symptoms comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof to a human patient in need thereof, wherein the patient is at least 18 years of age and wherein the withdrawal period is up to 14 days.

Embodiment 257. The method of embodiment 256, wherein the treatment comprises shortening the period of opioid withdrawal syndrome.

Embodiment 258. The method of embodiment 256 or embodiment 257, wherein treatment or improvement is measured using the Clinical Opioid Withdrawal Scale (COWS) and/or the Brief Opioid Withdrawal Scale-Gossop (SOWS-Gossop).

Embodiment 259. The method according to any of embodiments 256-258, characterized in that said composition is administered twice a day.

Embodiment 260. The method of any one of embodiments 256-259, wherein said composition comprises a dosage range of dexmedetomidine or a pharmaceutically acceptable salt thereof from about 30 to about 200 mcg.

Embodiment 261. The method of any one of embodiments 256-260, wherein said composition comprises a unit dose of about 30 mcg, about 60 mcg, about 90 mcg, about 120 mcg, or 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 262. The method according to any one of embodiments 256-261, characterized in that the withdrawal period is up to 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days.

Embodiment 263. The method of any one of embodiments 256-262, wherein the opioid is selected from the group consisting of, but not limited to, fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanylcarfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil butorphanol, methadone, dextropropoxyphene (propoxyphene) thebaine, sufentanil, or pentazocine.

Embodiment 264. The method of embodiment 263, wherein the opioid is selected from the group consisting of fentanyl.

Embodiment 265. The method of any one of embodiments 256-262, wherein the opioid is administered for a period of time exceeding neonatal treatment before withdrawal occurs.

Embodiment 266. The method according to any one of embodiments 256-265, characterized

- 72 047684 characterized in that the said composition is administered sublingually, buccally, orally, intranasally or parenterally.

Embodiment 267. The method according to any of embodiments 256-266, characterized in that said composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 268. The method according to embodiment 267, characterized in that said composition is administered sublingually in the form of a film.

Embodiment 269. The method according to any of embodiments 256-266, characterized in that said composition is administered buccally in the form of a film, patch or tablet.

Embodiment 270. The method according to embodiment 269, characterized in that said composition is administered buccally in the form of a film.

Embodiment 271. The method according to any one of embodiments 256-270, characterized in that the subject receives a treatment that does not induce clinically significant effects on the cardiovascular system.

Embodiment 272. The method of any one of embodiments 256-271, wherein a single dose of the composition comprising about 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for at least about 24 hours.

Embodiment 273. The method according to any one of embodiments 256-272, characterized in that said composition comprises dexmedetomidine hydrochloride.

Embodiment 274. The method according to any one of embodiments 256-273, characterized in that the opioid withdrawal symptom is agitation.

Embodiment 275. The method according to any of embodiments 256-274, characterized in that said composition is administered twice a day for 7 days.

Embodiment 276. A pharmaceutical composition comprising from about 20 to about 240 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 277. The composition of embodiment 276, wherein the dexmedetomidine is present as dexmedetomidine hydrochloride.

Embodiment 278. The composition of embodiment 276 or embodiment 277, wherein the dose of dexmedetomidine is about 120 mcg.

Embodiment 279. The composition of any one of embodiments 276-278, wherein the dose of dexmedetomidine is about 180 mcg.

Embodiment 280. The composition according to any one of embodiments 276-279, characterized in that said composition is formulated for sublingual or buccal administration.

Embodiment 281. The composition of embodiment 280, wherein said composition is formulated for sublingual administration in the form of a tablet, film, spray, gel or drops.

Embodiment 282. The composition of embodiment 280, wherein said composition is formulated for buccal administration in the form of a film, patch or tablet.

Embodiment 283. The composition of any one of embodiments 276-282, wherein when administered to a patient with agitation associated with schizophrenia or bipolar disorder, the agitation is significantly reduced within about 2 hours after administration of said composition, as measured by the mean change in the agitation component score of the Positive and Negative Syndrome Scale (PEC) from baseline.

Embodiment 284. The composition of embodiment 283, wherein agitation is significantly reduced within about 30 minutes to about 1 hour.

Embodiment 285. The composition of embodiment 283 or embodiment 284, wherein the patient experiences a decrease in PEC score of >40% compared to baseline.

Embodiment 286. The composition of embodiment 285, wherein the patient experiences a decrease in PEC score by >60% compared to baseline.

Embodiment 287. The composition of any one of embodiments 283-286, wherein the PEC score is >30% lower than with placebo.

Embodiment 288. The composition of embodiment 287, wherein the PEC score is >60% lower than with placebo.

Embodiment 289. The composition of any one of embodiments 283-288, wherein the mean change in PEC score is greater than -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition.

Embodiment 290. The composition of embodiment 289, wherein the average change in PEC score is greater than -6 compared to baseline within 2 hours after administration of the composition.

Embodiment 291. The composition of embodiment 289, characterized in that

- 73 047684 the average change in RES score is more than -8 compared to the baseline level within 2 hours after administration of the composition.

Embodiment 292. The composition of any one of embodiments 283-291, wherein the reduction in PEC score is maintained for at least 6 hours after administration of the composition.

Embodiment 293. The composition of any one of embodiments 283-292, wherein the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 24 hours after administration of the composition.

Embodiment 294. The composition of any one of embodiments 283-293, wherein the subject is treated without experiencing a clinically significant sedative effect.

Embodiment 295. The composition of any one of embodiments 283-294, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

Embodiment 296. The composition of any one of embodiments 276-295, wherein when administered to a patient suffering from schizophrenia or bipolar disorder, a single dose provides an average Cmax in the range of from about 80 to about 125% of from about 100 to about 800 ng/L.

Embodiment 297. The composition of embodiment 296, wherein the geometric mean Cmax is from about 200 to about 400 ng/L.

Embodiment 298. The composition of embodiment 296, wherein the mean Cmax value is in the range of about 80 to about 125% of about 230 to about 440 ng/L.

Embodiment 299. The composition of any one of embodiments 276-298, wherein when administered to a patient suffering from schizophrenia or bipolar disorder, a single dose provides a mean AUC _0-inf in the range of from about 80 to about 125% from about 590 to about 9500 h*ng/L.

Embodiment 300. The composition of embodiment 299, wherein the mean AUC _0-inf is in the range of about 80 to about 125% of about 1400 to about 4000 ng*h/L.

Embodiment 301. The composition of embodiment 299, wherein the mean AUC _0-inf is in the range of about 80 to about 125% of about 1800 to about 3800 ng*h/L.

Embodiment 302. The composition of any one of embodiments 276-301, wherein when administered to a patient suffering from schizophrenia or bipolar disorder, a single dose provides a mean time to reach maximum plasma concentration (Tmax) in the range of from about 80 to about 125% from about 1 to about 8 hours.

Embodiment 303. The composition of embodiment 302, wherein the average T _max value is in the range of from about 80 to about 125%.

Embodiment 304. The composition of embodiment 302, wherein the average T _max value is about 2 hours.

Embodiment 305. The composition of any one of embodiments 296-304, wherein the pharmacokinetic parameters are non-steady-state.

Embodiment 306. The composition according to any one of embodiments 283-305, characterized in that the patient is in a post-meal state.

Embodiment 307. The composition according to any one of embodiments 283-305, characterized in that the patient is in a fasting state.

Embodiment 308. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said dose provides one or more of the following pharmacokinetic parameters:

(1) the mean Cmax is in the range of about 80 to about 125% from about 110 to about 400 ng/L; and/or (2) the mean AUC _0-inf is in the range of about 80 to about 125% from about 590 to about 4400 h*ng/L; and/or (3) the mean T _max is in the range of about 80 to about 125% from about 1 to about 4 h.

Embodiment 309. The method according to embodiment 308, characterized in that the patient has schizophrenia.

Embodiment 310. The method of embodiment 308 or embodiment 309, wherein the patient has bipolar I disorder.

Embodiment 311. The method according to any one of embodiments 308-310, characterized in that said composition comprises dexmedetomidine hydrochloride.

Embodiment 312. The method according to any of embodiments 308-311, characterized in that said composition is administered sublingually or buccally.

- 74 047684

Embodiment 313. The method according to embodiment 312, characterized in that said composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 314. The method according to embodiment 312, characterized in that said composition is administered buccally in the form of a film, patch or tablet.

Embodiment 315. The method of any one of embodiments 308-314, further comprising administering a second dose after a period of time in the range of about 30 minutes to about 12 hours.

Embodiment 316. The method of embodiment 315, wherein said additional dose is about 60 or 90 mcg.

Embodiment 317. The method of embodiment 315 or embodiment 316, wherein the second dose is administered after a period of about 2 hours.

Embodiment 318. The method according to any of embodiments 308-317, characterized in that the patient is in a post-meal state.

Embodiment 319. The method according to any of embodiments 308-317, characterized in that the patient is in a fasting state.

Embodiment 320. The method of any one of embodiments 308-319, wherein agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Positive and Negative Syndrome Scale (PEC) agitation component score relative to baseline.

Embodiment 321. The method of embodiment 320, wherein agitation is significantly reduced within about 30 minutes to about 1 hour.

Embodiment 322. The method of embodiment 320 or embodiment 321, wherein the patient experiences a decrease in PEC score of >40% compared to baseline.

Embodiment 323. The method of embodiment 322, wherein the patient experiences a decrease in RES score by >60% compared to baseline.

Embodiment 324. The method according to any one of embodiments 320-323, characterized in that the PEC score is >30% lower than with placebo.

Embodiment 325. The method of embodiment 324, wherein the RES score is >60% lower than with placebo.

Embodiment 326. The method of any one of embodiments 320-325, wherein the mean change in PEC score is greater than -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition.

Embodiment 327. The method of embodiment 326, wherein the average change in PEC score is greater than -6 compared to baseline within 2 hours after administration of the composition.

Embodiment 328. The method of embodiment 326, wherein the average change in PEC score is greater than -8 compared to baseline within 2 hours after administration of the composition.

Embodiment 329. The method according to any one of embodiments 320-328, characterized in that the reduction in the PEC score is maintained for at least six hours after administration of the composition.

Embodiment 330. The method of any one of embodiments 320-329, wherein the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 6 hours after administration of the composition.

Embodiment 331. The method of any one of embodiments 308-330, wherein the subject is treated without experiencing a clinically significant sedative effect.

Embodiment 332. The method of any one of embodiments 308-331, wherein the subject is treated without experiencing clinically significant cardiovascular effects.

Embodiment 333. The method according to any one of embodiments 308-332, characterized in that two or more pharmacokinetic parameters are present.

Embodiment 334. The method according to any one of embodiments 308-333, characterized in that all three pharmacokinetic parameters are present.

Embodiment 335. The method of any one of embodiments 308-334, wherein the mean Cmax value is in the range of about 80 to about 125% of about 238 ng/L.

Embodiment 336. The method of embodiment 335, wherein the average C _max value is about 238 ng/L.

Embodiment 337. The method of any one of embodiments 308-336, wherein the single dose administration provides a mean AUC _0-mf in the range of about 80

- 75 047684 to about 125% of about 1810 ng*h/l.

Embodiment 338. The method of embodiment 337, wherein the average value is about 1810 ng*h/L.

Embodiment 339. The method of any one of embodiments 308-338, wherein the single dose administration provides an average Tmax in the range of about 80 to about 125% of about 2 hours.

Embodiment 340. The method according to embodiment 339, characterized in that the average value of T _max is about 2 hours.

Embodiment 341. The method according to any one of embodiments 308-340, characterized in that the pharmacokinetic parameters are non-steady-state.

Embodiment 342. A method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said dose provides one or more of the following pharmacokinetic parameters:

(1) the mean C _max is in the range of about 80 to about 125% from about 100 to about 800 ng/L; and/or (2) the mean AUC _0-mf is in the range of about 80 to about 125% from about 600 to about 9500 h*ng/L; and/or (3) the mean T _max is in the range of about 80 to about 125% from about 1 to about 8 h.

Embodiment 343. The method according to embodiment 342, characterized in that the patient has schizophrenia.

Embodiment 344. The method of embodiment 342 or embodiment 343, wherein the patient has bipolar I disorder.

Embodiment 345. The method according to any one of embodiments 342-344, characterized in that said composition comprises dexmedetomidine hydrochloride.

Embodiment 346. The method according to any of embodiments 342-345, characterized in that said composition is administered sublingually or buccally.

Embodiment 347. The method according to embodiment 346, characterized in that said composition is administered sublingually in the form of a tablet, film, spray, gel or drops.

Embodiment 348. The method according to embodiment 346, characterized in that said composition is administered buccally in the form of a film, patch or tablet.

Embodiment 349. The method of any one of embodiments 342-348, further comprising administering a second dose after a period of time in the range of about 30 minutes to about 12 hours.

Embodiment 350. The method of embodiment 349, wherein said additional dose is about 60 or 90 mcg.

Embodiment 351. The method of embodiment 349 or embodiment 350, wherein the second dose is administered after a period of about 2 hours.

Embodiment 352. The method according to any of embodiments 342-351, characterized in that the patient is in a post-meal state.

Embodiment 353. The method according to any of embodiments 342-351, characterized in that the patient is in a fasting state.

Embodiment 354. The method of any one of embodiments 342-353, wherein agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Positive and Negative Syndrome Scale (PEC) agitation component score relative to baseline.

Embodiment 355. The method of embodiment 354, wherein agitation is significantly reduced within about 30 minutes to about 1 hour.

Embodiment 356. The method of embodiment 354 or embodiment 355, wherein the patient experiences a decrease in PEC score of >40% compared to baseline.

Embodiment 357. The method of embodiment 356, wherein the patient experiences a decrease in RES score by >60% compared to baseline.

Embodiment 358. The method according to any one of embodiments 354-357, characterized in that the PEC score is >30% lower than with placebo.

Embodiment 359. The method of embodiment 358, wherein the RES score is >60% lower than when using placebo.

Embodiment 360. The method of any one of embodiments 354-359, wherein the mean change in PEC score is greater than -4 (i.e., a decrease of 4 or more points) compared to baseline within 2 hours after administration of the composition.

Embodiment 361. The method according to embodiment 360, characterized in that the medium

- 76 047684 its change in the RES score is more than -6 compared to the initial level within 2 hours after the administration of the composition.

Embodiment 362. The method of embodiment 360, wherein the average change in PEC score is greater than -8 compared to baseline within 2 hours after administration of the composition.

Embodiment 363. The method according to any one of embodiments 354-362, characterized in that the reduction in the PEC score is maintained for at least 6 hours after administration of the composition.

Embodiment 364. The method of any one of embodiments 354-363, wherein the average change in PEC score is greater than or equal to -8 and is maintained for from 2 hours after administration to at least 6 hours after administration of the composition.

Embodiment 365. The method of any one of embodiments 342-364, wherein the subject is treated without experiencing clinically significant sedation.

Embodiment 366. The method according to any one of embodiments 342-365, characterized in that the subject is treated without experiencing clinically significant cardiovascular effects.

Embodiment 367. The method according to any one of embodiments 342-366, characterized in that two or more pharmacokinetic parameters are present.

Embodiment 368. The method according to any one of embodiments 342-367, characterized in that all three pharmacokinetic parameters are present.

Embodiment 369. The method of any one of embodiments 342-368, wherein the mean Cmax value is in the range of about 80 to about 125% of about 440 ng/L.

Embodiment 370. The method of embodiment 369, wherein the average C _max value is about 440 ng/L.

Embodiment 371. The method of any one of embodiments 342-370, wherein the single dose administration provides a mean AUC _0-mf in the range of about 80 to about 125% of about 3800 ng*hr/L.

Embodiment 372. The method of embodiment 371, wherein the average value is about 3800 ng*h/L.

Embodiment 373. The method of any one of embodiments 342-372, wherein the single dose administration provides an average Tmax in the range of about 80 to about 125% of about 2 hours.

Embodiment 374. The method according to embodiment 373, characterized in that the average value of T _max is about 2 hours.

Embodiment 375. The method according to any one of embodiments 342-374, characterized in that the pharmacokinetic parameters are non-steady-state.

Embodiment 376. The method of any of the previous embodiments, wherein agitation is reduced to 1 (very much improved) or 2 (much improved) within 2 hours after administration of the composition, as measured by the Clinical Global Impression of Improvement scale.

Embodiment 377. The method of embodiment 376, wherein the agitation is reduced within about 30 minutes to about 1 hour.

Embodiment 378. The method of embodiment 377, wherein the agitation is reduced within about 30 minutes.

Embodiment 379. The method according to any one of embodiments 376-378, characterized in that agitation is reduced to 1 (very strong improvement).

Embodiment 380. The method of any one of embodiments 376-379, wherein the reduction in agitation is maintained for more than about 2 hours.

Embodiment 381. The method of any one of embodiments 376-380, wherein the reduction in agitation is maintained for more than about 4 hours.

Embodiment 382. The method of any one of embodiments 376-381, wherein the reduction in agitation is maintained for more than about 6 hours.

Embodiment 383. The method of any one of embodiments 376-382, wherein the reduction in agitation is maintained for more than about 8 hours.

Embodiment 384. The method according to any one of embodiments 376-383, characterized in that said composition comprises 120 mcg of dexmedetomidine.

Embodiment 385. The method according to any one of embodiments 376-383, characterized in that said composition comprises 180 mcg of dexmedetomidine.

Embodiment 386. The method according to any one of embodiments 376-385, characterized in that the patient has schizophrenia.

Embodiment 387. The method according to any one of embodiments 376-386, characterized

- 77 047684 characterized by the fact that the patient has bipolar disorder.

Embodiment 388. The method of any of the previous embodiments, wherein agitation is reduced to 3 (mild agitation) or 4 (normal behavior) within 2 hours after administration of the composition, as measured by the Agitation and Calmness Evaluation Scale (ACES).

Embodiment 389. The method of embodiment 388, wherein the agitation is reduced within about 30 minutes to about 1 hour.

Embodiment 390. The method of embodiment 388 or embodiment 389, wherein agitation is reduced to 4 (normal behavior).

Embodiment 391. The method of any one of embodiments 388-390, wherein the reduction in agitation is maintained for more than about 2 hours.

Embodiment 392. The method of any one of embodiments 388-391, wherein the reduction in agitation is maintained for more than about 4 hours.

Embodiment 393. The method of any one of embodiments 388-392, wherein the reduction in agitation is maintained for more than about 6 hours.

Embodiment 394. The method of any one of embodiments 388-393, wherein the reduction in agitation is maintained for more than about 8 hours.

Embodiment 395. The method according to any one of embodiments 388-394, characterized in that said composition comprises 120 mcg of dexmedetomidine.

Embodiment 396. The method according to any one of embodiments 388-394, characterized in that said composition comprises 180 mcg of dexmedetomidine.

Embodiment 397. The method according to any one of embodiments 388-396, characterized in that the patient has schizophrenia.

Embodiment 398. The method according to any one of embodiments 388-397, characterized in that the patient has bipolar disorder.

Embodiment 399. The method according to any of the previous embodiments, characterized in that the patient experiences a decrease in agitation by > 40 on the PEC scale.

Embodiment 400. The method of embodiment 399, wherein the agitation is reduced within about 30 minutes to about 1 hour.

Embodiment 401. The method of embodiment 399 or embodiment 400, wherein the patient experiences a decrease in agitation by > 60.

Embodiment 402. The method according to any one of embodiments 399-401, characterized in that the patient experiences a decrease in agitation by > 80.

Embodiment 403. The method of any one of embodiments 399-402, wherein the reduction in agitation is maintained for more than about 2 hours.

Embodiment 404. The method of any one of embodiments 399-403, wherein the reduction in agitation is maintained for more than about 4 hours.

Embodiment 405. The method of any one of embodiments 399-404, wherein the reduction in agitation is maintained for more than about 6 hours.

Embodiment 406. The method of any one of embodiments 399-405, wherein the reduction in agitation is maintained for more than about 8 hours.

Embodiment 407. The method according to any one of embodiments 399-406, characterized in that said composition comprises 120 mcg of dexmedetomidine.

Embodiment 408. The method according to any one of embodiments 399-406, characterized in that said composition comprises 180 mcg of dexmedetomidine.

Embodiment 409. The method according to any one of embodiments 399-408, characterized in that the patient has schizophrenia.

Embodiment 410. The method according to any one of embodiments 399-409, characterized in that the patient has bipolar disorder.

Embodiment 411. A method for achieving a reduction in the PEC score for agitation over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the reduction in the PEC score is from about -8 to about -10, and wherein said extended period is from about 2 to about 6 hours.

Embodiment 412. The method of embodiment 411, wherein said composition comprises dexmedetomidine hydrochloride.

Embodiment 413. The method of embodiment 411 or 412, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg.

Embodiment 414. The method of embodiment 411 or 412, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg.

Embodiment 415. The method according to any one of embodiments 411-414, characterized

- 78 047684 characterized by the fact that the specified extended period is approximately 4 hours.

Embodiment 416. The method of embodiment 415, wherein said extended period is about 6 hours.

Embodiment 417. The method according to any one of embodiments 411-416, characterized in that the decrease in the PEC score is about -10.

Embodiment 418. A method for achieving an improvement in ACES score for agitation over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the improvement in ACES score is from about 3 to about 4, and wherein said extended period is from about 2 to about 6 hours.

Embodiment 419. The method of embodiment 418, wherein said composition comprises dexmedetomidine hydrochloride.

Embodiment 420. The method of embodiment 418 or 419, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg.

Embodiment 421. The method of embodiment 418 or 419, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg.

Embodiment 422. The method according to any one of embodiments 418-421, characterized in that said extended period is about 4 hours.

Embodiment 423. The method of embodiment 422, wherein the prolonged period is about 6 hours.

Embodiment 424. The method of any one of embodiments 418-423, wherein the ACES score is about 4.

Embodiment 425. A method for achieving an improvement in a CGI-I score for agitation over an extended period of time in a subject with bipolar disorder or schizophrenia, comprising administering to said subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 to about 180 mcg, wherein the improvement in the CGI-I score is from about 1 (very strong improvement) to about 2 (strong improvement), and wherein said extended period is from about 2 to about 6 hours.

Embodiment 426. The method of embodiment 425, wherein said composition comprises dexmedetomidine hydrochloride.

Embodiment 427. The method of embodiment 425 or 426, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg.

Embodiment 428. The method of embodiment 425 or 426, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg.

Embodiment 429. The method according to any one of embodiments 425-428, characterized in that said extended period is about 4 hours.

Embodiment 430. The method of embodiment 425, wherein the prolonged period is about 6 hours.

Embodiment 431. The method according to any one of embodiments 425-430, characterized in that the CGI-I score is about 1.

Embodiment 432. The method according to any one of embodiments 110-112, characterized in that each water-soluble polymer is hydroxypropyl cellulose.

Embodiment 433. The method according to any one of embodiments 103-113, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 434. The method according to any one of the corresponding preceding embodiments, characterized in that dexmedetomidine hydrochloride is administered in the form of a film, wherein said film is a self-supporting soluble film comprising:

(a) a composition comprising:

(i) dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da) and (iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing comprising:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b).

Embodiment 435. The method according to any one of the corresponding preceding embodiments, characterized in that dexmedetomidine hydrochloride is administered in the form of a film, wherein said film is a self-supporting soluble film comprising:

- 79 047684 (a) a composition consisting essentially of:

(i) dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da);

(iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b).

Embodiment 436. The method of embodiment 434 or embodiment 435 wherein dexmedetomidine hydrochloride is present in an amount of about 0.1 to about 0.2% w/w based on the total weight of the film; hydroxypropyl cellulose (40,000 Da) is present in an amount of about 4 to about 6% w/w based on the total weight of the film; hydroxypropyl cellulose (140,000 Da) is present in an amount of about 4 to about 6% w/w based on the total weight of the film; hydroxypropyl cellulose (370,000 Da) is present in an amount of about 27 to about 30% w/w based on the total weight of the film; polyethylene oxide (60,000 Da) is present in an amount of about 55 to about 60% w/w based on the total weight of the film.

Embodiment 437. A self-supporting soluble film comprising:

(a) a composition consisting essentially of:

(i) about 180 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da) and (iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b).

Embodiment 438. The film of embodiment 437 wherein dexmedetomidine hydrochloride is present in an amount of about 0.1 to about 0.2% w/w of the total weight of the film; hydroxypropyl cellulose (40,000 Da) is present in an amount of about 4 to about 6% w/w of the total weight of the film; hydroxypropyl cellulose (140,000 Da) is present in an amount of about 4 to about 6% w/w of the total weight of the film; hydroxypropyl cellulose (370,000 Da) is present in an amount of about 27 to about 30% w/w of the total weight of the film; polyethylene oxide (60,000 Da) is present in an amount of about 55 to about 60% w/w of the total weight of the film.

Embodiment 439. A self-supporting soluble film comprising:

(a) a composition consisting essentially of:

(i) about 120 mcg dexmedetomidine hydrochloride;

(ii) hydroxypropyl cellulose (40,000 Da) and (iii) hydroxypropyl cellulose (140,000 Da); and (b) a film backing consisting essentially of:

(i) hydroxypropyl cellulose (40,000 Da);

(ii) hydroxypropyl cellulose (140,000 Da);

(iii) hydroxypropylcellulose (370,000 Da) and (iv) polyethylene oxide (60,0000 Da);

wherein the composition of part (a) is present on the surface of the film substrate (b).

Embodiment 440. The film of embodiment 439, wherein dexmedetomidine hydrochloride is present in an amount of about 0.1 to about 0.2% w/w of the total weight of the film; hydroxypropyl cellulose (40,000 Da) is present in an amount of about 4 to about 6% w/w of the total weight of the film; hydroxypropyl cellulose (140,000 Da) is present in an amount of about 4 to about 6% w/w of the total weight of the film; hydroxypropyl cellulose (370,000 Da) is present in an amount of about 27 to about 30% w/w of the total weight of the film; polyethylene oxide (60,000 Da) is present in an amount of about 55 to about 60% w/w of the total weight of the film.

Embodiment 441. The method according to any one of the corresponding preceding embodiments, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a sublingual spray, a sublingual drop, a sublingual gel, a buccal tablet, or a sublingual tablet, as presented in Table 1, Table 2, Table 3, Table 4, or Table 5, respectively.

- 80 047684

Example 1. Composition of sublingual film with dexmedetomidine

Table 6. Dexmedetomidine coated on the surface of a polymer matrix in a film composition

Ingredients Concentration g/100 g (film 10 µg) Concentration g/100 g (film 20 µg) Function Composition containing a medicinal product Dexmedetomidine hydrochloride 0,136 0.267 Active agent Hydroxypropyl cellulose, HPC-SSL (Yes = 40,000) 0.301 0.593 Film-forming material Hydroxypropyl cellulose (Da = 140,000) 0.301 0.593 Film-forming material FD&C Blue #1 Granulated 0,002 0,004 Color Ethyl alcohol as a solvent qs qs Solvent Polymer matrix composition Hydroxypropyl cellulose (Da = 140,000) 4,803 4,768 Film-forming material Hydroxypropyl cellulose, HPC-SSL (Yes = 40,000) 4,803 4,768 Film-forming material Hydroxypropyl cellulose (Da = 370,000) 28,809 28,601 Film-forming material Durable Emerald Green (No. 06507) 0,129 0,128 Color Sucralose, USP grade NF 0.993 0.985 Sweetener Peppermint Oil, NF 2,104 2,089 Aromatic substance Polyethylene oxide (Sentry Polyox WSR 205 LEO NF) (Yes = 600,000) 57,618 57,202 Film-forming material and mucoadhesive Water as a solvent qs qs Solvent

(A) The process of preparing the polymer matrix

Polymer Blend: Polyethylene oxide and fast emerald green tint were mixed in water for at least 180 minutes at a speed of about 1400 rpm to about 2000 rpm. Sucralose, hydroxypropyl cellulose (molecular weight 140K), hydroxypropyl cellulose, HPC-SSL (molecular weight 40K), and hydroxypropyl cellulose (molecular weight 370K) were added and mixed for at least 120 minutes at a speed of about 1600 to 2000 rpm. Peppermint oil was added to the water, then the resulting dispersion was added to the polymer mixture and mixed for at least 30 minutes. The resulting mixture was further mixed under vacuum (248 Torr) for at least 30 minutes at a speed of 350 rpm and a temperature of 22.9 °C.

Coating station: The roll was placed on the roll unwinding stand and the leading edge passed through the guide bars and coating bars. The silicone coated side of the block was positioned face up. A gap of 40 mm was maintained between the coating bars. The oven set temperature was adjusted to 70°C and the final drying temperature was adjusted to 85°C.

Coating/Drying Process: The resin mixture was poured onto the substrate between the guide rails and the coating bars. The substrate was slowly pulled by hand through the coating bar at a constant speed until no liquid remained on the coating bars. The substrate was cut by hand into approximately 12 inch long sheets using a safety knife. Each sheet was placed on a drying board and tapped at the corners to prevent curling during drying. The sheets were oven dried to less than 5% moisture content (approximately 30 minutes) and then removed from the drying board. The coating weight was checked against the acceptance criteria and if within the acceptance criteria, the sheets were stacked and placed in a 34 inch x 40 inch foil pouch lined with PET release liner.

- 81 047684 (B) Process of preparation of the precipitation solution:

FDC blue was dissolved in ethyl alcohol for at least 180 min. Dexmedetomidine hydrochloride was added to the ethyl alcohol solution with continuous stirring for 10 min at a speed of about 400 rpm to about 800 rpm. Hydroxypropyl cellulose (40K) and hydroxypropyl cellulose (140K) were added to the mixture and stirred for at least 30 min until all materials were dissolved.

(C) Process of preparation of microprecipitated matrix:

The precipitation solution obtained in step (B) described above was poured into a pipette to the required volume (determined according to the concentration of the specific drug in the final product). An appropriate amount (1.5 μl = approximately 5 μg) of the precipitation solution was applied (e.g. as drops) onto the polymer matrix obtained in step (A), which was repeated a total of 10 times (i.e. 10 depositions/drops) with an interval between each deposition to prevent coalescence of deposits/drops and to allow subsequent cutting of the film into individual unit dosage forms containing the drug. The film was initially cut into individual unit dosage forms of 22 mm x 8.8 mm dimensions, containing a single deposition of the composition containing the drug. The cut microprecipitated matrices were then dried in an oven at 70°C for 10 min and further cut into 10 unit dosage forms, each containing one deposition of the drug-containing composition.

(D) Packing:

Each unit dosage form was individually sealed in a foil pouch and then heat sealed. If the heat seal was acceptable, the package was considered an acceptable unit dosage form for commercial use.

Other concentration unit dosage forms (e.g., 40 and 60 mcg films) were prepared in a similar manner by varying the concentrations of drug, polymers, and dye in the drug-containing composition. For example, 40 and 60 mcg films were prepared from drug-containing compositions containing approximately 2 and 3 times the amount of drug, polymers, and dye, respectively, as in the 20 mcg drug-containing film composition described in Table 6 above.

- 82 047684

Example 2.

Table 7. Dexmedetomidine coated on the surface of a polymer matrix in a film composition

Ingredients Concentration mg/unit dosage form (film 80 mcg) Concentration mg/unit dosage form (film 120 mcg) Concentration mg/unit dosage form (film 180 mcg) Function Composition containing a medicinal product Dexmedetomidine hydrochloride 0,0945 0,142 0.213 Active agent Hydroxypropyl cellulose, HPC-SSL (Da = 40,000) 0,0812 0,122 0,183 Film-forming material Hydroxypropyl cellulose (Da = 140,000) 0,0812 0,122 0,183 Film-forming material FD&C Blue #1 Granulated 0,0008 0,001 0,002 Color Ethyl alcohol as a solvent q.s q.s. q.s. Solvent Polymer matrix composition Hydroxypropyl cellulose (Da = 140,000) 0.627 0.627 0.627 Film-forming material Hydroxypropyl cellulose, HPC-SSL (Yes = 40,000) 0.627 0.627 0.627 Film-forming material Hydroxypropyl cellulose (Da = 370,000) 3,763 3,763 3,763 Film-forming material A durable emerald green shade (No. 0,017 0,017 0,017 Color 06507) Sucralose, USPNF grade Peppermint oil, NF 0.130 0.275 0.130 0.275 0.130 0.275 Sweetener Flavoring substance Polyethylene oxide (Sentry Polyox WSR 205 LEO NF) (Yes = 600,000) 7,526 7,526 7,526 Film-forming material and mucoadhesive Water as a solvent qs qs qs Solvent

The formulations (80 μg, 120 μg and 180 μg) in Table 7 were prepared using the same manufacturing process described above in Example 1.

Example 3. A multicenter, randomized, double-blind, placebo-controlled, phase Ib, multiple dose escalation study to determine the efficacy, pharmacokinetics, and safety of dexmedetomidine hydrochloride sublingual film in the treatment of agitation associated with schizophrenia.

Main objective:

To determine the dose of dexmedetomidine hydrochloride sublingual film required to effectively reduce symptoms of acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder, as assessed by the change from baseline in the agitation component of the Positive and Negative Syndrome Scale (PEC) after treatment with the drug.

Secondary objectives:

To determine the pharmacokinetics, safety profile and tolerability of sublingual film of dexmedetomidine hydrochloride of different concentrations in patients with acute agitation associated with schizophrenia, schizoaffective disorder or schizophreniform disorder.

1. Description of the overall clinical improvement after drug administration using the Clinical Global Impression of Improvement (CGI-I) scale.

2. Description of the duration of the calming effect measured using the RES and

- 83 047684

ACES.

3. To determine the safety profile of dexmedetomidine hydrochloride sublingual film as assessed by vital signs and adverse event reports.

4. Description of general tolerability in the context of adverse event reports and local (oral/sublingual) tolerability of the sublingual film.

5. Description of the pharmacokinetics of dexmedetomidine hydrochloride sublingual film in patients.

6. Visual analogue scales (VAS) to determine the subject's opinion of taste and acceptability, as well as questions regarding the attractiveness of the study drug.

Methodology.

This was a phase Ib study with a two-stage adaptive design. It was a randomized, double-blind, placebo-controlled, multiple-ascending dose study evaluating the efficacy, pharmacokinetics, safety, and tolerability of sublingual dexmedetomidine hydrochloride film in adult (18-65 years) men and women with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder.

The first stage was designed to characterize the safe and tolerable dose range that produces calming effects as measured by the RES total score. The second stage was designed to include a total of 40 subjects in each dose group in a three-group placebo-controlled design to better characterize a wider range of safety and tolerability and to better estimate variability (effect size).

In the first phase, an adaptive evaluation of 20 mcg, 60 mcg, and 120 mcg dose escalation schedules was conducted, with the option of testing another dose if safety or tolerability reports were observed. Each cohort included adult men and women with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder. Investigators were permitted to repeat the dose 1 hour after the initial dose if no significant efficacy was observed (<40% change from baseline in PEC score) (maximum number of doses per subject was 2) and there were no safety concerns.

Blind periodic safety reviews were conducted after dosing of patients in each cohort to review all safety data as they became available. Dose escalations were permitted unless safety or tolerability concerns became apparent at the periodic safety review. Additional doses were selected based on blinded safety and tolerability reviews of all subject cohorts.

Eligible subjects (those with acute agitation due to schizophrenia, schizoaffective disorder, or schizophreniform disorder) were identified from outpatient clinics, mental health facilities, psychiatric clinics, or emergency medical services, including medical/psychiatric observation units, and could be newly admitted to hospital with acute agitation or already hospitalized for chronic comorbidities. Subjects were either residents of the clinical trial center or hospitalized to remain under medical observation during eligibility screening procedures.

After eligibility was confirmed, subjects were randomized to receive dexmedetomidine hydrochloride sublingual film or placebo film. At the beginning of each study session, a single dose of dexmedetomidine hydrochloride sublingual film was self-administered sublingually by subjects, following training with placebo film and under the supervision of unblinded personnel who were not involved in the safety or efficacy assessment. The drug film was left in the sublingual (SL) cavity until it dissolved. Subjects were also assessed for local irritation around the area where the film was placed. Efficacy and safety assessments were performed periodically before and after dosing. If the decrease in PEC score was less than or equal to 40% one hour after the first administration, the investigator could administer a second dose of dexmedetomidine hydrochloride sublingual film (same randomized dose) with an additional PEC assessment 1.5 hours after dosing. Every effort was made to complete all patient assessments according to protocol. However, if the patient's clinical situation warranted it, standard treatment was started, preferably after completion of the 4-hour assessment. In Step 1, each cohort included 27 subjects randomized 2:1 to receive dexmedetomidine hydrochloride sublingual film or placebo film (i.e., 18 received dexmedetomidine hydrochloride sublingual film and 9 received placebo film). Three doses were initially planned (a total of 81 subjects). The protocol allowed for other or additional doses to be tested based on ongoing safety analysis, and two additional dose levels were tested: 80 and 180 mcg (Table 8).

- 84 047684

Performance ratings:

The efficacy of dexmedetomidine hydrochloride sublingual film in reducing acute agitation was assessed using the agitation component of the Positive and Negative Syndrome Scale (PEC) at screening, baseline (which is the period before dosing), and 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, and 24 h after the first dose.

General agitation and sedation were assessed using the Agitation and Serenity Scale (ACES) at baseline (pre-dose) and 2 and 4 hours after the first dose.

Change in agitation in response to treatment was also measured by the Clinical Global Impression-Improvement (CGI-I) scale at 1, 2, and 4 hours after the first dose.

Safety and tolerability assessments:

Tolerability was assessed by analyzing AEs, clinical laboratory test results, electrocardiogram (ECG) rhythm strip, and vital signs. All observed and self-reported AEs were recorded. The relationship of AEs to study drugs was defined by the investigators as unrelated, unlikely/remotely related, possibly related, probably related, or definitely related.

Resting vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate, and ECG were measured prior to RC assessment. Resting vital signs (SBP, DBP, and HR) were measured at Screening, baseline (pre-dose), and 30 min, 1, 2, 4, and 8 h after the first dose. Orthostatic measurements including (SBP, DBP, HR, respiratory rate, and temperature) were performed at Screening, pre-dose, and 2, 4, and 24 h after the first dose. ECG was obtained at Screening, baseline (pre-dose), and 2 and 24 h after the first dose. The SL application site (buccal mucosa) was also examined for signs of local irritation.

Safety and tolerability assessments were performed before the morning of Day 3 (day of discharge) and repeated on Day 7 (+2). AE assessments were performed at screening, baseline (pre-dose), and 2 hours after the first dose on Day 3 and Day 7 (+2). Laboratory safety studies, including biochemistry, hematology, urinalysis, UDS, breath alcohol, and urine pregnancy testing, were performed at screening, Day 3, and Day 7 (+2).

Appropriate studies were repeated if any abnormal vital signs, clinical laboratory tests, physical examination findings, or ECG parameters were determined by the investigator to be clinically significant, including test results obtained on the last day of the study or at early study termination. For any test result abnormality determined to be clinically significant, reanalysis was performed during the observation period and until the value returned to baseline (or within normal limits) or until the abnormality was deemed stable and no longer of clinical concern by the investigator.

Three samples were identified for analysis for the study:

Safety population: all subjects receiving study drug

Intention-to-treat (ITT) set: all subjects in the safety evaluable population who are assessed by the PEC score.

Per-protocol (PP) population: all subjects in the ITT population with no significant protocol deviations

Subjects were treated with a range of widely prescribed antipsychotic drugs.

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Table 8. Groups and interventions

Groups Intervention Placebo comparator: placebo Sublingual film without active drug; single administration Product: Placebo Film Placebo Film for Dexmedetomidine Hydrochloride Experimental: 20 mcg Sublingual film containing 20 mcg dexmedetomidine; single administration with repeat dose after 1 hour Product: Sublingual film containing dexmedetomidine hydrochloride Introduction: Sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia Experimental: 60 mcg Sublingual film containing 60 mcg dexmedetomidine; single administration Product: Sublingual film containing dexmedetomidine hydrochloride. Introduction: Sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia Experimental: 80 mcg Sublingual film containing 80 mcg dexmedetomidine; single administration Product: Sublingual film containing dexmedetomidine hydrochloride. Introduction: Sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia Experimental: 120 mcg 2 sublingual films, Product: Sublingual film containing dexmedetomidine hydrochloride. each containing 60 mcg dexmedetomidine; single administration of 2 films Introduction: Sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia Experimental: 180 mcg 3 sublingual films, each containing 60 mcg dexmedetomidine; single administration of 3 films Product: Sublingual film containing dexmedetomidine hydrochloride. Introduction: Sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia

Number of subjects (planned and analyzed):

In Stage 1, approximately 81 subjects were planned to be enrolled in 3 cohorts (27 per cohort), however, including 2 additional cohorts (dexmedetomidine hydrochloride sublingual films 80 mcg and 180 mcg), a total of 135 subjects were included in 5 cohorts and analyzed.

Diagnosis and main eligibility criteria

Inclusion criteria:

1. Male and female patients aged 18 to 65 years inclusive.

2. Patients who meet the criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

3. Patients who exhibit clinical agitation at screening and at baseline (pre-dose with a total score > 14 on 5 items (impaired impulse control, tension, hostility, uncooperativeness, and agitation), including the PANSS agitation component (PEC).

4. Patients with > 4 points on at least 1 of 5 items of the RES scale at baseline (before dosing).

5. Patients who have read, understood and provided written informed consent.

6. Patients in good general health prior to study entry, as determined by detailed medical history, physical examination, 12-lead ECG with rhythm strip, blood chemistry profile, hematology data, urinalysis, and the principal investigator's opinion.

7. Female participants if they are of childbearing potential and sexually active, and male participants if they are sexually active with a partner of childbearing potential, who agree to use a medically acceptable and effective method of birth control throughout the study and for one week after the end of the study. Medically acceptable methods of contraception that the participant can use

- 86 047684 and/or his/her partner, include abstinence from sexual intercourse, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppositories, surgical sterilization, and progestin-only implant or injection. Prohibited methods include: the calendar method, withdrawal, condom only, or diaphragm only.

Exclusion criteria:

1. Patients with agitation due to acute intoxication, including positive breath alcohol or narcotic or over-the-counter drug (except tetrahydrocannabinol (THC)) detection on urine screening.

2. Patients who received treatment with benzodiazepines, other hypnotics, or short-acting oral or intramuscular neuroleptics within 4 hours prior to administration of the study drug.

3. Treatment with alpha-1-noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin and prazocin) or other prohibited drugs.

4. Patients with significant risk of suicide or homicide as assessed by the investigator or any suicidal behavior in the last 6 months prior to screening.

5. Female patients who have a positive pregnancy test on screening or who are breastfeeding.

6. Patients with a history of hydrocephalus, seizure disorder, or severe head injury, stroke, transient ischemic attack, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal neurologic manifestations.

7. History of syncope or other syncopal attacks, existing signs of hypovolemia, orthostatic hypotension, screening heart rate < 55 beats per minute (bpm) or systolic blood pressure (SBP) < 110 mmHg or diastolic blood pressure (DBP) < 70 mmHg.

8. Patients with laboratory or ECG abnormalities deemed clinically significant by the investigator or designee [progressive heart block (second-degree atrioventricular block or higher without pacemaker), diagnosed sick sinus syndrome] that may have clinical consequences for the patient's participation in the study.

9. Patients with serious or unstable medical conditions. These include pre-existing hepatic (moderate to severe liver failure), renal, gastrointestinal, respiratory, cardiovascular (including coronary artery disease, congestive heart failure), endocrinological, or hematological diseases.

10. Patients who received study drug within 30 days prior to the current episode of agitation.

11. Patients who are unable to use sublingual film or who for any reason are considered by the investigator to be unsuitable candidates for dexmedetomidine; for example, patients with a history of allergic reactions to dexmedetomidine.

Study drug, dose and route of administration:

Sublingual film of dexmedetomidine (formulation according to Examples 1 and 2 above) was studied in a small solid film dosage form with dimensions of approximately 193.6 ^mm2 in area and 0.7 mm thick, designed to completely dissolve in the SL space within 2-3 min.

Reference therapy, dose and route of administration:

Corresponding placebo films for sublingual administration as described above.

Duration of treatment: 1 day

Outcome measures: The primary outcome measures in this study were efficacy, pharmacokinetics, safety, and tolerability at each dose level.

Efficacy: The efficacy of dexmedetomidine hydrochloride sublingual film in reducing acute agitation was assessed using the agitation component of the Positive and Negative Syndrome Scale (PEC). The PEC scale included 5 items related to agitation: impaired impulse control, tension, hostility, uncooperativeness, and excitement; each item could be scored from 1 (minimum) to 7 (maximum) points. Thus, the total score for the PEC scale, consisting of 5 subscales, could range from 5 to 35 points.

General agitation and sedation were assessed using the Agitation and Serenity Scale (ACES), in which 1 = marked agitation; 2 = moderate agitation; 3 = mild agitation; 4 = normal behavior; 5 = mild calm; 6 = moderate calm; 7 = marked calm; 8 = deep sleep; and 9 = sleep without awakening.

Change in agitation in response to treatment was also measured using the Clinical Global Impression scale.

- 87 047684 on improvement (CGI-I). Scores on the CGI-I scale range from 1 to 7: 0 = not assessed (absent), 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worsened, 6 = much worsened, 7 = very much worsened.

Pharmacokinetics:

A pharmacokinetic analysis was performed using plasma dexmedetomidine concentrations following administration of dexmedetomidine hydrochloride sublingual films. A dose proportionality analysis was performed.

Safety and tolerability: AEs, clinical laboratory test results, ECG with rhythm strip, vital signs and signs of local irritation (buccal) were monitored for safety and tolerability.

Additional ratings:

Demographic data

Medical history

Pre- and concomitant therapy

Physical examination and

Pregnancy test

Statistical analysis:

Efficiency analyses.

The primary efficacy endpoint in this study was the absolute change from baseline in RES score at 120 min (2 h). The intention-to-treat (ITT) set, consisting of all patients who received any study drug and had both a baseline assessment and at least 1 post-dose efficacy assessment, was analyzed. Analyses were performed using a restricted mixed-effects model for repeated measures with maximum likelihood of change from baseline with baseline as a covariate and time point, and its interaction with treatment group as repeated measures, using an unstructured covariance structure. Responders were compared using Fisher's exact test.

Pharmacokinetic analyses:

Pharmacokinetic analysis was performed using the validated Phoenix® WinNonlin® version 8.1 software. A non-compartmental analysis was also performed on the final reviewed data, which included a total of 135 participants in 5 cohorts receiving dexmedetomidine sublingual films 20 mcg, 60 mcg, 80 mcg (1 film of 20 mcg and 1 film of 60 mcg), 120 mcg (2 films of 60 mcg), and 180 mcg (3 films of 60 mcg). All areas under the concentration-time curve (AUC) were calculated using the linear trapezoidal method. Dose proportionality was assessed using the power model for PK parameters. Plots of mean and individual concentration (sorted by dose level) versus time were constructed.

Safety and tolerability analyses:

Safety data were analyzed for all subjects who received at least 1 dose of study drug. The number and percentage of subjects with 1 or more AEs were summarized by treatment, relationship to study drug, and severity. AEs were coded using the Medical Dictionary of Terminology for Regulatory Activities (Med DRA). Lists of subjects who discontinued study drug due to AEs, serious AEs, and/or death are presented. Laboratory parameters were summarized by treatment using descriptive statistics and fact sheets of clinically significant abnormalities. Vital signs and ECG data were summarized for changes from baseline at each dose level using descriptive statistics.

Sample size determination: The sample size was based on clinical experience and judgment regarding the design and objectives of the study in Stage 1. A sample size of at least 18 subjects receiving active drug in each dose cohort should provide adequate clinical information to achieve the study objectives.

All efficacy, safety, and tolerability measurements were performed at regularly scheduled intervals as described in Table 9.

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Table 9. Schedule of procedures

Treatment Evaluation, Day 1 Activity Screening Before Dose ¹ Time after administration of dose ¹ Day 2, observation (+1) Day 3, discharge Day 7 (+2) Moment in time Before treatment -1 hour TO time 0 10 min 20 min 30 min 45 min 1 1,5 2 h 4 h 6 h 8 h 24 h (-9/+12 h) End of study Informed consent X Medical history X Demographic data X Body mass X X Height X BMI X MINI X PANSS ¹⁰ X X X Physical examination X X Lab. security research X X X ECG with rhythm strip ⁹ X X X X Resting vital signs ² X X X X X X X X X Orthostatic Vital Signs ² X X X X X X Hospitalization in the department X Training/checking X

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administration of the study drug Inclusion/exclusion criteria X X Randomization X Administration of study drug ⁸ PCRS ¹¹ RES ³ ACES CGI severity ⁴ CGI improvement ⁴ C-SSRS Score of buccal mucosa (SL) for local irritation ⁷ Visual analogue scale Question about drug attractiveness Taking samples for RC ⁶ Concomitant medication X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X* X X X X X X X X X X X X X X X therapy Adverse events X X X X X X X X X X X X X X X

Abbreviations: ACES = Agitation-Calmness Scale; BMI = body mass index; CLIA = Clinical Laboratory Improvement Act Amendments; CGI-I = Clinical Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; C-SSRS = Columbia Suicide-Impairment Severity Scale; DBP = diastolic blood pressure; ECG = electrocardiogram; MINI = Brief International Neuropsychiatric Interview Manual; PANSS = Positive and Negative Syndrome Scale; PCRS = Placebo Control Reminder Script; PEC = Positive and Negative Syndrome Scale-Arousal Component; PK = pharmacokinetic; SBP = systolic blood pressure; SL = sublingual; UDS = urine drug screen

Notes on the procedure schedule:

'Predose assessments had a window of 60 min before the first dose. All subsequent assessment times are relative to the first dose. All postdose assessments had a window of ±3 min to 2 h and ±10 min to 8 h.

² Resting vital signs (SBP, DBP, and HR) will be measured at screening, pre-dose, and 30 min, 1, 2, 4, and 8 h after the first dose. Triplicate measurements were taken if systolic BP < 90 mmHg, diastolic BP < 60 mmHg, or pulse < 60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate, and temperature) will be taken at screening, pre-dose, and 2, 4, and 24 h after the first dose. Vital signs were determined before each PK sample was collected.

³ The RES scale assessment was performed at screening, before the dose was administered and at 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6 and 24 h after the first dose.

⁴ CGI Severity was assessed at screening and predose. CGI Improvement was assessed at 1, 2, and 4 hours after the first dose. PEC (preceded by a placebo control reminder script [PCRS] when appropriate) was assessed before any

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⁵ Laboratory safety assessments included biochemistry, hematology, urinalysis, UDS (local lab) (performed at Screening only), breath alcohol screening (performed at Screening only), and urine pregnancy screening (performed at Screening only). Laboratory assessments at Screening/Enrollment: Specimens collected in a local lab within 7 days prior to Screening may be sufficient, with the exception of urine drug screening. If same-day results are not available, a benchtop or non-CLIA test may be performed for confirmation; however, results from a CLIA-certified lab must be reported when received.

⁶ Blood samples for PK analysis were collected pre-dose (up to 15 min before the first and, if applicable, the second dose), 1, 1.5, 2, 4, 6, 8-10 h (one sample was collected between 8 and 10 h), and 24 h after the first dose. A sample may be waived if the physician indicates in the original documentation that the patient is in a mental state that does not support collection of a PK sample. Non-consent or refusal of all or any PK sample collections was restrictive and did not result in ET. All PK sample collections had a window of ±3 min, except for the 24 h post-dose collection, for which the window was ±1 h.

*For repeat-dose subjects only: A blood sample for PK analysis was collected 2.5 h after the first dose in addition to other time points.

^7. Inspection of the buccal mucosa (after 30 min ±15 min and at other times ±30 min) for local irritation, performed by blinded personnel.

Day 2, observation, with a window of ±1 day.

⁸ In the clinical judgment of the investigator, the same randomized dose may be re-administered after 1 hour if there was no clinical effect (change in RES score from baseline < 40%) and if there are no safety concerns.

⁹ Pre-dose ECGs were not repeated if a screening ECG was recorded on the day of dosing. Post-treatment ECGs were collected before PK assessment. ¹⁰ PANSS were performed at any time on the day of dosing before the specified dose and after dosing. A full PANSS assessment should be performed in addition to a separate PEC assessment.

11PCRS was performed immediately prior to RES assessment

Summary of results:

1. Analyzed datasets

The number of subjects in each data set was the same for all 3 populations (i.e., safety, ITT, and PP populations) (Table 10). In addition, the number of subjects in each data set was the same for the pharmacokinetic population because all subjects provided blood samples for analysis.

Table 10. Summary of analyzed data sets

Dataset Sublingual film with dexmedetomidine Total (No. 135) Placebo (No. 45) 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Population of patients for safety assessment 45 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135 (100.0) Set of all patients randomized according to the intended treatment 45 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135 (100.0) Population of patients who complied with protocol requirements 45 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 18 (100.0) 135 (100.0)

Pharmacokinetics:

A total of 135 subjects were enrolled and received study drug and comprised the Safety Population. Of the 135 subjects, all subjects completed the inpatient period of study drug treatment; 127 subjects completed the study end point (i.e., Study Day 7). Of the 8 subjects who did not complete the study, 7 subjects were lost to follow-up after hospital discharge on Study Day 3, and 1 subject withdrew from the study on Study Day 3.

2. Demographic and baseline characteristics:

The mean age of subjects in the Safety Assessment Population (N=135) was 47.6 years, the majority of subjects were male (65.9% [89/135]), and the mean

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The BMI was 30.58 kg/m2. Subjects were predominantly black or African American (74.8% [101/135]) and of non-Hispanic or Latino origin (90.4% [122/135]). The majority of subjects in all treatment groups had a diagnosis of schizophrenia (according to the Mini-International Manual of Neuropsychiatric Interview [MINIPlus]). The proportion of subjects with schizophrenia ranged from 72.2% to 83.3% in the dexmedetomidine sublingual film treatment groups. Based on the MINI-Plus results, all subjects in the study met the inclusion criteria for a diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder (Table 11).

Table 11. Demographic and baseline characteristics

Parameter Placebo (No. 45) Sublingual dexmedetomidine film With Total (No. 135) 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Age (in years) Mean (SD) 48.4 (10.88) 50.1 (7.37) 45.8 (10.87) 50.2 (9.72) 40.5 (8.40) 49.1 (10.61) 47.6 (10.26) Median 52,0 50,0 47,0 52,0 40,0 48,0 50,0 Min - Max 21, 63 29, 59 26, 63 26, 63 25, 54 26, 64 21, 64 Gender, n% Men 27 (60.0) 9 (50.0) 15 (83.3) 13 (72.2) 13 (72.2) 12 (66.7) 89 (65.9) Women 18 (40.0) 9 (50.0) 3 (16.7) 5 (27.8) 5 (27.8) 6 (33.3) 46 (34.1) Race, n% Black or African American 37 (82.2) 13 (72.2) And (61.1) 12 (66.7) 15 (83.3) 13 (72.2) 101 (74.8) Caucasian 7(15.6) 5 (27.8) 7 (38.9) 6 (33.3) 2(I,1) 4 (22.2) 31 (23.0) Asian 0 0 0 0 0 1 (5.6) 1 (0.7) Multiple 1 (2,2) 0 0 0 0 0 1 (0.7) Unknown 0 0 0 0 1 (5.6) 0 1 (0.7) Ethnicity, n% Not of Spanish or Latin American descent 44 (97.8) 16 (88.9) 15 (83.3) 15 (83.3) 16 (88.9) 16 (88.9) 122 (90.4) Spanish or Latin American descent 1 (2,2) 2(I,1) 3 (16.7) 3 (16.7) 2(I,1) 2(I,1) 13 (9.6) Height (cm) Mean (SD) 171.15 (10.25) 169.29 (10.63) 174.08 (11.12) 174.90 (10.66) 175.33 (13.81) 174.87 (8.95) 172.85 (10.87) Median 169,00 170.30 174.05 175.90 175.70 175.25 173,00 Min - Max 149.9, 198.1 149.9, 188.0 150.5, 195.0 157.0, 198.1 137.0, 205.0 160.0, 188.4 137.0, 205.0 Weight (kg) Mean 86.86 (SD) (16.62) 86.92 (18.83) 94.89 (15.53) 92.84 (19.77) 90.54 (18.04) 100.53 (19.10) 91.05 (18.06) Median 84.10 82,50 97,10 91.95 90,80 100.45 91,00 Min - Max 56.8, 121.2 58.9, 119.6 64.9, 127.7 65.3, 133.6 57.2, 135.4 68.4, 143.2 56.8, 143.2 Body mass index (kg/ ^m2 ) Mean (SD) 29.74 (5.61) 30.23 (5.37) 31.45 (5.47) 30.56 (7.02) 29.81 (6.96) 32.97 (6.47) 30.58 (6.06) Median 29,27 29.58 31.09 30.03 29.08 32.56 29,40 Min - Max 17.9, 41.5 20.9, 40.3 22.5, 42.8 20.9, 44.5 18.3, 45.4 24.8, 45.4 17.9, 45.4

Abbreviations: cm = centimeter; kg = kilogram; max = maximum; min = minimum; SD = standard deviation;

Percentages are based on the number of Safety Assessment Population subjects in each treatment group.

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3. Efficiency

Dexmedetomidine sublingual film significantly reduced the severity of agitation from baseline as measured by the PEC, ACES, and CGI-I scores. Key efficacy data at 2 hours post-dose are presented below.

(a) Primary efficacy endpoint (PEC score reduction): A reduction in PEC (PANSS or Positive and Negative Syndrome Scale, agitation component) score for agitation was observed with rapid reassurance without excessive sedation at the clinical index time point and earlier time points. The primary efficacy endpoint was the mean change from baseline in PEC total score at 2 h (120 min) compared with placebo. There were 5 dose cohorts (20, 60, 80, 120, and 180 mcg) with 18 active patients (90 patients total) and 9 placebo-treated patients (45 patients total) in each cohort. Active patients in each of the 5 dose cohorts who received placebo were compared with placebo-treated patients from all 5 groups (placebo pool). Change from baseline in RES score at 2 hours in patients receiving dexmedetomidine sublingual film was compared with placebo using a mixed-effects model for repeated measures (MMRM) analysis with baseline RES score, treatment group, time, the interaction between treatment group and time, and the interaction between baseline RES score and time as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film, as measured by reduction in PEC score, is dose-dependent and robust. The reduction in PEC score from baseline in the 180 mcg dose group demonstrated a significant response, with a mean change from baseline in total PEC score (CFB) of -10.8 at 2 hours post-dose compared with placebo (Table 12 and Fig. 1). Mean changes from baseline were -9.2 and -7.3 points, respectively, for the 120 mcg and 80 mcg treatment groups compared with placebo (mean change 4.5). LSM mean differences from placebo were -2.9 (P=0.0210), -4.6 (P=0.0003), and -6.3 (P<0.0001) for the 80, 120, and 180 mcg treatment groups (Table 11). Mean changes from baseline to 2 h postdose in the 20 and 60 mcg groups were not significantly different from placebo. Furthermore, because early onset of action is an important attribute of therapy to reduce agitation, the 180 mcg group demonstrated a statistically significant difference from placebo as early as 45 min postdose (LS mean difference -3.5 [P<0.0049]).

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Table 12. Summary of changes from baseline to all time points in PANSS-PEC total score by treatment group (intention-to-treat set)

Moment in time Statistics Placebo (No. 45) Sublingual film with dexmedetomidine 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Initial level, η Mean (SD) 18.1 (2.37) 17.5 (2.33) 17.5 (2.07) 17.4 (1.42) 18.3 (1.64) 18.3 (2.95) 10 minutes after dose administration Mean(SD) 16.0 (4.33) 16.2 (2.86) 15.1 (3.92) 15.2 (3.26) 17.8 (3.19) 16.8 (4.26) Change from baseline, mean (SD) -2.1 (3.60) -1.3 (1.67) -2.4 (3.45) -2.2 (3.01) -0.6(2.31) -1.5 (2.68) Change from baseline, LS mean (SE) -2.1 (0.5) -1.4 (0.7) -2.5(0.7) -2.3 (0.7) -0.5 (0.7) -1.4 (0.7) LSM difference (SE) ^a 0.7 (0.9) -0.4 (0.9) -0.2 (0.9) 1.6 (0.9) 0.7 (0.9) 20 minutes after dose administration Mean(SD) 15.2 (4.41) 15.1 (2.88) 14.1 (4.64) 14.2 (3.81) 15.8 (3.47) 15.6 (4.12) Change from baseline, mean (SD) -2.9 (3.60) -2.4 (2.33) -3.4 (4.29) -3.2 (3.89) -2.5 (3.03) -2.7 (2.72) Change from baseline, LS mean (SE) -2.9 (0.5) -2.5 (0.8) -3.5 (0.8) -3.3 (0.8) -2.4 (0.8) -2.6 (0.8) LSM difference (SE) ^a 0.4 (1.0) -0.6 (1.0) -0.4 (1.0) 0.5 (1.0) 0.2 (1.0) 30 minutes after dose administration Mean(SD) 14.8 (4.94) 14.2 (2.79) 13.1 (4.97) 12.7 (3.82) 15.0 (3.74) 14.2 (4.48) Change from baseline, mean (SD) -3.3 (4.46) -z,z (3.07) -4.4 (4.67) -4.7 (3.82) -3.3 (3.56) -4.1 (3.26)

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Change from baseline, LS mean (SE) -3.2 (0.6) -3.4 (0.9) -4.5 (0.9) -4.8 (0.9) -3.2(0.9) 4.0(0.9) LSM difference (SE) ^a -0.2(1.1) -1.2(1.1) -1.5 (1.1) 0.0 (1.1) -0.7 (1.1) 45 minutes after dosing Mean (SD) 14.5 (4.88) 13.8 (3.15) 12.4 (5.41) 11.3 (4.80) 13.3 (4.66) 11.1 (5.08) Change from baseline, mean (SD) -3.6 (4.14) -3.7 (2.83) -5.1 (5.I) -6.1 (5.13) -5.1 (4.92) -7.2 (4.73) Change from baseline, LS mean (SE) -3.6 (0.7) -3.8 (1.0) -5.2 (1.0) -6.2 (1.0) -5.0(1.0) -7.1 (1.0) LSM difference (SE) ^a -0.2 (1.2) -1.6(1.2) -2.6 (1.2) -1.4(1.2) -3.5 (1.2) 1 hour after dose administration Mean (SD) 14.0 (4.65) 13.0 (4.33) I,4 (5.40) 10.9 (5.03) 10.9 (5.29) 9.2 (4.08) Change from baseline, mean (SD) -4.1 (4.29) -4.5 (3.67) -6.1 (5.49) -6.5 (5.28) -7.4 (5.48) -9.1 (4.58) Change from baseline, LS mean (SE) -4.0, 0.7 -4.6(1.1) -6.2(1.1) -6.6 (1.1) -7.3 (1.1) -9.0 (1.1) LSM difference (SE) ^a -0.6 (1.3) -2.2 (1.3) -2.6 (1.3) -3.3 (1.3) -5.0 (1.3) P-value ¹³ 0,6647 0,0968 0,0488 0,0130 0,0002 1.5 hours after dose administration Mean (SD) 13.8 (4.62) 12.1 (4.13) i,z (5,26) 10.8 (5.81) 10.8 (5.52) 7.8 (3.05)

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Change from baseline, mean (SD) -4.3 (4.43) -5.4 (3.96) -6.2 (5.24) -6.6 (6.05) -7.5 (5.57) -10.4 (4.38) Change from baseline, LS mean (SE) -4.3 (0.7) -5.5 (1.1) -6.3 (1.1) -6.7 (1D) -7.4(1.1) -10.4 (1.1) LSM difference (SE) ^a -1.2(1.3) -2.0 (1.3) -2.4 (1.3) -3.1(1.3) -6.1 (1.3) P-value ¹³ 0.3661 0,1279 0,0743 0,0199 <0.0001 2 hours after dosing Mean(SD) 13.6 (4.56) 11.0 (3.87) I,4 (5.07) Yu,1 (5.45) 9.1 (4.20) 7.4 (2.68) Change from baseline, mean (SD) -4.5 (4.58) -6.5 (3.91) -6.1 (5.09) -7.3 (5.70) -9.2 (4.47) -10.8 (3.15) Change from baseline, LS mean (SE) -4.5 (0.7) -6.6 (1.0) -6.1 (1.0) -7.4 (1.0) -9.1 (1.0) -10.8 (1.0) LSM difference (SE) ^a -2.1 (1.2) -1.7(1.2) -2.9 (1.2) -4.6 (1.2) -6.3 (1.2) P-value ^ь 0,0933 0,1850 0,0210 0,0003 <0.0001 4 hours after dosing Mean(SD) 13.7 (4.13) 9.4 (3.90) I,2 (5.11) 10.2 (5.12) 9.1 (3.69) 7.3 (2.54) Change from baseline, mean (SD) -4.4 (4.44) -8.1 (4.32) -6.3 (5.22) -7.2 (5.48) -9.2 (4.02) -10.9 (3.61) Change from baseline, LS mean (SE) -4.3 (0.7) -8.1(1.0) -6.4(1.0) -7.3 (1.0) -9.1 (1.0) -10.9 (1.0) LSM difference (SE) ^a -3.8 (1.2) -2.1 (1.2) -2.9 (1.2) -4.8 (1.2) -6.5 (1.2)

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P-value ⁶ 0,0022 0,0895 0,0172 0,0001 <0.0001 6 hours after dosing Mean(SD) 13.1 (4.22) 10.0 (4.00) I,9 (5.21) Yu,1 (4.90) 9.3 (4.23) 7.2 (2.51) Change from baseline, mean (SD) -5.0 (4.79) -7.5 (4.03) -5.6 (5.19) -7.3 (5.30) -9.1 (5.00) -11.1 (3.47) Change from baseline, LS mean (SE) -4.9 (0.7) -7.6(1.1) -5.6(1.1) -7.4 (1.1) -9.0(1.1) -11.0 (1.1) LSM difference (SE) ^a -2.7 (1.3) -0.7 (1.3) -2.5 (1.3) -4.0(1.3) -6.0 (1.3) P-value ⁶ 0,0375 0.5752 0,0490 0,0018 <0.0001 24 hours after dosing Mean(SD) 13.5 (3.91) I,4 (3.58) 13.6 (4,U) i,z (4,18) 12.8 (3.59) 9.4 (4.82) Change from baseline, mean (SD) -4.6 (4.03) -6.1 (4.23) -3.9 (4.34) -6.1 (4.50) -5.6 (3.29) -8.9 (3.53) Change from baseline, LS mean (SE) -4.6 (0.6) -6.2 (0.9) -4.0 (0.9) -6.2 (0.9) -5.5 (0.9) -8.8 (0.9) LSM difference (SE) ^a -1.6(1.1) 0.6(1.1) -1.6 (1.1) -0.9(1.1) -4.2 (1.1) P-value ⁶ 0,1464 0.5697 0,1407 0,4310 0,0002

Note: The number of subjects for all time points was 18 subjects for each dexmedetomidine sublingual film treatment group and 45 subjects for the placebo group a Treatment effect between dexmedetomidine sublingual film and placebo ^b P-value comparing dexmedetomidine sublingual film and placebo Analysis of PEC responders: The proportion of responders, defined as those with a 40% reduction in PEC total score from baseline at 2 hours post-dose, was highest in the 180 mcg group (94.4% [P<0.0001] for 180 mcg, 68.8% [P=0.0158] for 120 mcg, 58.8% for 80 mcg [P=0.0759]), and was significantly higher than with placebo (31% of responders) (Table 13 and Fig. 2). The response rate with 180 mcg was significantly higher than with placebo beginning at 45 min postdose (44.4% vs. 16.7%, respectively), continued to increase through 2 h (to 94.4% at 4 and 6 h), and was maintained for at least 24 h postdose (83.3% vs. 17.5%, respectively). Finally, the duration of the sedative effect of the 180 mcg dose was markedly prolonged, with a sustained statistically significant reduction in RES score evident at 24 h. Following a single dose, 83.3% of subjects in the 180 mcg group maintained a response at 24 h, with a mean reduction in RES score of -8.9 (mean CFB), compared with 37.5% in the 120 mcg group (-5.6 mean CFB) and 43.8% in the 80 mcg group (-6.1 mean CFB). The response rates over time for the 80 and 120 mcg groups were high and similar between the 2 groups (Table 13 and Fig. 2).

Table 13. Percentage of responders by RES scores (Aggregate of all randomized patients according to assigned treatment)

Moment in time Statistics Placebo (No. 45) Sublingual dexmedetomidine film With 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) 10 minutes after dose administration Percentage of respondents 11.9% 0% 12.5% 5.9% 6.3% 5.6% 20 minutes after dose administration Percentage of respondents 14.3% 0% 25.0% 23.5% 6.3% 5.6% 30 minutes after dose administration

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Percentage of respondents 21.4% 11.8% 37.5% 23.5% 12.5% 11.1% 45 minutes after dosing Percentage of respondents 16.7% 17.6% 37.5% 41.2% 25.0% 44.4% 1 hour after dose administration Percentage of respondents 21.4% 29.4% 43.8% 58.8% 56.3% 55.6% P-value ^a 0,5178 0,1091 0,0120 0,0236 0,0150 1.5 hours after dose administration Percentage of respondents 26.2% 41.2% 56.3% 52.9% 50.0% 77.8% P-value ^a 0,3505 0,0612 0,0699 0,1190 0,0004 2 hours after dosing Percentage of respondents 31.0% 58.8% 43.8% 58.8% 68.8% 94.4% P-value ^a 0,0759 0.3735 0,0759 0,0158 <0.0001 4 hours after dosing Percentage of respondents 21.4% 64.7% 50.0% 64.7% 68.8% 94.4% P-value ^a 0,0024 0,0519 0,0024 0,0015 <0.0001 6 hours after dosing Percentage of respondents 28.6% 64.7% 43.8% 58.8% 68.8% 94.4% P-value ^a 0,0173 0,3510 0,0399 0,0075 <0.0001 24 hours after dosing Percentage of respondents 17.5% 43.8% 26.7% 43.8% 37.5% 83.3% P-value ^a 0,0838 0,4676 0,0838 0,1610 <0.0001

A responder is defined as a subject who achieves a RES score reduction of >40% from baseline after dosing.

The numbers of subjects with no missing data in the dexmedetomidine sublingual film treatment groups were: 18 (180 mcg), 17 (20 and 80 mcg), and 16 (60 and 120 mcg); 42 subjects in the placebo group had no missing data.

^a P-value is based on the comparison of dexmedetomidine sublingual film with placebo using the Fisher's Exact Test PANSS-EC (5-item subscale scores): 5-item PEC agitation subscale scores (i.e., impaired impulse control, tension, hostility, uncooperativeness, and excitement) are summarized in Table 14. At 2 hours post-dose, there were significant improvements (i.e., decreases) from baseline in all 5 PEC subscale scores in the 80 g, 120, and 180 groups compared with placebo; except for agitation in the 80 mcg group.

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Table 14. Change from baseline in PANSS-EC subscale items at 2 h post-dose in patients with schizophrenia (Intention-to-treat set)

PANNS-EC subscale Statistics Placebo (No. 45) Sublingual dexmedetomidine film with 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Weakening of impulse control Baseline, mean (SD) 3.5 (0.63) 3.5 (0.62) 3.5 (0.62) (0.49) 3.4 (0.50) 3.4 (0.70) 2 hours after dosing Mean(SD) 2.7 (0.87) 2.1 (1.13) 2.2 (1.11) 1.9 (1.06) 1.7 (0.75) 1.4 (0.70) Change from baseline, mean (SD) -0.8 (0.89) -1.4 (1.14) -1.3 (1.13) -1.4 (1.04) -1.7 (1.03) -2.0 (0.91) Change from baseline, LS mean (SE) -0.8 (0.1) -1.4 (0.2) -1.3 (0.2) -1.4 (0.2) -1.7 (0.2) -2.0 (0.2) LSM difference (SE) ^a -0.6 (0.3) -0.5 (0.3) -0.6 (0.3) -0.9 (0.3) -1.2 (0.3) p-value 0,0307 0,0810 0,0178 0,0009 <0.0001 Voltage Baseline, mean (SD) 4.0 (0.64) 3.8 (0.65) 3.6 (0.92) 3.8 (0.71) 4.1 (0.47) 4.1 (0.87) 2 hours after dosing Mean (SD) z,o (1,13) 2.4 (1.15) 2.3 (1.32) 2.1 (1.23) 1.9 (1.06) 1.5 (0.71) Change from baseline, mean (SD) -1.0 (1.24) -1.3 (1.14) -1.3 (1.19) -1.7 (1.45) -2.2 (0.92) -2.6 (1.04) Change from baseline, LS mean (SE) -0.9 (0.2) -0.5 (0.3) -0.5 (0.3) -0.8 (0.3) -1.2 (0.3) -1.6 (0.3) LSM difference (SE)a -0.5 (0.3) -0.5 (0.3) -0.8 (0.3) -1.2 (0.3) -1.6 (0.3) p-value 0,1397 0,0947 0,0085 0,0002 <0.0001 Hostility Baseline, mean (SD) 3.5 (0.73) 3.5 (0.62) 3.6 (0.70) 3.3 (0.77) 3.6 (0.62) 3.6 (0.61) 2 hours after dosing Mean (SD) 2.6 (1.12) 2.2 (0.71) 2.4 (1.04) 1.9 (1.11) 1.8 (0.79) 1.4 (0.51) Change from baseline, mean (SD) -0.9 (1.11) -1.3 (0.84) -1.2 (1.15) -1.4 (1.14) -1.7 (1D8) -2.2 (0.71) Change from baseline, LS mean (SE) -0.9 (0.1) -1.3 (0.2) -1.1 (0.2) -1.5 (0.2) -1.7 (0.2) -2.1 (0.2) LSM difference (SE)a -0.4 (0.3) -0.2 (0.3) -0.6 (0.3) -0.8 (0.3) -1.2 (0.3) p-value 0,0973 0.3609 0,0272 0,0029 <0.0001 Refusal to cooperate Baseline, mean (SD) 3.3 (0.72) 3.2 (0.81) 3.3 (0.83) 3.4 (0.92) 3.4 (0.70) 3.2 (0.81) 2 hours after dosing Mean(SD) 2.5 (0.97) 2.0 (0.84) 2.2 (0.94) 2.0 (1.24) 1.7 (0.91) 1.4 (0.62)

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Change from baseline, mean (SD) -0.8 (0.98) -1.2 (1.06) -1,1 (1,I) -1.4 (1.33) -1.8 (1.06) -1.8 (0.81) Change from baseline, LS mean (SE) -0.8 (0.1) -1.3 (0.2) -1.1 (0.2) -1.4 (0.2) -1.7 (0.2) -1.8 (0.2) LSM difference (SE)a -0.5 (0.3) -0.3 (0.3) -0.6 (0.3) -1.0 (0.3) -1.0 (0.3) p-value 0,0669 0.2607 0,0268 0,0004 0,0001 Excitement Baseline, mean (SD) 3.8 (0.64) 3.5 (0.62) 3.6 (0.70) 3.5 (0.62) 3.8 (0.71) 3.9 (0.64) 2 hours after dosing Mean (SD) 2.7 (1.07) 2.3 (0.83) 2.3 (1.24) 2.1 (1.37) 1.9 (1.06) 1.6 (0.70) Change from baseline, mean (SD) -1.1 (1.11) -1.2 (0.88) -1.2 (1.22) -1.4 (1.46) -1.9 (1.02) -2.3 (0.77) Change from baseline, LS mean (SE) -1.1 (0.2) -1.3 (0.2) -1.3 (0.2) -1.5 (0.2) -1.8 (0.2) -2.2 (0.2) LSM difference (SE)a -0.2 (0.3) -0.2 (0.3) -0.4 (0.3) -0.8 (0.3) -1.2 (0.3) p-value 0.3967 0.4394 0,1577 0,0081 <0.0001

Secondary performance parameters to be determined:

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at 2 hours post-dose were consistent with the PEC total score results and indicated improvement in agitation symptoms following treatment with dexmedetomidine sublingual film.

ACES scores: The secondary objective of this study was to evaluate the duration of the calming effect of sublingual dexmedetomidine thin film using the Agitation and Calmness Evaluation Scale (ACES) at pre-dose, 2 h, and 4 h after the first dose. The ACES score was consistent with the analysis of the primary efficacy endpoint and was statistically significant for calming as measured by the ACES at 2 h compared with placebo at the three highest doses assessed (80 mcg; p=0.0150), (120 mcg; p=0.0003), and (180 mcg; p<0.0001). At 2 hours post-dose, subjects in the 80 mcg, 120 mcg, and 180 mcg treatment groups demonstrated significantly greater improvements than placebo on the ACES scale (+2.3 [P=0.0150], +3.1 [P=0.0003], and +4.2 [P=<0.0001], respectively, compared with placebo +1.2). Improvements at 4 hours post-dose were similar (+2.1 [P=0.0252], +3.2 [P=<0.0001], and +4.1 [P=<0.0001], compared with placebo +1.1) (Table 15 and Fig. 3). Regarding the calming effect (measured by the ACES scale), the mean scores in the 120 and 180 mcg groups increased from about 2 moderate agitation at baseline to 5.1 mild calm and 6.2 moderate calm, respectively, at 2 hours post-dose, compared with a score of 3.4 mild agitation in the placebo group. The improvement in calmness between groups was statistically significant with P values of 0.0003 and <0.0001, respectively, compared with placebo (Table 15).

Time to resolution of agitation: percentage of subjects achieving a score

ACES of at least 4 (normal)) at 2 and 4 hours post-dose are shown in Figure 3. At 2 and 4 hours post-dose, the percentage of subjects achieving an ACES score of at least 4, indicating resolution of agitation, was significantly higher in the 120 mcg group (72.2% [P=0.0045] and 77.8% [P=0.0016], respectively) and the 180 mcg group (88.9% [P<0.0001] and 83.3% [P=0.0002], respectively) compared with the placebo group (31.1% at 2 and 4 hours post-dose). With respect to sedation (measured by the ACES scale), the results showed that a total of 9 subjects in the treatment groups had a deep sleep score of 8 at 2 hours and/or 4 hours post-dose, but no subject in any treatment group had a sleep without arousal score of 9 (Table 16). The sedative effect was maintained for at least 6 hours, as evidenced by separation from placebo for the 80, 120, and 180 mcg dose groups.

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Table 15. Change from Baseline in ACES Score at 2 and 4 Hours Post-Dose (Intention-to-Treat Set)

Time after dose administration Placebo (N=45) Sublingual film with dexmedetomidine 20 mcg (N=18) 60 mcg (N=18) 80 mcg (N=18) 120 mcg (N=18) 180 mcg (N=18) Initial level, η Mean (SD) 2.1 (0.55) 2.3 (0.49) 2.2 (0.55) 2.2 (0.55) 2.0 (0.34) 1.9 (0.54) 2 hours after dosing Mean (SD) 3.4 (1.55) 3.8 (1.11) 4.2 (1.70) 4.6 (2.25) 5.1 (2.05) 6.2 (1.58) Change from baseline, mean (SD) ^a 1.2 (1.46) 1.4 (1.29) 2.0 (1.71) 2.3 (2.43) 3.1 (2.03) 4.2 (1.83) Change from baseline, LS mean (SE) ^b 1.2 (0.3) 1.6 (0.4) 2.1 (0.4) 2.4 (0.4) 3.0 (0.4) 4.1 (0.4) LSM difference (SE) ^C 0.4 (0.5) 0.8 (0.5) 1.2 (0.5) 1.8 (0.5) 2.9 (0.5) p-value ¹¹ 0,4371 0,0795 0,0150 0,0003 <0.0001 4 hours after dosing Mean (SD) 3.2 (1.42) 4.4 (1.54) 3.9 (1.76) 4.3 (2.22) 5.2 (1.72) 6.0 (1.75) Change from baseline, mean (SD) ^a 1.1 (1.40) 2.1 (1.53) 1.7 (1.81) 2.1 (2.19) 3.2 (1.69) 4.1 (2.04) Change from baseline, LS mean (SE) ^b 1.1 (0.3) 2.3 (0.4) 1.8 (0.4) 2.2 (0.4) 3.1 (0.4) 3.9 (0.4) LSM difference (SE) ^C 1.2 (0.5) 0.7 (0.5) 1.1 (0.5) 2.0 (0.5) 2.8 (0.5) p-value ¹¹ 0,0164 0,1524 0,0252 <0.0001 <0.0001

a Change from baseline (pre-dose) in ACES score with positive values in favor of improvement.

^b Least square mean and standard error per treatment group.

^c Treatment effect: least squares mean difference, standard error, and 95% confidence intervals between dexmedetomidine sublingual film and placebo.

^d p-value comparing sublingual film with dexmedetomidine and placebo

Table 16. Proportion of subjects with ACES scores of 8 (deep sleep) or 9 (sleep without arousal) for all dose groups

ACES Score Dose group Number of subjects at baseline Number of subjects at time 2 h Number of subjects at time 4h Deep Sleep ACES Score = 8 Placebo 0 0 0 20 mcg 0 0 1 60 mcg 0 0 0 80 mcg 0 1 1 120 mcg 0 2 0 180 mcg 0 2 3 Sleep without waking up ACES Score = 9 Placebo 0 0 0 20 mcg 0 0 0 60 mcg 0 0 0 80 mcg 0 0 0 120 mcg 0 0 0 180 mcg 0 0 0

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CGI-I Score:

Mean CGI-S scores at baseline were comparable across treatment groups (range, 3.9 to 4.3). CGI-S scores indicated that subjects had clinical evidence of agitation (i.e., moderate severity) prior to dosing (Table 17). Significant improvements in agitation (i.e., lower CGI-I scores) from baseline were observed 1 hour postdose in the dexmedetomidine 120 and 180 mcg sublingual film groups. Mean (SD) scores were 2.3 (1.13) and 2.1 (0.87), respectively, compared with 3.0 (0.98) in the placebo group (Table 18). LSM differences from placebo were -0.7 (P=0.0167) and -0.9 (P=0.0019) in the 120 and 180 mcg groups, respectively. Significant improvements in agitation status (i.e., lower mean CGI-I scores) from baseline were observed at 2 hours post-dose in the 120 mcg group (1.9 [P=0.0007]) and 180 mcg group (1.4 [P<0.0001]), compared with a mean score of 3 in the placebo group (Table 18). LSM differences from placebo were -1.1 (P=0.0007) and -1.6 (P<0.0001). Significant improvements were also observed at 4 hours after dosing with dexmedetomidine 120 and 180 mcg sublingual film. The percentage of subjects achieving a CGI-I score of 1 or 2 (very much improved or much improved) at 2 hours postdose was significantly higher in the 120 mcg group (66.7% [P=0.0125]) and in the 180 mcg group (94.4% [P<0.0001]) than in placebo (31.0%). Significant improvements were also observed at 1 hour and 4 hours postdose in both treatment groups (Table 19 and Fig. 4).

Table 17. Mean CGI-S scores at baseline (Intention-to-treat population)

Moment in time Statistics Placebo (No. 45) Sublingual film with dexmedetomidine 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Number of subjects 45 18 18 18 18 18 Baseline (before dose administration) Mean(SD) 4.2 (0.44) 3.9 (0.47) 4.1 (0.68) 4.1 (0.32) 4.3 (0.57) 4.3 (0.46) Minimum - maximum 3.0-5.0 3.0-5.0 3.0-5.0 4.0-5.0 3.0-5.0 4.0 - 5.0

Table 18. Summary of changes from baseline in CGI-I scores (Intention-to-treat set)

Sublingual film dexmedetomidine With Moment in time Statistics Placebo (No. 45) 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Number of subjects 45 18 18 18 18 18

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30 minutes after dose administration Mean (SD) 3.1 (1.04) 3.1 (0.76) 2.8(1.15) 3.2(1.15) 3.1 (0.76) 3.1 (0.76) LS mean(SE) ^a 3.2 (0.1) 3.1 (0.2) 2.8 (0.2) 3.2 (0.2) 3.1 (0.2) 3.1 (0.2) LSM difference (SE) ^b -0.1 (0.3) -0.4 (0.3) -0.0 (0.3) -0.1 (0.3) -0.1 (0.3) P-value ^with 0,7431 0,1778 0,9022 0,7431 0,7431 1 hour after dose administration Mean (SD) 3.0 (0.98) 2.9 (0.83) 2.4 (1.20) 2.8 (1.42) 2.3 (1.13) 2.1 (0.87) LS mean (SE) ^a 3.0 (0.2) 2.9 (0.3) 2.4 (0.3) 2.8 (0.3) 2.3 (0.3) 2.1 (0.3) LSM difference (SE) ^b -0.1 (0.3) -0.6 (0.3) -0.2 (0.3) -0.7 (0.3) -0.9 (0.3) P-value ^with 0,7098 0,0645 0.5769 0,0167 0,0019 2 hours after dosing Mean (SD) 3.0 (1.09) 2.4 (0.98) 2.3 (1.13) 2.6(1.54) 1.9(1.00) 1.4 (0.61) LS mean(SE) ^a 3.0 (0.2) 2.4 (0.3) 2.3 (0.3) 2.6 (0.3) 1.9 (0.3) 1.4 (0.3) LSM difference (SE) ^b -0.6 (0.3) -0.7 (0.3) -0.4 (0.3) -1.1 (0.3) -1.6 (0.3) P-value ^with 0,0701 0,0190 0,2034 0,0007 <0.0001 4 hours after dosing Mean (SD) 3.0(1.08) 2.4 (0.92) 2.8 (1.22) 2.6 (1.60) 1.8 (0.73) 1.4 (0.62) LS mean(SE) ^a 3.0 (0.2) 2.4 (0.3) 2.8 (0.3) 2.7 (0.3) 1.8 (0.3) 1.4 (0.3) LSM difference (SE) ^b -0.6 (0.3) -0.2 (0.3) -0.3 (0.3) -1.2 (0.3) -1.5 (0.3) P-value ^with 0,0516 0,5071 0,4139 0,0001 <0.0001

Clinical Global Impression of Improvement scale, scores range from 1 (very much improved) to 7 (much improved).

Test statistics and estimates were obtained from a restricted mixed effects model for repeated measures with maximum likelihood of change for observed values with time point and its interaction with treatment group as repeated measures using an unstructured covariance structure.

^a Least square mean and standard error per treatment group. Corresponding estimates for the placebo group are not included because they differ depending on the dexmedetomidine sublingual film comparison group.

^b Treatment effect: least squares mean difference, standard error, and 95% confidence intervals between dexmedetomidine sublingual film and placebo ^with p-value comparing dexmedetomidine sublingual film and placebo

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Table 19. Percentage of CGI-I responders over time (Intention-to-treat set of all randomized patients)

Moment in time Statistics Placebo (No. 45) Sublingual film with dexmedetomidine 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) 30 minutes after dose administration Percentage of respondents 22.2% 22.2% 38.9% 27.8% 22.2% 22.2% P-value ^a 1,000 0,2158 0,7457 1,000 1,000 1 hour after dose administration Percentage of respondents 24.4% 38.9% 44.4% 44.4% 55.6% 72.2% P-value ^a 0.3549 0,1383 0,1383 0,0361 0,0011 2 hours after dosing Percentage of respondents 31.1% 55.6% 55.6% 50.0% 66.7% 94.4% P-value ^a 0,0896 0,0896 0,2462 0,0125 <0.0001 4 hours after dosing Percentage of respondents 32.6% 55.6% 44.4% 57.1% 83.3% 94.4% P-value ^a 0,1499 0.3968 0,1231 0,0005 <0.0001

^a P-value is based on the comparison of dexmedetomidine sublingual film with placebo using Fisher's exact test

Pharmacokinetic results

Pharmacokinetic analysis was performed using the validated Phoenix® WinNonlin® version 8.1 software. A noncompartmental analysis was also performed using the final reviewed data, which included a total of 135 participants in 5 cohorts receiving dexmedetomidine sublingual film 20 mcg, 60 mcg, 80 mcg (1 x 20 mcg film and 1 x 60 mcg film), 120 mcg (2 x 60 mcg films), and 180 mcg (3 x 60 mcg films). Measurable dexmedetomidine concentrations were observed in the first collected plasma sample post-dose (1 hour) for all dose levels and are presented in Table 20. There were no measurable concentrations before dosing (0 hour) at any dose level. Measurable concentrations of dexmedetomidine were observed for up to 8 hours at all dose levels, with measurable concentrations at 24 hours in some subjects at each dose level (Table 20; Figs. 5A and 5B). Dexmedetomidine sublingual film is rapidly absorbed, with peak concentrations occurring, on average, at about 2.5 hours post-dose. The median T _max ranged from 1.50 to 2.31 hours, while the median t1/2 ranged from 2.36 to 3.06 hours for the 5 dose levels. Exposure (C _max and AUC) increased approximately proportionally with dose over the dose range studied (20 mcg to 180 mcg) after a single dose. The median C _max ranged from about 40 to about 500 ng/L. Once absorbed, the drug is eliminated with a half-life of about 3 hours, which was similar across dose groups. In the 20 mcg dose group, 8 of 18 subjects received a second dose of dexmedetomidine sublingual film, with exposure (Cmax and AUC) approximately 2-fold higher than in the group that did not receive a second dose.

The observed exposure after a single dose of 180 mcg (mean C _max : 379 ng/L; mean AUC 2881 ng/L) (Table 20) was significantly lower than the mean exposure (when assessed

PRECEDEX® at the approved IV dose): C _max : 1339 ng/L; AUC: 31713 ng.h/L (PKPD18-1054) with the maximum approved dose of dexmedetomidine.

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Table 20. Individual and summary statistics of dexmedetomidine PK parameter estimates in plasma after administration of dexmedetomidine sublingual film to patients with schizophrenia.

Cohort Dose (mcg) Repeat dose Subject ID Stakh (ng/l) Ttah (h) AUClast (h*ng/l) AUCinfobs (h*ng/l) tl/2 (I) 1 20 No 01-001 35.54 1.50 224,01 NC NC 01-002 38.55 1.50 186.08 NC 3.79 01-010 59.82 1,00 104.40 NC 2,12 01-026 14.07 4.02 57.43 NC NC 07-015 33,41 1.53 177,60 NC 5.36 07-030 34.31 2,00 176.11 203.81 2.29 10-027 35,38 2,00 184.37 NC 3.64 23-016 69.05 1.48 264.45 NC 2.95 23-018 40.37 1.97 154.62 186.40 3.17 23-020 38,49 1.95 190.81 226.26 2.51 N 10 10 10 3 8 Average value 39.90 1.89 171.99 205.49 3.23 SD 15.02 0.81 57.74 19.98 1.05 CV% 37.64 42.89 33.57 9.72 32,61 min. 14.07 1,00 57.43 186.40 2,12 Median 37,02 1.74 180.99 203.81 3.06 Max. 69.05 4.02 264.45 226.26 5.36 Geometric mean 37.16 1.78 160.36 204.85 3.0 9 Geometric CV% 43.89 36.99 45,49 9.72 31,23 1 20 Yes 01-009 130.44 2,00 662,46 NC 3.94 01-013 122.23 2,00 486.82 563,33 2.73 05-007 49.87 2.50 230,06 NC 4.02 05-008 66,64 2,12 272.47 304.52 2,00 05-021 86,86 2.50 410,74 NC 3.10 05-023 52.29 2.50 236.04 NC NC 05-024* 138.69 8.03 1912,52 NC NC 07-028 125.70 2,00 476.62 519.25 1.81 N 8 8 8 3 6 Average value 96.59 2.96 585,96 462.37 2.93

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SD 36.95 2.06 556.20 138.47 0.94 cv% 38.26 69.85 94.92 29.95 31.98 min. 49.87 2,00 230,06 304.52 1.81 Median 104.54 2.31 443.68 519.25 2.91 Max. 138.69 8.03 1912,52 563,33 4.02 Geometric mean 89.71 2.61 453,42 446,60 2.80 Geometric CV% 44,50 49.35 78,77 34,37 34.49 2 60 No 01-044 93.67 1,00 442.23 NC 3.10 01-047 73.42 1,00 265.85 293.67 2.23 01-055 113.35 1.50 474,46 562,60 2.87 01-056 154.79 1.50 413,53 428,64 1.48 03-036 83.52 1.55 347.11 369,07 1.62 05-050 121,52 1,00 355,87 381.27 1.84 05-052 105.84 1.50 330,30 369,14 2.36 06-033 253.14 1.45 737,87 834,44 2.27 06-034 206.42 1.53 887.27 1007,71 2.35 06-041 144.27 2.07 1714.29 1882,10 6.98 06-043 186.40 1,02 748,96 877,63 2.53 07-048 201,12 0.98 874,85 1030,25 2.81 08-046* 93.22 2,00 346.61 NC NC 09-042 146.17 3.95 2072,02 2195,38 5.43 10-032 136.25 1.50 650,22 NC NC 10-035 127.27 1.50 519,54 616,68 2.78 10-039 144.93 1,00 603,55 691,00 2.27 10-045 127.30 1.50 495,69 548,50 2.30 N 18 18 18 15 16 Average value 139.59 1.53 680,71 805,85 2.83 SD 47.22 0.69 481,66 555,95 1.42 CV% 33.83 45,0 70,76 68,89 50,15 min. 73.42 0.98 265.85 293.67 1.48 Median 131.78 1.50 507,61 616,68 2.36 Max. 253.14 3.95 2072,02 2195,38 6.98

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Geometric mean 132.56 1.43 575,95 674,14 2.60 Geometric CV% 33.88 36.02 59.93 65,01 40.94 3 120 No 01-059 128.89 2,00 1143,72 1192,51 5.28 01-062 380.78 2,00 2927,15 2958,80 3.64 01-065 393.58 4.00 3935,47 4063,95 4.62 01-080 316,57 1,00 1536,77 1538,84 2.60 01-082 315,51 4.00 4156,65 4371,55 5.32 01-086 201,58 1,00 915,85 918,48 2.56 03-068 308,19 1,02 1039.39 1039,79 2.02 06-077 108.84 3.82 585.94 586.93 2.59 06-078 228.53 1.47 NC NC NC 06-083 154.65 1.47 592.96 593.28 2.01 06-084 160.33 1.47 682.91 683,47 2.59 07-066 366,09 2,00 3920,86 4012,15 4.35 10-063 184.22 2,00 NC NC 3.50 10-076 149.11 2,00 990,19 989,76 2.81 23-069 286.88 2,00 1230,19 1230,90 1.98 23-070 243.63 1.52 NC NC 3.21 23-073* 125.62 4.00 NC NC NC 23-074 233.12 1.55 1162,59 1166,09 2.83 N 18 18 18 14 16 Average value 238,12 2,13 1513,91 1810,47 3.25 SD 92.98 1.06 1264,13 1395,65 1,1 cv% 39.05 50,03 83,50 77.09 34.27 min. 108.84 1,00 499,50 586.93 1.98 Median 230.83 2,00 970,38 1179,30 2.82 Max. 393.58 4.00 4158,05 4371,55 5.32 Geometric mean 220,53 1.91 1169,33 1411,79 3.08 Geometric CV% 42.89 49.10 78,73 81,15 33.71 4 180 No 01-089 490,60 1,00 5498,99 5592,92 3.92 01-097 636,45 1.50 2508,31 2676,44 1.76

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01-105 685,45 1,00 2628,09 3126,77 2.73 01-111* 88,10 8.00 1311,33 NC NC 05-088 127.77 1,02 520,53 569,19 2.03 05-098 563.94 1.47 2435,38 2644,08 1.86 05-100 487,88 1.47 4630,43 4705,04 3.90 06-091 592.99 3.98 6835,79 7310,47 5.92 06-093 406,57 2.07 2173,00 NC 3.22 07-095* 443,70 2,00 1911,81 NC NC 10-090 546,65 2,00 3808,10 NC 5.19 10-123 797.37 1.50 8928,20 9468,70 5.80 10-127 640,01 2,00 2444,45 2746,20 2.30 10-129 483,07 2,00 3578,09 4340,66 9.65 23-103 225,12 1.98 1034,07 1140.28 1.90 23-104 227,51 1.97 1086,53 NC 2.94 23-125 237.95 1.98 943.23 1049.33 2,10 23-126 224.88 1.98 1243,11 NC 2.84 N 18 18 18 12 16 Average value 439.22 2.16 2973,31 3780,85 3.63 SD 206.41 1.60 2255,10 2663,22 2,12 CV% 46.99 73.99 75,84 70.44 58.29 min. 88,10 1,00 520,53 569,19 1.76 Median 485,48 1.98 2439,91 2936,49 2.89 Max. 797.37 8.00 8928,20 9468,70 9.65 Geometric mean 379,13 1.87 2294.38 2881,18 3.20 Geometric CV% 68,19 52.19 87.67 100.34 53.08 5 80 No 01-144 160.18 2,00 784.24 917,99 2.49 02-133 142.99 2.03 747,42 886.35 2.41 02-142 222.79 2,00 2480,66 2594,62 5.37 03-112 68.41 1.55 416,50 NC NC 03-114 70.46 1.03 244.38 NC NC 03-120 107,00 1.53 450.79 531,82 2.67 03-134 135.30 1.55 759,89 894.79 2.57

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08-092 167.57 1.88 938,26 NC NC 08-094 199.63 1.45 684,60 737,33 1.88 08-109 102.29 1.50 561,56 NC 3,12 09-137 151.89 2.25 635,19 767,51 3.07 20-115 224.70 1,22 1114,91 1366,03 2.72 20-138 175.94 4.32 2218,17 2334,99 5.33 20-140 182.32 1.58 659,20 702.28 1.78 20-141 253.29 1,20 888,38 NC 4.75 22-131 184.62 2,12 1020,28 NC 2.96 24-116 315,11 1.53 1145.23 1305,66 2.53 24-130 139.94 4.03 1325,85 1375,38 4.93 N 18 18 18 12 15 Average value 166.91 1.93 948,64 1201,23 3.24 SD 62.75 0.88 579,45 651,50 1,22 CV% 37.59 45.71 61.08 54.24 37.76 min. 68.41 1.03 244.38 531,82 1.78 Median 163.88 1.57 772,07 906,39 2.72 Max. 315,11 4.32 2480,66 2594,62 5.37 Geometric mean 155.27 1.79 816,58 1071,37 3.05 Geometric CV% 42.27 38,50 60,56 51.21 36.76

3. Safety and tolerability:

Dexmedetomidine sublingual film (Example 1 and 2 formulations) was well tolerated and had an appropriate safety profile in subjects with agitation. Tables 21 and 22 present the rates of subjects experiencing at least 1 treatment-emergent adverse event (TEAE) by treatment group for the safety population. A total of 55 subjects (40.7% [55/135]) experienced at least 1 TEAE. The proportions of subjects experiencing TEAEs were similar in the 80 mcg, 120 mcg, and 180 mcg dose groups (55.6%, 66.7%, and 66.7%, respectively). In comparison, the proportion of subjects experiencing TEAEs was lower in the 20 mcg and 60 mcg dose groups (27.8% and 33.3%, respectively) and in the placebo group (22.2%). The majority (81.1%) of TEAEs across all treatment groups were mild in severity. Almost all (90.9%) of TEAEs were considered related to study drug across all treatment groups. No subjects experienced a TEAE that was considered severe in intensity. There were no reports of deaths, SAEs, or discontinuations due to AEs in this study (Tables 21 and 22).

The TEAEs reported in this study were consistent with the known common adverse reactions of dexmedetomidine, namely dry mouth, bradycardia, hypotension, and somnolence (Table 21).

The most common TEAE was somnolence, reported by 26 subjects, of which 20 were mild and 4 were moderate. The incidence of somnolence by group was 16.7% (20 mcg and 60 mcg), 22.2% (120 mcg), 33.3% (80 mcg), and 44.4% (180 mcg); the incidence in the placebo group was 4.4%. The second most frequently reported TEAE was dry mouth, reported by 5.6%, 16.7%, 16.7%, and 11.1% of subjects in the 20 mcg, 80 mcg, 120 mcg, and 180 mcg groups, respectively, compared with 13.3% of subjects in the placebo group. No subjects in the 60 mcg dose group reported dry mouth. All dry mouth events were mild.

In the dexmedetomidine hydrochloride treatment groups, TEAEs associated with vital signs were: hypotension in 6 subjects (n=2 [120 mcg], n=4 [180 mcg]), orthostatic hypotension (n=1 [80 mcg], n=1 [120 mcg], and n=1 [180 mcg]), and bradycardia (n=1 [20 mcg]). These events resolved in all subjects.

Three laboratory adverse events (total bilirubin 3 times the upper limit of normal, urine glucose 3+, and urine protein 4+) were observed at each respective clinical center and remained unresolved at this time. Otherwise, there were no clinically significant laboratory or ECG changes. None of the physical examination findings were considered clinically significant by the investigators. No subject had an adverse local reaction (i.e., local irritation) to study drug, as determined by buccal mucosa examination.

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In addition, dose-dependent reductions in SBP and DBP were observed with maximal changes at 2 h post-dose:

SBP: -4.6 (9.63), -5.6 (10.85), -8.2 (11.50), -12.1 (20.50) and -14.7 (12.09) mmHg in the 20 mcg, 60 mcg, 80 mcg, 120 mcg and 180 mcg groups, respectively, and +1.2 (9.23) mmHg in the placebo group.

DBP: 0.3 (10.39), -5.3 (7.86), -6.4 (8.05), -7.8 (9.40) and -6.6 (6.41) mmHg in the 20 mcg, 60 mcg, 80 mcg, 120 mcg and 180 mcg groups, respectively, and +0.2 (7.82) mmHg in the placebo group.

HR: -0.1 (6.24), -3.9 (9.13), -0.8 (8.39), -2.2 (13.03), and -10.7 (12.97) bpm in the 20 mcg, 60 mcg, 80 mcg, 120 mcg, and 180 mcg groups, respectively, and -0.8 (8.29) bpm in the placebo group.

In addition, measurements of SBP, DBP, and HR in the orthostatic position were performed after the subject stood for 5 min.

Mean changes from baseline to 2 hours post-dose for standing SBP, DBP, and HR are shown below (Figs. 7A, 7B, and 7C). These changes are similar to the changes from baseline in resting SBP, DP, and HR measurements (Figs. 6A, 6B, and 6C). A total of 3 subjects (1 in each of the 80 mcg, 120 mcg, and 180 mcg dose groups) experienced TEAEs of orthostatic hypotension.

Mean (±SD) changes from baseline in standing SBP, DBP, and HR at 2 h post-dose were as follows:

SBP: -3.1 (8.34), -4.6 (9.04), -12.6 (12.83), -11.9 (16.43) and -15.0 (11.3) mmHg in the 20 mcg, 60 mcg, 80 mcg, 120 mcg and 180 mcg dose groups, respectively, and +0.5 (8.35) mmHg in the placebo group.

DBP: -1.4 (6.97), -4.2 (4.78), -6.7 (8.49), -6.9 (7.86) and -7.1 (8.51) mmHg in the 20 mcg, 60 mcg, 80 mcg, 120 mcg and 180 mcg dose groups, respectively, and -1.3 (7.36) mmHg in the placebo group.

HR: 0.6 (7.92), -4.3 (11.87), -1.1 (10.47), -1.7 (13.98), and -10.4 (10.08) bpm in the 20 mcg, 60 mcg, 80 mcg, 120 mcg, and 180 mcg dose groups, respectively, and -0.3 (9.88) bpm in the placebo group.

Table 21. Treatment-emergent adverse events by system organ class and preferred term during treatment period (Safety Evaluable Population)

Organ System Class Preferred Term Placebo (No. 45) Sublingual film with dexmedetomidine 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Any AE 10 (22.2) 5 (27.8) 6 (33.3) 10(55.6) 12 (66.7) 12 (66.7) Nervous system disorders 6 (13.3) 4 (22.2) 4 (22.2) 8 (44.4) 9 (50.0) 9 (50.0) Drowsiness 2(4,4) 3 (16.7) 3 (16.7) 6(33.3) 4 (22.2) 8 (44.4) Headache 2(4,4) 1 (5.6) 0 1 (5.6) 3 (16.7) 0 Dizziness 2(4,4) 0 2(I,1) 1 (5.6) 1 (5.6) 0 Paresthesia 0 0 0 1 (5.6) 1 (5.6) 0 Hypoesthesia 0 0 1 (5.6) 0 0 0 Sedation 0 0 0 0 0 1 (5.6) Gastrointestinal disorders 7 (15.6) 2(11,1) 1 (5.6) 4(22.2) 4 (22.2) 2 (11.1) Dry mouth 6(13.3) 1 (5.6) 0 3 (16.7) 3 (16.7) 2(I,1) Constipation 0 0 1 (5.6) 1 (5.6) 0 0 Diarrhea 0 0 0 0 1 (5.6) 0 Dyspepsia 0 1 (5.6) 0 0 0 0 Nausea 1 (2,2) 0 0 0 0 0 Toothache 1 (2,2) 0 0 0 0 0 Vascular disorders 0 0 0 1 (5.6) z (16.7) 5 (27.8) Hypotension 0 0 0 0 2(I,1) 4 (22.2) Orthostatic hypotension 0 0 0 1 (5.6) 1 (5.6) 1 (5.6)

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Laboratory and instrumental data 3(6,7) 0 1 (5.6) 0 1 (5.6) 1 (5.6) Increased alanine aminotransferase 1 (2,2) 0 0 0 0 0 Increased aspartate aminotransferase 1 (2,2) 0 0 0 0 0 Increased level of bilirubin in the blood 0 0 1 (5.6) 0 0 0 Presence of glucose in urine 0 0 0 0 1 (5.6) 0 Increase in heart rate 1 (2,2) 0 0 0 0 0 Increased liver function tests 1 (2,2) 0 0 0 0 0 Presence of protein in urine 0 0 0 0 0 1 (5.6) Infectious and parasitic diseases 1 (2,2) 0 1 (5.6) 0 1 (5.6) 0 Phlegmon 0 0 0 0 1 (5.6) 0 Nasopharyngitis 1 (2,2) 0 0 0 0 0 Urinary tract infection 0 0 1 (5.6) 0 0 0 Heart disorders 0 0 0 0 1 (5.6) 0 Bradycardia 0 0 0 0 1 (5.6) 0 Musculoskeletal and connective tissue disorders 0 0 0 1 (5.6) 0 0 Pain in the limb 0 0 0 1 (5.6) 0 0

Table 22. Summary of Adverse Events (Safety Evaluation Population)

Category, η (%) Placebo (No. 45) Dose group 20 mcg (No. 18) 60 mcg (No. 18) 80 mcg (No. 18) 120 mcg (No. 18) 180 mcg (No. 18) Any TEAE 10(22.2) 5 (27.8) 6 (33.3) 10 (55.6) 12 (66.7) 12 (66.7) Any treatment-related TEAE 10 (22.2) 4 (22.2) 5 (27.8) 10(55.6) 10 (55.6) P (61.1) Severity of TEAE Light 8 (17.8) 5 (27.8) 5 (27.8) 9 (50.0) And (61.1) 7 (38.9) Average 2 (4.4) 0 1 (5.6) 1 (5.6) 1 (5.6) 5 (27.8) Heavy 0 0 0 0 0 0 Any SAE 0 0 0 0 0 0 Any AE leading to discontinuation of treatment 0 0 0 0 0 0

Abbreviations: AE = adverse events;

TEAE = treatment-emergent adverse event;

SAE = serious adverse event

Percentages are based on the number of subjects. Safety assessment populations in each treatment group. If a subject experienced more than one adverse event in a category, the subject was counted only once in that category.

Conclusion: Dexmedetomidine sublingual film significantly reduced the severity of agitation from baseline as measured by the PEC, CGI-I, and ACES scales in patients with schizophrenia. The primary endpoint was met in the 80 mcg, 120 mcg, and 180 mcg treatment groups as there was a significant improvement in PEC total scores from baseline to 2 hours post-dose with mean changes of -7.3, -9.2, and -10.8 points, respectively, versus -4.5 for placebo. The LSM differences from placebo were -2.9 (P=0.0210), -4.6 (P=0.0003), and -6.3 (P<0.0001) for the 80 mcg, 120, and 180 mcg groups versus placebo. The proportion of responders (i.e., >40% reduction in RES total score) at 2 hours post-dose was significantly higher in the 120 and 180 mcg dose groups (68.8% [P=0.0158]) and 94.4% [P<0.0001], respectively) compared with placebo (31.0%). In addition, changes in secondary efficacy endpoints (i.e., ACES and

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CGI-I) scores at 2 h post-dose were consistent with the RES total score results and indicated improvement in agitation symptoms following treatment with dexmedetomidine sublingual film.

Example 4. A multicenter, randomized, double-blind, placebo-controlled, phase Ib/II, dose-escalating study to investigate the efficacy, pharmacokinetics, and safety of dexmedetomidine hydrochloride sublingual film in dementia-associated agitation

Main objective:

To describe the safety and tolerability of single doses of dexmedetomidine hydrochloride effective in the treatment of acute agitation associated with dementia.

Secondary objective:

1. To describe the onset and magnitude of the calming effect of different doses of dexmedetomidine hydrochloride on symptoms of acute agitation associated with dementia compared with placebo.

2. Describe the duration of the calming effect measured using the PEC and ACES scales.

3. To describe the tolerability and safety profile of dexmedetomidine hydrochloride as measured by adverse events and vital signs compared with placebo.

4. Describe the clinical effects measured by the Clinical Global Impression-Agitation Severity Scale (CGI-S) and then by the Clinical Global Impression-Improvement Scale (CGI-I) after drug administration.

5. Describe the frequency of agitation using the Cohen-Mansfield Agitation Inventory (CMAI) at baseline, 1 hour, and 2 hours post-dose.

6. Determine the approximate dissolution time of films with dexmedetomidine hydrochloride in the sublingual space.

7. Assess local tolerance by examining the buccal mucosa after application of the film with dexmedetomidine hydrochloride.

8. Describe the pharmacokinetics and exposure of dexmedetomidine following lingual administration of a dose of dexmedetomidine hydrochloride.

Methodology.

This is a phase Ib study with an adaptive design. This is a randomized, double-blind, placebo-controlled, multiple-ascending dose study evaluating the efficacy, pharmacokinetics, safety, and tolerability of dexmedetomidine hydrochloride in adult (65 years and older) men and women with acute agitation associated with dementia.

The study will attempt to characterize the safe and tolerable dose range in at least 30 subjects (active agent:placebo randomization is 4:1) per dose level, at each of three dose levels, that produces a calming effect as measured by the Pittsburgh Agitation Scale (PAS) (Table 23).

Three dose levels of 30, 60, and 90 mcg are planned to be evaluated, with the possibility of testing different doses based on tolerability and safety. This design is adaptive because the doses selected for testing may differ from those indicated based on the safety analyses. Doses lower or higher may be selected for testing and repeated up to 180 mcg in each cohort. Dexmedetomidine hydrochloride films may be divided in half if necessary to provide half the dose. With the exception of the first dose cohort (30 mcg), each subsequent dose level will be approved after safety analysis in the cohort of the previous dose level. Dosing may be repeated if persistent or recurrent agitation is not significantly improved (CGI-I score 1 or 2 as very much or much improved) and there are no apparent adverse events. Dosing may be repeated up to two times (in the same Active:Placebo randomisation group) for all cohorts except for the 90 mcg dose which may be repeated only once (for a total of 180 mcg) if necessary, 2 hours after the first dose, but only after a 2-hour assessment and only within 12 hours of the first dose. Patients may be re-dosed only if they are haemodynamically stable, do not have hypotension (diastolic/systolic pressure should be greater than 90/60) and do not have bradycardia (must be greater than 60 bpm).

Patients should also not be re-dosed if they experience orthostatic hypotension (a 20-unit drop in SBP or DBP) or if they experience an AE. This not only determines the individual response to one dose, but also determines whether the subject responds to a second dose and may respond to a higher dose or be classified as a non-responder to dexmedetomidine hydrochloride despite exposure to a higher total dose.

Periodic safety reviews will be conducted on an ongoing basis to review data from all subjects who have been prescribed and administered the medicinal product as data and test results become available. Dose escalation will be permitted unless a safety or tolerability issue becomes apparent during the periodic safety review.

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Patients enrolled in the study at an investigational site are sequentially assigned to the lowest dose cohort (including placebo) and then to an escalating dose cohort. This adaptive, sequential dose escalation design ensures subject safety; the lowest dose cohort completes first, the higher dose cohort completes last. In addition, those subjects assessed as requiring a second dose for efficacy have early evidence of the safety/tolerability of higher doses because they are effectively exposed to doses that approximate the next dose cohort. Most patients will be enrolled and assessed in lower dose cohorts before the higher dose cohort is completed. In addition, if intolerance data are obtained from an analysis combining pharmacokinetics, exposure, and safety/tolerability across all subjects and doses, the dosing regimen can be modified or a different dose can be selected to test the hypothesis that a (usually lower) dose regimen is better tolerated. Eligible patients (with any type of dementia) were identified in SNIFF, mental health settings, psychiatric clinics, or emergency medical services, including medical/psychiatric observation units, and could be newly admitted to hospital with acute agitation or already hospitalized for chronic comorbidities. Subjects will likely remain in their primary care facility while undergoing screening procedures to assess eligibility. Once eligibility is confirmed, subjects will be randomized to receive dexmedetomidine hydrochloride film or placebo film. At the beginning of each study session, the patient will administer a single dose of dexmedetomidine hydrochloride film sublingually, receiving, where possible, instructions from an unblinded staff member who will not be involved in the assessment of safety or efficacy. The film will remain in the sublingual cavity until it dissolves. Participants will also be assessed for local irritation around the area where the film will be placed. Efficacy and safety assessments will be conducted periodically before and after dosing. The next cohort will be dosed after enrollment in most of the previous panels has been completed, consistent with regular ongoing periodic safety and pharmacokinetic reviews as eligible subjects are treated, dosed, and data become available.

Vital signs and ECG will be assessed at the time points specified in the Procedure Schedule. Participants will be allowed to drink water ad libitum 15 minutes after completion of dosing. Safety and tolerability assessments will be performed until the morning of Day 3 (discharge day) and will be repeated on Day 7+2. Smoking will be permitted in accordance with study site protocol. Following completion of the 4-hour assessment, rescue therapy may be initiated at the discretion of the PI with standard treatment, which may include lorazepam 0.5-5 mg PO/IM or antipsychotics PO/IM.

Appropriate studies will be repeated if any abnormal vital signs, clinical laboratory tests, physical examination findings, or ECG parameters are determined by the investigator to be clinically significant, including test results obtained on the last day of the study or upon early termination of the study. Any abnormal test result determined to be clinically significant will be re-analyzed during the observation period and until the value returns to baseline (or within normal limits) or until the investigator deems the abnormality to be no longer clinically significant. Subjects with clinically significant urinary tract infection (UTI) confirmed by clinical laboratory test results will be excluded from the study.

Performance ratings:

Efficacy analysis will be performed up to and including 24 hours after the first dose. The effects of dexmedetomidine hydrochloride on acute agitation will be assessed using the following scales: Pittsburgh Agitation Scale (PAS), PANSS-EC (PEC), CMAI, CGI-Agitation Severity, and CGI-Agitation Improvement. If no significant improvement is observed on the CGI scale (CGI-I score of -1 or 2 as very much or much improved) and there are no obvious safety concerns, a second film (with the same active substance versus placebo) may be administered.

Safety and tolerability assessments:

AEs, clinical laboratory tests, ECG, and vital signs will be monitored, and all observed and self-reported AEs will be recorded. Blood pressure, heart rate, and ECG assessments will be performed according to the assessment schedule. Any assessment with a clinically significant (as determined by the investigator) abnormal vital sign, clinical laboratory test, physical examination result, or ECG parameter will be repeated until the value returns to baseline (or within normal limits) or until the investigator deems the abnormality to be of no clinical significance. Orthostatic assessments will be performed according to CDC recommendations for older adults (e.g., 1- and 3-min standing blood pressure). Assessment

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Groups Intervention Active comparator: Cohort 1: 30 mcg Cohort 1 consists of 10 patients, of which 8 patients receive 30 mcg film and the remaining 2 patients receive placebo. Sublingual film containing dexmedetomidine hydrochloride for the treatment of agitation associated with dementia Product: Placebo film Placebo film for dexmedetomidine hydrochloride Active comparator: Cohort 2: 60 mcg Cohort 2 consists of 10 patients, of which 8 patients receive 60 mcg film and the remaining 2 patients receive placebo. Product: Sublingual film containing dexmedetomidine hydrochloride for the treatment of agitation associated with dementia Product: Placebo film Placebo film for dexmedetomidine hydrochloride Active comparator: Cohort 3: 90 mcg Cohort 3 consists of 10 patients, of which 8 patients receive 90 mcg film and the remaining 2 patients receive placebo Product: Sublingual film containing dexmedetomidine, hydrochloride for the treatment of agitation associated with dementia Product: Placebo film Placebo film for dexmedetomidine hydrochloride

Number of subjects (planned)

At least 30 subjects (10 per cohort) will be enrolled at 3 study sites in the United States. However, it is possible that the sponsor may decide to increase the number of sites and subjects per dose cohort (up to a total of 80 patients) as the study progresses.

Subjects:

Eligible individuals with any form of dementia who have a recent history of agitation (6 months or less) or their legally authorized representative (LAR) will sign informed consent. Once eligibility is confirmed, subjects will be randomized to receive dexmedetomidine hydrochloride sublingual film or placebo film. Ten (10) subjects with acute dementia-associated agitation will be included in each cohort (4:1 randomization; eg, eight dexmedetomidine hydrochloride sublingual films, two placebo films). Once subjects become agitated, they will be assessed on Day 1.

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Table 24. Schedule of procedures

Activity Prescreening ⁸ Screening Before the dose is administered Treatment Evaluation, Day 1 Day 2J observation (+1) Day 3, discharge Day 7 (+2) Moment in time Before treatment Before treatment -1 hour before time 0 5 m i n 10 m i n 15 m i n 30 m and n 1 h 2 h 4 h 6 h 8 h 24 h (-9/+12 pm) End of study Informed consent X Medical history X X Demographic data X X Body weight X X Height X Mini-Mental State Examination X X Clinical Dementia Rating Scale X X Physical examination X X X Lab. safety research ³ X X X UTI and pregnancy X

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ECG with rhythm strip ⁷ X X X X Pulse oximeter X X X X X X X X Resting vital signs ² X X X X X X X X X X Vital Signs in Orthostatic Position ² X X X X X X X X X Inclusion/exclusion criteria X X X Randomization X CMAI X X X X X X X Administration of study drug ⁶ X PAS X X X X X X X X X X X RES X X X X X X X X X X ACES X X X X X CGI-severity of agitation X X X CGIImprovement/change in agitation X X X X X C-SSRS X X X Score of buccal mucosa (SL) ⁵ X X X X X X X Taking samples for RK ⁴ X X X * X X X Accompanying- X X X X X X X X X X X X X X X drugs Adverse events X X X X X X X X X X X X X X X

Notes on the procedure schedule:

1. Pre-dose assessments had a window of 60 min before the first dose. If possible, pre-dose CMAI assessment should be completed within 45 min before dose, and PAS, PEC, and CGI-S assessments should be completed within 15 min before dose. The timing of all subsequent assessments is relative to the first dose. All post-dose assessments will have a window of -10/+20 min to 2 h and ±30 min to 8 h. All post-dose efficacy assessments should be completed before any other assessments at each time point.

2. Resting vital signs (SBP, DBP, and HR) will be measured after the subject has been lying down for 5 min during prescreening, screening, predose, and at 30 min, 1, 2, 4, 6, 8, and 24 hours after the first dose. Triplicate measurements will be taken if systolic BP<90 mmHg, diastolic BP<60 mmHg, or pulse <60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate, and temperature) will be taken at 1 and 3 min after the subject assumes the upright position (consistent with CDC recommendations for older adults), prescreening, screening, predose, and 30 min, 1, 2, 4, 8, and 24 h after the first dose. Vital signs should be assessed prior to PK specimen collection.

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3. Laboratory parameters for safety analysis will include biochemistry, hematology, urinalysis, and UDS (at a local lab, during prescreening only). Samples collected in the lab within 28 days prior to dosing may be sufficient, with the exception of urine drug screening.

4. Blood samples for PK analysis will be collected at 30 min, 1, 2, 4, 8-10 h (one sample collected between 8 and 10 h), and 24 h after the first dose. A sample may be waived if the physician indicates in the initial documentation that the patient is in a mental state that does not support the collection of a PK sample. Non-consent or refusal of all or any PK sample collections will not be restrictive and will not result in early termination (ET). All PK sample collections will have a window of ±10 min, except for the 24 h post-dose time point, which will have a window of ±1 h. *For repeat-dose subjects only: a PK sample will be collected at 2.5 h after the first dose in addition to the other time point collections.

5. Inspection of the buccal mucosa for local irritation and drug dissolution time will be performed by unblinded personnel at 5, 10, 15, 30 min, 2, 4 and 24 hours after the first dose.

6. Based on the clinical judgment of the investigator, the same randomized dose or a lower dose may be repeated 2 hours after completion of the first dose assessment, in the event of persistent or recurrent agitation as measured by the scale (improvement in CGI-I score) and in the absence of safety concerns. Dosing may be repeated twice within 12 hours, except for the 90 mcg cohort, which may only be repeated once. If necessary, placement of study drug in the patient's mouth may be performed by unblinded study center personnel. Administration of antihypertensive or other medications may be delayed on the day of study drug administration at the discretion of the PL.

7. A pre-dose ECG should be recorded, but if it cannot be assessed, this will not constitute a protocol deviation. Post-dose ECGs should be performed before pharmacokinetic assessment.

8. Day 1 procedures must be completed within 28 days of the prescreening assessments. If a subject does not become agitated within the 28-day window, the subject is considered a prescreening failure. However, the subject may be rescreened once at the discretion of the investigator.

Diagnosis and main eligibility criteria:

Inclusion Criteria

1. Male and female patients 65 years of age and older.

2. Patients meeting DSM-5 criteria for neurocognitive disorder or dementia with a history of acute agitation.

3. History of agitation to the extent that it impairs social functioning, requires personnel or medical intervention (kicking, biting, flailing, etc.), or impairs the ability to perform functional activities of daily living.

4. Patients who meet the IP A diagnostic criterion for agitation.

5. Patients assessed as having clinical agitation at pre-dose with a total score > 8 on 4 items (aberrant vocalization, motor agitation, aggression, and resistance to care), including the Pittsburgh Agitation Scale (PAS).

6. Patients with a score > 2 on at least 1 of 4 items on the Pittsburgh Agitation Scale (PAS).

7. Patients who have read, understood and provided written informed consent or who have a legally authorized representative (LAR).

8. Patients in good general health prior to study entry, as determined by a detailed medical history, physical examination, 12-lead ECG, blood chemistry profile, hematology data, urinalysis, and the principal investigator's opinion.

9. Female participants if they are of childbearing potential and sexually active, and male participants if they are sexually active with a partner of childbearing potential, who agree to use a medically acceptable and effective method of birth control throughout the study and for one week thereafter. Medically acceptable methods of contraception that a participant and/or his/her partner may use include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppositories, surgical sterilization, and progestin-only implant or injection. Prohibited methods include the calendar method, withdrawal, condom only, or diaphragm only.

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Exclusion criteria

1. Patients with agitation due to acute intoxication should be excluded. The detection of over-the-counter drugs on urine screening excludes the subject.

2. Patients treated with benzodiazepines, other sedatives, hypnotics, or oral or short-acting intramuscular neuroleptics within 4 hours prior to study drug administration should be excluded.

3. Treatment with alpha-1-noradrenergic blockers, alpha-adrenergic blockers within 8 hours before dosing.

4. Patients who started taking any new long-term medications within the last 14 days prior to screening, with the exception of over-the-counter drugs taken sporadically, should be excluded.

5. Patients at significant risk of suicide or homicide as assessed by the investigator or any patient with a yes answer to items 4 or 5 on the CSSRS.

6. Patients with a history of hydrocephalus, seizure disorder, or severe head injury, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, or focal neurologic symptoms, recent major (non-microvascular) stroke, and who are medically unstable or in recovery should be excluded. Patients with a remote history of stroke may be included regardless of lesion size/location.

7. Patients with a history of clinically significant syncope or other syncopal attacks, orthostatic hypotension within the last two years, existing signs of hypovolemia, orthostatic hypotension (decrease in systolic BP by >20 mmHg after 1 and 3 minutes of standing) and bradycardia with a baseline (pre-dose) heart rate <60 beats per minute or systolic blood pressure <110 mmHg or diastolic BP <70 mmHg should be excluded.

8. Patients with laboratory or ECG abnormalities deemed clinically significant by the investigator or designee [progressive heart block (second-degree atrioventricular block or higher without pacemaker), diagnosed sick sinus syndrome] that may have clinical consequences for the patient's participation in the study should be excluded.

9. Patients with serious or unstable or uncontrolled medical conditions should be excluded. These include pre-existing hepatic (moderate to severe liver failure), renal, gastrointestinal, respiratory, cardiovascular (including ischemic heart disease, congestive heart failure), endocrinological, or hematological diseases.

10. Patients who received the study drug within 30 days prior to the current episode of agitation should be excluded.

11. Patients who the investigator considers for any reason to be unsuitable candidates for dexmedetomidine or unable to use the sublingual film should be excluded, for example, patients with a history of allergic reactions to dexmedetomidine should be excluded.

12. Patients experiencing clinically significant pain, according to the investigator.

Methodology for assigning subjects to treatment groups

Once eligibility is confirmed, subjects will be randomized to receive dexmedetomidine hydrochloride film or placebo film. In each of the three-dose cohorts, 10 participants (8 treated, 2 placebo) will be randomized to receive dexmedetomidine hydrochloride film or placebo in a 4:1 ratio. Randomization in the study will be computer-generated.

Administration of the drug

Administration of the desired dose can be accomplished by cutting the film widthwise straight down the middle to obtain a half dose. Administration of the desired dose can be accomplished by administering 1 to 3 films [e.g., a 60 mcg dose can be administered with half a 60 mcg dose (30 mcg) to obtain a 90 mcg dose]. At the beginning of each session in the study, subjects will be instructed on how to self-administer the study product. If the subject is self-administering, he/she will self-administer the dexmedetomidine hydrochloride dose or placebo film sublingually under the supervision of an unblinded staff member who will not be involved in the assessment of safety or efficacy. The study product will remain in the sublingual cavity until dissolved. If sublingual administration is not possible, the film can be placed behind the lower lip. The location of film placement should be noted on the subject's chart. An objective examination of the buccal mucosa will be performed by unblinded center personnel and the film dissolution time will be recorded in accordance with Table 24.

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Research procedures

Subjects or their LARs will provide written informed consent and incompetent assent, if applicable, prior to any study-related procedures, including discontinuation of prohibited concomitant medications. The schedule of procedures to be performed during the study is provided in Table 24.

Estimates in the study

Efficacy: The effect of the study drug will be assessed using several validated instruments as described below.

PANSS-Excitation Component (RES)

Agitation and Calmness Evaluation Scale (ACES)

Cohen-Mansfield Agitation Inventory (CMAI):

The effect of the drug on the frequency of acute agitation will also be assessed using the CMAI. The CMAI is a rating questionnaire consisting of 29 behaviors, each rated on a 7-point frequency scale. It is possible that all 29 behaviors will not be relevant to a particular patient. Only the behaviors exhibited by the subject at baseline will be assessed throughout the study, resulting in a modified CMAI score. Behaviors present immediately before dosing will be assessed at all post-dose time points. At each post-dose time point, the assessor will note items (behaviors) that were not present before dosing and have not recurred since the last CMAI assessment. If they occur, these items should be included in the ratings.

Pittsburgh Agitation Scale (PAS):

The Pittsburgh Agitation Scale (PAS) is a direct observational instrument designed to monitor the severity of agitation associated with dementia. The patient is assessed in four behavior groups (scaled from 0 to 4): aberrant vocalization, motor agitation, aggression, and resistance to care.

CGI-S and CGI-I for agitation:

The CGI-I and CGI-S scales will focus on the severity of agitation rather than the overall severity of dementia.

The Clinical Global Impression of Severity (CGI-S) will be assessed based on the severity of agitation at screening and pre-dose (immediately before dosing).

The severity of agitation is assessed using the following scale:

= Not rated = Normal, no symptoms at all = Minimal symptoms: few or mild symptoms, little impairment of patient functioning = Mild symptoms: low level of symptoms, little impairment of social functioning = Moderate symptoms: some severe symptoms, some impairment of functioning = Severe symptoms: severe symptoms with very significant impairment of functioning = Severe symptoms: very severe symptoms that prevent patients from interacting with others = Extremely symptomatic: extremely severe symptoms, patient is incapacitated or very dangerous to self or others, requires special care and observation

The effect of the drug on agitation will be assessed using the Clinical Global Impression-Improvement (CGI-I) scale at post-dose and compared to pre-dose agitation at baseline. CGI-I scores range from 1 to 7:

= not rated (absent), 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse

Clinical diagnosis and description of dementia

The dementia subtype will be determined and recorded based on a clinical neurological and psychiatric assessment, including review of all available medical information, medical records, documentation of previous assessments, family/caregiver interview, records, laboratory, genetic or other biomarkers, and neuroimaging results (if available). The following scales will characterize the subject's dementia (DSM-5 major neurocognitive disorder) in terms of cognitive and functional impairment:

MMSE

The Mini-Mental State Examination (MMSE) is an instrument used to assess cognitive abilities in older adults. The domains measured

- 119 047684 The MMSE measures orientation in time and place, memorization, attention and counting, recall, naming, repetition, comprehension, reading, writing, and drawing. The total score for this test is 30. Any score of 24 or higher (out of 30) indicates normal cognitive function. Scores below this value may indicate severe (<9 points), moderate (10-18 points), or mild (19-23 points) cognitive impairment.

CDR®

The CDR® (Center for Alzheimer's Disease Research, Washington University, St. Louis) is a 5-point scale used to characterize six domains of cognitive and functional performance relevant to Alzheimer's disease and related dementias: memory, orientation, judgment and problem solving, social activities, home and hobbies, and self-care. A score of 0 indicates no cognitive impairment, and the remaining four scores refer to different stages of dementia, with:

CDR-0 = normal

CDR-0.5 = very mild dementia

CDR-1 = mild dementia CDR-2 = moderate dementia CDR-3 = severe dementia.

Safety

Safety will be assessed during the study by monitoring and recording adverse events, clinical laboratory test results (hematology, biochemistry, and urinalysis), vital sign measurements (systolic and diastolic blood pressure, heart rate measured as pulse, respiratory rate, and temperature), ECG, and physical examination results.

Adverse events (AEs) will be characterized by type, severity, seriousness, and relationship to treatment. AEs will be coded by the preferred term and system organ class using MedDRA version 20.0.

Pharmacokinetics

Blood samples (4 ml) will be collected at 0.5, 1, 2, 4, 8 and 24 hours post-dose according to the Procedure Schedule (Table 24).

For each subject, up to 6 blood samples (24 mL of blood) will be collected during the study for pharmacokinetic analysis. In addition, approximately 15 mL of blood will be collected at Screening, approximately 15 mL of blood will be collected on Day 3 Discharge, and approximately 15 mL of blood will be collected on Day 7(+2) for clinical laboratory testing. The total volume of blood collected during the study is expected to be approximately 69 mL.

For repeat-dose subjects only: An additional PK blood sample (4 mL) will be collected 2.5 hours after the first dose in addition to the other time points, for a total of approximately 73 mL. All PK sample collections will only occur after all other assessments have been completed at that time point.

Pharmacokinetic analyses

All pharmacokinetic parameters will be calculated using non-compartmental analysis using WinNonlin software. Actual sampling time will be considered in all pharmacokinetic analyses. Protocol time will be considered for calculation of mean plasma concentrations for graphical display. Other PK analyses may be performed as needed.

Example 5. A multicenter, randomized, double-blind, placebo-controlled, dose-ascending, phase Ib/II study to investigate the efficacy, pharmacokinetics, and safety of dexmedetomidine hydrochloride sublingual film for the treatment of acute opioid withdrawal symptoms in patients with opioid-related psychiatric disorder who are physically dependent on opioids.

Main objective:

To establish the safety and tolerability of escalating doses of dexmedetomidine hydrochloride sublingual film compared with placebo in subjects with opioid use disorder who are physically dependent on opioids and maintained on oral morphine.

Secondary objectives:

To establish the efficacy of dexmedetomidine hydrochloride sublingual film compared with placebo in improving the following parameters:

1. Opioid withdrawal symptoms:

Short Opioid Withdrawal Scale-Gossop (SOWS-Gossop) and

Clinical Opioid Withdrawal Scale (COWS)

2. Time to study dropout after opioid cessation

3. Percentage of subjects who dropped out of the study after stopping opioids

4. Safety assessment reflected in the Agitation and Emotional Stability Scale (ACES) score

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Purpose: To evaluate pharmacokinetics in patients who have experienced opioid withdrawal syndrome.

Study Design: This inpatient, Phase 1b study will evaluate the safety, pharmacokinetics, and early signs of efficacy of dexmedetomidine hydrochloride sublingual film dose escalation compared with placebo after cessation of morphine maintenance therapy. The opioid maintenance phase will occur on Study Days 1-5; the dexmedetomidine hydrochloride sublingual film/placebo randomized phase will occur on Study Days 6-12. These phases will be followed by 2 days of sublingual placebo (for dexmedetomidine) and morphine-placebo treatment for all remaining subjects on Days 13-14.

Following a 30-day screening period, eligible adult male and female subjects with OUD who are physically dependent on opioids will be admitted to an inpatient unit. At the start of the opioid maintenance phase (Study Days 1-5), subjects (n=125 participants) will receive oral morphine (30 mg) four times daily (qid) approximately every 6 hours or up to 5 times daily as needed. The total morphine dose during the first two stabilization days (Study Days 1-2) may vary at the discretion of the investigator from 120 to 150 mg daily depending on the patient's history of abuse and the need for a higher dose to stabilize withdrawal symptoms. For the next three days (Study Day 35), all subjects will receive the standard dose of morphine (30 mg qid) for a total of 120 mg daily. In addition, all subjects will receive placebo films at approximately 12 hour intervals during this opioid maintenance phase (i.e., Days 1-5) to simulate and thus blind the dexmedetomidine sublingual film treatment on Days 6-12.

Beginning on the morning of Day 6, blinded abrupt discontinuation of active morphine begins with replacement of active morphine with morphine placebo. Placebo morphine capsules are identical in appearance to the morphine capsules taken during opioid maintenance therapy. On this day (Study Day 6), subjects will be randomized (in each cohort, 20 subjects will receive active dexmedetomidine sublingual film and 5 subjects will receive placebo) to receive either placebo or dexmedetomidine hydrochloride films administered twice daily (BID), approximately 12 hours apart, at approximately 8 a.m. and 8 p.m. Placebo sublingual film or dexmedetomidine sublingual film will be administered on Days 6–12. On Days 13 and 14, all remaining subjects will receive placebo morphine capsules (4 times daily) and placebo sublingual films (2 times daily).

A total of 5 cohorts are expected to be tested (n=25 per cohort), with the possibility of adding cohorts or selecting other doses/schedules based on ongoing safety analysis and clinical monitoring. Doses will be: 30 mcg (Cohort 1), 60 mcg (Cohort 2), 90 mcg (Cohort 3), 120 mcg (Cohort 4), and 180 mcg (Cohort 5). Safety and tolerability will be continually monitored and summarized following completion of dosing in each cohort and clinical safety analysis. Opioid withdrawal studies with placebo arms are likely to have high dropout rates, so subjects who drop out before Day 6 may be replaced to ensure a sufficient sample size moving into the treatment phase. The study is designed to be flexible and adaptable, so the dosing frequency, doses, and number of cohorts receiving dexmedetomidine hydrochloride sublingual film may be modified based on analysis of safety, tolerability, and efficacy data.

Opioid withdrawal symptoms (SOWS-Gossop and COWS) will be measured throughout the inpatient period pre-admission, 2 hours post-admission, pre-2nd dose, and 2 hours post-2nd dose. Additional scales/SOWS-Gossop/COWS may be used at the discretion of the investigator. Transition to opioid use disorder treatment will be completed before patients leave the unit.

Vital signs, SOWS-Gossop, COWS, pulse oximetry, and electrocardiogram (ECG) with rhythm strip will be measured according to the assessment schedule (Table 25). Sublingual film with dexmedetomidine or placebo will be self-administered sublingually by the patient under observation, and subjects will be allowed to drink fluids as desired 15 minutes after completion of the dose. Safety and tolerability assessments will be performed until the morning of Day 14 (the day of discharge).

Appropriate studies will be repeated if any abnormal vital signs, clinical laboratory tests, physical examination data, or ECG parameters are determined by the investigator to be clinically significant, including test results obtained on the last day of the study or at early termination of the study. Any test result abnormality determined to be clinically significant will be re-analyzed during the observation period and until the value returns to baseline (or within normal limits) or until the investigator deems the abnormality to be stable and no longer of clinical concern.

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Diagnosis and main eligibility criteria:

Inclusion Criteria

1. Men and women aged 18 to 65 years.

2. Meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for moderate to severe opioid use disorder and confirm the disorder according to the Brief International Manual of Neuropsychiatric Interview (MINI) with physiological dependence, as evidenced by a clinical opioid withdrawal syndrome (COWS) score > 5 or a positive naloxone test on admission on Day 1.

3. Subjects who are able to read, understand and sign written informed consent.

4. Women of childbearing potential must have a negative pregnancy test result and agree to abstain or use an acceptable method of contraception during the study.

Exclusion criteria

1. A positive urine pregnancy test during screening or testing or breastfeeding.

2. History of clinically significant cardiac disease, heart rate <55 beats per minute or systolic blood pressure <110 mmHg or diastolic blood pressure <70 mmHg at screening and baseline.

3. A current or past significant clinical disease or disorder that, in the opinion of the investigator, increases the risk or may complicate the interpretation of the study parameters, as evidenced by the results of screening laboratory tests.

4. Liver dysfunction (demonstrated by ascites or bilirubin level >10% above the upper limit of normal [ULN] or liver function tests >3 x ULN) at the screening visit.

5. Acute active hepatitis B or C confirmed by a positive serologic test and aspartate aminotransferase (AST)/alpha-aminotransferase (ALT) level >2 x ULN.

6. Clinically significant ECG abnormalities such as second or third degree heart block, uncontrolled arrhythmia, or QTc interval > 450 ms for men and > 470 ms for women at screening or pre-dose.

7. Any mental disorder that compromises the ability to perform research procedures.

8. Currently meets DSM-5 criteria for moderate to severe substance abuse disorder for any substance other than opioids, caffeine, or nicotine.

9. History of suicidal behavior within the last 1 year prior to screening.

10. Participation in a clinical trial of a non-FDA-approved drug within 30 days prior to screening.

11. Use of any excluded drugs at screening or expected/mandatory use during the study period.

12. Subjects with a history of morphine intolerance.

13. Any findings that, in the opinion of the Principal Investigator, would compromise the subject's ability to comply with the visit schedule or visit requirements of the protocol.

Treatment under investigation

Study drug, dose and route of administration:

Sublingual film with dexmedetomidine hydrochloride 30, 60, 90, 120 and 180 mcg in the form of a dexmedetomidine composition in the form of a thin film for sublingual (SL) administration. The drug is a composition in a small-sized solid dosage film form, intended for complete dissolution in the SL space within 1-3 minutes.

Reference therapy, dose and route of administration:

Corresponding placebo films for sublingual administration as described above.

Duration of treatment:

mg 4 times a day or 5 times a day morphine and placebo (dexmedetomidine) sublingual film: 5 days;

Sublingual film dexmedetomidine hydrochloride 2 times a day or sublingual film placebo and morphine placebo: 7 days, sublingual film placebo (dexmedetomidine) and morphine placebo: 2 days.

Research procedures

Subjects will provide written informed consent prior to any study-related procedures, including discontinuation of prohibited concomitant medications.

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Table 25. Schedule of visits and assessments

Inpatient treatment (14 days) Screening ¹ Morphine maintenance therapy Detoxification Observation for one week Randomization and first day of treatment Treatment phase Post-treatment phase or ET Day From -2 to -1 Day 1-5 Day 6 Day 7 - 12 Day 13 - 14 Day 21 (± 3 days) Administration of Naloxone ² X Informed consent X Inclusion/Exclusion Criteria ⁵ X X Mini Brief International Manual for the Neuropsychiatric Interview (MINI) X Columbia University Suicide Severity Rating Scale (C-SSRS) X Randomization (Day 6) X Demographic data X

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Medical and psychiatric history X Concomitant drug therapy X X X X X X Physical examination and 12-lead ECG ⁴ X X X X X Lab. security research X X X Vital Sign Measurements ⁵ X X X X X X Buccal mucosa assessment SL ⁶ X X X X Rapid urine pregnancy test ⁷ X X AE Monitoring X X X X X X Urine Toxicology/BAL ⁸ X X X X X Retrospective timeline X X Pharmacokinetics ⁹ X _x w SOWS & Cows ¹¹ X X X X X Morphine administration Sublingual dexmedetomidine film administration or placebo ¹² X X X Morphine placebo administration ¹³ X X Administration of sublingual placebo film (for dex) and morphine placebo X Agitation and Calmness Evaluation Scale (ACES) ¹⁴ X X X

Notes:

1. All procedures must be completed before randomization of subjects and within 30 days after signing informed consent.

2. Subjects may be given a naloxone challenge on admission if no withdrawal signs/symptoms are present. If naloxone is administered, subjects may receive morphine to alleviate opioid withdrawal symptoms that may be present at the end of the challenge.

3. Inclusion/exclusion criteria were assessed at screening and prior to dosing on Randomization Day 6.

4. An ECG will be recorded at Screening, before the morning dose of sublingual film placebo (dex) on Days 1-5, before the dose on Day 6, and on Days 13-14.

5. Vital sign measurements will include orthostatic blood pressure, pulse, and oxygen saturation measurements. These will be recorded once daily on Days 1-5, before each dose on Days 6-12, and once daily on Days 13 and 14.

6. Inspection of the buccal mucosa for signs of local irritation will be performed 30 min after the first dose on Days 1, 6, and 12. Inspection of the buccal mucosa will be performed before discharge on Day 14. Additional inspection of the buccal mucosa may be performed at the discretion of the investigator or in the event of an appropriate adverse event.

7. During screening, a rapid urine pregnancy test will be performed. As part of inpatient treatment, a rapid urine pregnancy test will be performed on Day 1 of the study.

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8. Urine drug screening will include testing for opioids (fentanyl), buprenorphine, methadone, benzodiazepines, cocaine (benzoylecgonine), amphetamines, and other drugs of abuse. Breath alcohol levels (BAL) will be assessed at screening, Day 1, and follow-up.

9. Blood samples for pharmacokinetic analyses will be collected only on Days 6 and 12 of the inpatient phase of the study at 0, 2, 6, and 12 hours after the first dose of dexmedetomidine sublingual film for the day. The 12 hour sample will be collected immediately prior to the next dose of dexmedetomidine sublingual film or placebo sublingual film (for dexmedetomidine). A window of +/- 5 minutes per PK sample will be allowed without protocol deviation.

10. PK samples will be collected on Day 12 at the scheduled time only.

11. COWS and SOWS-Gossop assessments will be performed pre-dose, 2 hours post-dose, pre-dose 2, and 2 hours post-dose 2. Additional assessments may be performed at the discretion of the investigator.

12. Sublingual film administration of dexmedetomidine or placebo will be performed twice daily (approximately 8:00 AM and 8:00 PM [+/- 30 min]). On Days 1-5, subjects will receive placebo (dex) sublingual films approximately 12 hours apart in addition to morphine treatment.

13. Placebo morphine will be administered at approximately the same time as on Days 1-5.

14. The Agitation and Calmness Scale (ACES) assessment will be performed approximately two hours after (-5/+15 min) the sublingual dose of dexmedetomidine or placebo (at approximately 10:00 and 22:00).

Evaluation criteria:

Efficacy assessment: To determine the preliminary efficacy of sublingual administration of dexmedetomidine hydrochloride sublingual film in the target patient population compared with placebo, as measured by improvement in peak SOWS-Gossop scores.

The effect of the study drug will be assessed using several validated instruments as described below.

Brief Gossop Opioid Withdrawal Scale (also -Gossop)

The SOWS-Gossop is a 10-item patient questionnaire designed to measure withdrawal symptoms in opioid-dependent subjects (Gossop, 1990). Each of the 10 items represents a symptom: Feeling Nausea, Abdominal Cramps, Muscle Spasms/Twitching, Feeling Cold, Palpitations, Muscle Tension, Pain and Discomfort, Yawning, Watery Eyes, and Insomnia/Trouble Sleeping. Subjects rate the severity of each symptom over the past 24 hours by selecting None, Mild, Moderate, or Severe.

The SOWS-Gossop total score ranges from 0 to 30, with higher scores indicating greater severity of withdrawal symptoms.

The Clinical Opioid Withdrawal Scale (COWS) is an 11-item questionnaire designed to measure a patient's level of withdrawal (Wesson and Ling, 2003). Symptoms assessed include resting pulse rate, sweating, restlessness, pupil size, bone or joint pain, runny or watery nose, gastrointestinal upset, tremor, yawning, anxiety or irritability, and goose bumps. The COWS total score ranges from 0 to 48; 5 to 12 points are mild, 13 to 24 are moderate, 25 to 36 are moderately severe, and more than 36 are severe withdrawal

Safety and tolerability assessments:

To assess tolerability, COWS, SOWS-Gossop scores, adverse events (AEs), clinical laboratory test results, ECG with rhythm strip, pulse oximetry, and vital signs will be monitored. ACES will also be assessed as a safety measure. All observed and voluntarily reported AEs will be recorded. The relationship of AEs to study drugs will be defined by the investigators as unrelated, unlikely/remotely related, possibly related, probably related, or definitely related. Vital signs, including systolic blood pressure (SBP), diastolic blood pressure (DBP), orthostatic blood pressure, heart rate, and oxygen saturation, will be measured daily throughout the study.

The site of application of SL (the buccal mucosa) will also be examined for signs of local irritation.

Additional ratings:

Demographic data

Medical and psychiatric history

Pre- and concomitant therapy

Physical examination

Suicidality

Pregnancy

Pharmacokinetics

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Blood samples (4 mL) will be collected at 0, 2, 6, and 12 hours after administration of the first dose of dexmedetomidine hydrochloride sublingual film on Study Days 6 and 12. The 12 hour sample will be collected immediately prior to administration of the next dose of dexmedetomidine sublingual film or placebo.

Statistical analysis

Primary outcome: Safety and tolerability of escalating doses of dexmedetomidine hydrochloride sublingual film in subjects with OUD who are physically dependent on opioids.

Secondary outcomes:

1) Peak SOWS-Gossop score on Days 6-14.

2) Peak COWS score on Days 6-14

3) Average COWS scores per day for Days 6-14 (the average will be calculated for each day to assess the progression of withdrawal symptoms over time).

4) Average SOWS-Gossop scores per day on Days 6-14.

5) Time to withdrawal after discontinuation of morphine maintenance therapy (Days 6-14).

6) Percentage of subjects who dropped out after discontinuing opioid maintenance therapy in each treatment group between Days 6-14

7) General agitation and sedation will be assessed using ACES.

Efficiency analyses

Main analyses: Following the morphine maintenance phase, treatment differences between dexmedetomidine hydrochloride sublingual film and placebo in peak SOWS-Gossop scores on Days 6–14 will be analyzed using linear regression or a mixed-effects model for repeated measures [MMRM]. Treatment differences between dexmedetomidine sublingual film and placebo in peak SOWS scores on Day 7 (two days after opiate cessation) and in peak SOWS scores on Days 6 and 14 will be analyzed. The intention-to-treat set, consisting of all patients who received any study medication and had both a baseline assessment and at least 1 postdose efficacy assessment, will be analyzed.

Secondary analyses: Each peak COWS score on Days 6-14 will be compared between the dexmedetomidine hydrochloride sublingual film and placebo groups using linear regression or MMRM. Time to dropout after discontinuation of morphine maintenance therapy will be analyzed using a Cox proportional hazards model. Kaplan-Meier estimates will also be used to construct survival curves over time in each treatment group. A logistic regression model will be used to compare the dexmedetomidine hydrochloride sublingual film and placebo groups in the number of subjects who dropped out after opioid cessation. Lists of subjects who withdrew from the study due to AEs, serious AEs, and/or death or lack of response will be presented. Laboratory parameters will be summarized by treatment using descriptive statistics and fact sheets of clinically significant abnormalities. Vital signs and ECG data will be summarized for changes from baseline using descriptive statistics. The Chi-square test (or Fisher's exact test) will be used to compare the incidence of AEs or serious AEs related to blood pressure, heart rate, or respiratory activity between dexmedetomidine hydrochloride sublingual film and placebo at baseline on Day 6 and then daily for the remainder of the study.

Pharmacokinetic analyses

A separate SAP for pharmacokinetic analysis will be prepared for the study and completed prior to database lock. Data from subjects who participated in the study will be included in the pharmacokinetic analysis. Subjects with missing sample concentrations will be included in the pharmacokinetic analysis provided that their pharmacokinetic parameters can be adequately characterized based on the available data.

Safety analyses

Safety data will be analyzed for all subjects who received at least 1 dose of study drug. The number and percentage of subjects with 1 or more AEs will be summarized by treatment, relationship to study drug, and severity. All AEs will be coded using the Medical Dictionary of Terminology for Regulatory Activities (MedDRA).

Example 6. A randomized, double-blind, placebo-controlled, phase Ib/II study to determine the dose, efficacy, and safety of dexmedetomidine hydrochloride sublingual film for the treatment of patients hospitalized in the ICU with delirium and agitation.

Main objectives:

1. To evaluate the effect of dexmedetomidine sublingual film on cardiovascular parameters including blood pressure, heart rate and QTc interval in hospitalized patients with hyperactive delirium.

2. To assess the frequency of other side effects after the introduction of Dexmede sublingual film

- 126 047684 tomidine in the same group of patients.

3. To study the effect of dexmedetomidine sublingual film on agitation and severity of delirium

4. To determine the optimal dose of dexmedetomidine that effectively reduces agitation and the severity of delirium without causing significant side effects.

Inclusion/exclusion criteria

Inclusion criteria:

1. Adult patients admitted to the medical or surgical intensive care unit at MGH

2. Diagnosis of delirium, assessed according to DSM-5 criteria (DSM-5) by a licensed psychiatrist

3. Body mass index (BMI) from 18 to 30 kg/m2 inclusive at the time of screening

4. Weight of at least 60 kg (132 lbs) at time of screening

5. Physically fit enough to receive sublingual dexmedetomidine, as judged by the research and clinical team

Exclusion criteria:

1. According to documented clinical data or the report of the research team, the patient has the following diagnosed conditions:

Dementia

Significant traumatic brain injury

History of stroke with persistent neurological impairment

2. The presence of any of the following concomitant cardiovascular diseases

Sick sinus syndrome

Resting heart rate <55 beats per minute or systolic blood pressure <100 mmHg or >160 mmHg, or diastolic BP <70 mmHg or ~95 mmHg at study entry and prior to dosing.

Signs of cardiac ischemia on a 12-lead electrocardiogram (ECG)

Corrected QT interval > 450 ms

The presence of a permanent pacemaker

3. According to the medical record (records, current medication intake, regimens):

Second degree (or higher) atrioventricular block without pacemaker

Known allergy or adverse reaction to dexmedetomidine

Current use of dexmedetomidine

4. Inability to take sublingual dexmedetomidine due to severe agitation, neurological impairment, NPO status, or other reason.

5. Liver failure (liver function tests are more than 3 times the upper limit of normal)

6. Severe renal failure (GFR < 30 ml/min or the patient is on dialysis)

7. Weight < 60 kg

8. Pregnancy (in women; serum or urine hCG test)

9. Lack of fluency in English

10. Previous inclusion in the study with receipt of the study drug during the current or previous hospitalization

Evaluation of inclusion criteria:

Inclusion and exclusion criteria will be assessed in a stepwise manner. Before approaching participants/surrogates, study center staff will review the electronic medical record to assess exclusion conditions and discuss with the clinical teams if the presence or absence of such conditions is unresolved. Only those patients who clearly do not meet the exclusion criteria will be further assessed by the study psychiatrist for inclusion and exclusion criteria.

Specifically, the research psychiatrist will confirm the diagnosis of delirium by reviewing the medical records, assessing the potential participant, and discussing with the hospital clinical team if any questions remain regarding the diagnosis after the assessment. Delirium will be diagnosed based on DSM-5 criteria:

1) There is a disturbance of attention and consciousness.

2) The mental disorder develops over a short period of time, represents a sharp change from the baseline, and tends to fluctuate throughout the day.

3) Additional cognitive impairments occur.

4) The presence of the disorder cannot be better explained by an underlying neurocognitive impairment (eg, dementia).

5) Disorders do not occur against the background of a sharply reduced level of awakening (for example, coma).

6) There is evidence that the disorder is a direct physiological consequence of another

- 127 047684 disease, intoxication or withdrawal of substances, exposure to a toxin or caused by multiple causes.

This clinical diagnosis will be made in the context of a psychiatric and cognitive assessment, including bedside tests of orientation, attention, and memory.

If the patient meets the criteria for delirium, the study psychiatrist will then review the patient's medical record and speak with the inpatient clinical team to determine if there are any exclusion criteria. To ensure that the clinical team believes the participant is medically capable of tolerating dexmedetomidine, they will be asked whether they consider the participant suitable for intravenous dexmedetomidine if he/she becomes agitated. If the participants meet the diagnostic criteria for delirium and do not meet any exclusion criteria, they will be considered eligible for inclusion in the study.

Upon enrollment, laboratory tests and an ECG will be performed to confirm clinical stability prior to drug administration. If a participant develops agitation immediately after enrollment and clinical stability is confirmed, the participant may be randomized to receive study drug. If the participant does not have signs of agitation, the participant will be monitored daily for the occurrence of agitation (RASS > 1) and randomized only if/after agitation develops. While patients with or without agitation will be eligible to participate in the study, only those participants who develop agitation will receive the dexmedetomidine film.

Research procedures

A. Data collection and monitoring

Primary screening and data collection

As noted, prior to study entry, study psychiatrists will assess the patient for inclusion and exclusion criteria through a brief review of medical records, discussion with the primary care team, diagnostic assessment (DSM-5 criteria), and assessment of decision-making capacity. For enrolled subjects, medical charts will be reviewed to collect baseline characteristics (Table 26 - flow chart).

Additional screening for eligibility to receive the study drug. After enrollment in the study, laboratory tests will be performed, including a comprehensive metabolic panel (glucose, sodium, potassium, chloride, bicarbonate, calcium, carbon dioxide, magnesium, blood urea nitrogen, creatinine, uric acid, inorganic phosphorus), as well as liver function tests (alkaline phosphatase, aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase, total bilirubin.

In addition, serum human chorionic gonadotropin (HCG; female participants only) will be measured. If the above laboratory tests have already been performed during this hospitalization, no new samples will be collected unless there is a change in clinical status that could affect them. Finally, a standard 12-lead ECG will be recorded. ECG parameters assessed will include heart rate and PR, QRS, QT, and QTc corrected for Bazett (QTcB) and Fridericia (QTcF). QTcF will be considered the standard QTc interval for the assessment of any changes in QTc in response to study drug. ECGs will be interpreted by the investigator and, if necessary, at the discretion of the principal investigator or designee, the results will be confirmed by a cardiologist, intensivist, or anesthesiologist. Administration of the study drug will not occur until all required laboratory test results are received and the participant is confirmed to be eligible to receive the study drug.

Monitoring the development of agitation:

The participant will be assessed daily during the workweek by a member of the study team using the Richmond Sedation-Agitation Scale (RASS). If/when the participant is found to be significantly agitated (defined as a RASS score > 1), the participant will undergo baseline monitoring procedures and will be randomized to receive one of two treatments.

Randomisation: Participants will be randomised to receive 20 or 60 mcg dexmedetomidine sublingually. Because dexmedetomidine is available as 10 and 60 mcg films, those assigned to 20 mcg will receive two 10 mcg films and those assigned to 60 mcg will receive a 60 mcg film and a placebo film to ensure blinding of staff and participants. Participants will be re-dosed every 30 min for up to three additional doses, resulting in maximum doses of 80 and 240 mcg, respectively. Both investigators and clinicians will be blinded to participant group, and only the study pharmacist will know the dose of drug in the films.

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Baseline monitoring

Once participants are enrolled, the research team will record baseline heart rate, blood pressure, and oxygen saturation. An ECG will be recorded and QTcF will be measured. The physician will then assess the patient using the RASS and DRS-R-98 scales to measure baseline agitation and delirium severity, respectively.

Administration of the drug

The dexmedetomidine sublingual film will be administered by the study physician or study nurse according to the manufacturer's instructions. Specifically, the film will be placed in the participant's mouth. Participants will be instructed to keep the film in their mouth until it dissolves. If the participant is unable to keep the medication in their mouth (e.g., spits it out), the participant will not be given a repeat dose. Dexmedetomidine administration will be repeated every 30 minutes unless the participant remains agitated (RASS >1) and meets cardiovascular discontinuation criteria. Administration times and maximum doses are provided in Table 27:

Table 27. Time of administration and maximum doses of the drug

Group Injection time (min) Total dose 0 30 60 90 20 mcg 20 mcg 20 mcg 20 mcg 20 mcg 80 mcg 60 mcg 60 mcg 60 mcg 60 mcg 60 mcg 240 mcg

Monitoring side effects

Heart rate, blood pressure, oxygen saturation, supplemental oxygen use, and pressor use will be continuously monitored and recorded every 30 minutes in the Epic participant card or via telemetry monitor/automated blood pressure cuff for 6 hours after the initial drug administration (baseline; Time 0). ECGs will be performed at 1, 5, 3, 4.5, and 6 hours, and the QTc interval will be calculated using the Fridericia formula as described above. Study site staff will also observe the participant and speak with a nurse at 6 hours to assess any other adverse events/complaints the patient may have had during the time following drug administration. Adverse events/complaints will be appropriately assessed based on the list of adverse events reported for dexmedetomidine during the post-marketing surveillance period.

Monitoring the severity of agitation and delirium

The study site staff (study coordinator, nurse, or study psychiatrist) will assess the patient with the RASS every 30 min (up to 6 h after baseline) to monitor for agitation. The DRS-R-98 will be assessed by the study physician at 1, 2, 3, 4, and 6 h after baseline to assess changes in delirium severity. If patients require additional treatment for agitation after drug administration during the 6-h monitoring period, all efficacy and safety assessments will continue from that time point, but these time points for these patients will not be analyzed in the primary data analysis.

The administration of the drug will be stopped at any time if any of the following occurs:

1) A decrease in systolic or diastolic blood pressure of more than 30 mm Hg.

2) A drop in only systolic BP < 95 mmHg.

3) A drop in only diastolic BP < 55 mmHg.

4) A decrease in heart rate by 20 beats per minute or a drop below 55 beats per minute.

5) ECG shows QTc > 500 ms.

6) Achieving a RASS score of -1.

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Table 26. Schedule of research procedures

Indicator Pre-switching Initial Level Introduction of the drug 30 min 1 h 1.5 h 2 h 2.5 h 3 h 3.5 h 4 h 4.5 h 6 h Screening for delirium (CAM-ICU) X Diagnosis of Delirium (DSM-5) X Agitation (RASS) X X X X X X X X X X X X X Delirium Severity (DSR-R-98) X X X X X X Pulse rate X X X X X X X X X X X X Blood pressure X X X X X X X X X X X X Oxygen saturation X X X X X X X X X X X X Electrocardiogram X X X X X Other side effects X

Investigational medicinal products

In this study, the authors will administer the drug sublingually in film form (dissolves sublingually) at a dose of 20 or 60 mcg (with repeated administration, participants can receive a total of up to 80 or 240 mcg, respectively).

Data collection

Baseline data. Before dexmedetomidine administration, the study physician will perform RASS and DRS-R-98 assessments to establish the level of agitation and severity of delirium. Heart rate, blood pressure, and oxygen saturation will be recorded from the participant's telemetry monitor and using an automated blood pressure cuff. Finally, an ECG will be recorded and the study physician will calculate the QTc interval.

Cardiovascular parameters and side effects

Following dexmedetomidine administration, heart rate, blood pressure, and oxygen saturation will be recorded every 30 minutes using a telemetry monitor or Epic card. Based on previous studies, the authors will monitor for the following adverse events:

(a) Bradycardia - heart rate < 55 beats per minute (or a decrease in heart rate of > 20% compared with baseline if baseline heart rate < 70 beats per minute);

(b) Hypotension - systolic blood pressure < 95 mmHg (or decrease in systolic blood pressure by > 20% from baseline if baseline systolic blood pressure < 120 mmHg), or addition or increase in the dose of vasopressors;

(c) Tachycardia - heart rate > 100 beats per minute (or increase in heart rate by > 20% compared with baseline if baseline heart rate > 83 beats per minute);

(d) Hypertension - systolic blood pressure > 160 mmHg (or increase in systolic blood pressure by > 20% compared with baseline if baseline systolic blood pressure > 133 mmHg);

(e) Hypoxia - oxygen saturation < 90% (or decrease in absolute oxygen saturation by > 5% if baseline oxygen saturation is < 95%), or increase in the amount of supplemental oxygen required to maintain oxygen saturation > 90%;

(f) ECG changes (including QTc prolongation) - ECG parameters will include heart rate, PR interval, QRS interval, QT interval, and QTc interval (rate correction using QTcB and QTcF methods). A summary of ECG findings and changes from baseline will be presented. The number and percentage of participants with an increase in QTc interval from baseline to the 90-minute ECG time point will be summarized using the following categories of changes:

a) Increase in QTc interval from baseline from >30 to <60 ms;

b) Increase in QTc interval compared to baseline >60 ms.

In addition, QTc values will be summarized by gender from normal to prolonged in accordance with the recommendations of the Committee for Proprietary Medicines (CPMP), which should be taken into account when assessing the potential for QT prolongation, as summarized in Table 28.

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Table 28. QTcF intervals: upper and lower limits of normal, borderline, and ___________prolonged intervals___________

Men Women Normal Borderline Elongated <430 ms >430 to <450 ms >450 ms <450 ms >450 to <470 ms >470 ms

Note: In accordance with the recommendations of the SRMR.

Similarly, the number and percentage of participants with absolute QTc interval values above defined thresholds will be summarized by gender, taking into account the following limits in accordance with the International Conference on Harmonization (ICH) E14 recommendations:

QTc interval >450 to <480 ms

QTc interval >480 ms

QTc interval >500 ms

A list of participants with a change in QTc from baseline of 30 to 60 ms and >60 ms will be provided. The sponsor will also be provided a list of participants with abnormal QTc interval values (>450 ms to <500 ms and >500 ms).

Non-cardiovascular side effects

At the final assessment (6 hours after the first dose of study medication), participants will be asked the following question: Have you noticed any new physical problems or side effects since taking the study medication? Additionally, the nurse who was primarily caring for the participant will be asked whether the patient had any signs or symptoms of new illnesses or side effects (e.g., muscle stiffness, tremor, rash) since receiving the medication, using a checklist of side effects reported during post-marketing surveillance.

Effect on agitation and severity of delirium (a) Agitation: Agitation will be measured using the 10-item RASS scale to quantify levels of consciousness and agitation. This validated measure can be completed in less than one minute and has clear definitions of levels of arousal/agitation. RASS assessments will be performed at baseline and every 30 min (up to 6 h after baseline) by the study coordinator, study nurse, or study psychiatrist.

(b) Severity of delirium:

The DRS-R-98 will be used to assess the severity of delirium. This 16-item scale can be used to screen/diagnose delirium, but also includes 13 items to assess the severity of delirium. This scale is reliable and has been validated in patients with delirium. The scale will be assessed by the study physician at baseline and then at 1, 2, 3, 4, and 6 hours after the initial administration of dexmedetomidine.

Example 7. A randomized, single-blind, placebo-controlled, single-dose, phase 1 study to investigate the pharmacokinetics, safety, and tolerability of dexmedetomidine sublingual film (formulation of Example 1) in healthy adult volunteers

This was a randomized, single-blind, placebo-controlled study to investigate the pharmacokinetics, safety, and tolerability of a single escalating dose with 4 dose groups in healthy adult men and women (18-65 years). The study protocol was reviewed and approved by the Institutional Review Board of the site(s). This study was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice (GCP) principles.

Primary objective: To determine the pharmacokinetics, safety and tolerability of dexmedetomidine sublingual film at different concentrations to determine appropriate dose concentrations for films to be used in subsequent clinical studies.

Secondary objectives:

1. To determine the PD effects of sublingual film containing dexmedetomidine at different concentrations.

2. To determine the relationship between PD effects and plasma dexmedetomidine concentrations.

3. Determine the time until the onset of drowsiness after sublingual administration of a film containing dexmedetomidine.

4. To determine the duration of the sedative effect after sublingual administration of a film containing dexmedetomidine.

5. Determine the approximate dissolution time of sublingual films with dexmedetomidine

- 131 047684 hydrochloride in SL space.

6. Determine the local irritation that may be caused by sublingual film with dexmedetomidine.

Evaluation criteria

Primary

Pharmacokinetics:

1. Area under the curve (AUC0-12, AUC0-24, AUC0-inf) from 0 to 12 h and from 0 to 24 h after dose administration for plasma dexmedetomidine concentration.

2. Determine the peak plasma concentration of dexmedetomidine (Cmax).

3. Determine the time corresponding to the peak concentration of dexmedetomidine (Tmax).

4. Determine the terminal half-life (t1/2) of dexmedetomidine from the central compartment.

5. Determine the volume of distribution (Vz) of dexmedetomidine.

6. Determine the clearance of dexmedetomidine (CL) from the central compartment.

Safety and tolerability

1. To determine electrocardiogram (ECG) parameters and abnormal vital signs, including adverse effects of dexmedetomidine sublingual film of varying concentrations on blood pressure (BP), heart rate, or respiration.

2. To determine pathologically altered laboratory values after administration of sublingual film with dexmedetomidine.

3. Determine changes in physical examination after administration of sublingual film with dexmedetomidine

4. Number of subjects experiencing AE up to day 14 after administration of dexmedetomidine sublingual film.

5. Number of subjects who discontinued study treatment or removed SL films due to AE or other reason.

6. Degree of tolerance of AE by assessing the number of subjects requiring: hemodynamic interventions to maintain VR; cardiac interventions to maintain heart rate; respiratory interventions to maintain oxygen saturation levels.

Secondary:

1. Sedative effect was assessed using RASS and visual analogue scale/sedation (VAS/S) on the day of administration of dexmedetomidine sublingual film.

2. Time in minutes and seconds from administration of dexmedetomidine sublingual film to reaching RASS-1 score on the day of administration of dexmedetomidine sublingual film.

3. Time in minutes and seconds from reaching the RASS-1 score to the disappearance of drowsiness on the day of taking dexmedetomidine sublingual film.

4. Time in minutes and seconds from a single administration of sublingual film of dexmedetomidine until its complete dissolution or up to 30 min.

Study design:

This was a randomized, single-blind, placebo-controlled study to investigate PK, safety, and tolerability in healthy adult men and women (aged 18-65 years). The study evaluated dose escalation of dexmedetomidine sublingual film in 4 cohorts of healthy adult participants.

Four (4) doses were evaluated based on three film strengths of 10 mcg, 40 mcg, and 60 mcg: 10 mcg, 20 mcg (2 films x 10 mcg), 40 mcg, and 60 mcg in Cohorts 1, 2, 3, and 4, respectively. During review of the safety and tolerability data in Cohort 3 (40 mcg), it was noted that 6 symptomatic subjects reported dizziness on standing, four of whom had concomitant intermittent hypotension or bradycardia (SBP/DBP/heart rate, with >30 mmHg decrease from baseline, SBP <90 or DBP<60, or heart rate <50). Since the results remained confounded, it was decided to reduce the planned dose for Cohort 4 to 40 mcg. The actual doses administered to subjects in this study included 10 mcg (Cohort 1), 20 mcg (Cohort 2), and 40 mcg (Cohorts 3 and 4).

All eligible participants who had been previously screened arrived at the clinical research unit (CRU) the day before admission and baseline assessment. They were kept in the CRU for 4 days (Days -1, 1, 2, and 3) and discharged on Day 4, and were under medical observation during this time.

All participants were assessed pre-dose between approximately 07:00 and 09:00 after an overnight fast of at least 8 h. Participants were given free access to drinking water for at least one hour before dosing. A venous catheter was inserted for PK sampling. At the beginning of each study session, a single dose of dexmedetomidine sublingual film (Example 1) was administered by unblinded personnel. Dexmedetomidine sublingual film

- 132 047684 was left in the sublingual cavity until dissolved. Assessments were made every 5 min for the first 15 min and then every 15 min to determine film dissolution time. Subjects were also assessed for local irritation in the area where the film was placed. Subjects were not allowed to sit or stand for the first 2 h after sublingual administration of dexmedetomidine film except to perform standing RT measurements. After 2 h, subjects were allowed to sit up in their beds but were required to rest in a supine or semi-recumbent position during sample collection. ECG, RT, and oxygen saturation were monitored as scheduled (Table 29). Subjects were given water ad libitum for at least 1 h after drug administration. Standard meals were offered at approximately 4, 8, and 12 h after sublingual dexmedetomidine film administration. However, no food or drink was permitted until the investigator confirmed that each subject was capable of oral administration based on the degree of sedation and ability to control urination. Toilet visits were also permitted but with a chaperone. There were no dietary restrictions on Days 2 and 3, but there was complete restriction of smoking and alcohol consumption for the entire duration of the CRU stay. Following plasma collection for 24 hours after administration of the dexmedetomidine sublingual film, safety and tolerability assessments continued until the morning of Day 4 (the day of discharge) and were repeated on Day 5, Day 7±1, and Day 14±2.

Number of subjects

The study evaluated dose escalation of dexmedetomidine sublingual film (Example 1 formulation) in 4 cohorts of healthy adult subjects. The first two cohorts (Cohort 1 and Cohort 2) included twelve (12) new subjects per group, randomized in a 2:1 ratio, i.e., 8 received dexmedetomidine sublingual film and 4 received placebo film.

Subjects who received active drug in Cohort 1/Cohort 2 were to be crossed over to receive the high dose of active drug in Cohort 3/Cohort 4, and subjects who received placebo in Cohort 1/Cohort 2 were to receive placebo in Cohort 3/Cohort 4, respectively. Six new subjects were to be randomized to receive active drug in Cohort 3/Cohort 4. Dose proportionality and dose response were to be assessed in subjects who crossed over to Cohort 3/Cohort 4. The effect of dexmedetomidine sublingual film on RT, HR, RASS score, other AEs, and PK parameters were to be assessed in new subjects who were not previously exposed to dexmedetomidine sublingual film. If a placebo-treated subject dropped out when moving from cohort 1 to cohort 3 or from cohort 2 to cohort 4, additional new subjects had to be randomized to give a total of 4 subjects in the placebo group in cohort 3 and cohort 4.

Table 29. Graph of assessments

Activity Screening Day -1 (Hospitalization; Visit 1) Day 1 (Administration of study drug dose) 1 Day 2 and 3 (Observation at CRU) Day 4 (At the time of discharge) Day 5 (Visit 2) ⁴ Day 7±1 (Visit z) ⁴ Day 14±2 (Visit 4, EOS) ⁴ Informed Consent Form X Demographic data X Medical history X X Weight/BMI X X X X X X Height X Criteria X X X

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inclusions/ exclusions Randomization X Lab. safety studies (Biochemistry, hematology, U/A, UDS ² were performed in the local laboratory of the department) X X X Pregnancy test (HCG in blood) X Pregnancy test (HCG in urine) X Coagulation (PT/INR) X Physical examination X X X X X X X Complete neurological examination X X Brief neurological examination X X (if drowsiness resolves after taking the drug) Vital signs (systolic X X 0 (before dose administration), 10, 20 and 30 min, then X X X X X

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systolic and diastolic blood pressure, pulse rate, respiration and oxygen saturation) every 15 min until 6 hrs. Thereafter, prior to FC sampling (if applicable) (± 15 mins) or hourly until sleep onset and again with the final sample taken after 24 hrs (± 15 mins). Blood pressure in standing position X(at night) X (-2 hours before dose, 2, 4, 6 hours after dose) X X ECG X X Every 3 hours (from 0 to 6 hours after dose administration (±15 min). X X X X X Hospitalization in the department X Preparation X

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investigational drug (unblinded pharmacist) Insertion of a venous catheter X Sublingual administration of the study drug X Dissolution of the film on the mucous membrane of the cheek X (Section 9.5.1.3.1) Buccal/sublingual examination for local irritation X X X (every hour, starting from the pre-dose period until bedtime and again with the last sample taken after 24 hours (±15 minutes). X X X X X RASS ³ X 0 min, every 5 min until drowsiness is reached (RASS score -1) then every 15 min until disappears

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Iya drowsiness Tso taking a sample of RK, BEFORE disappearance Iya drowsiness VAS/S Preparation Taking a sample of RK Extract X 0 min, every 30 min until drowsiness disappears Sampling time RK (±5 min) According to sampling schedule (Section 9.5.1.4.3) X Accompanying drugs X X X X X X X X Adverse events X (Section 9.5.1.3.2.7) X X X X X X X

ECG: Electrocardiogram; hCG: Human Chorionic Gonadotropin; PK: Pharmacokinetics; PT/INR: Prothrombin Time/International Normalized Ratio; RASS: Richmond Sedation-Agitation Scale; U/A: Urinalysis; UDS: Urine Drug Screen; VAS/S: Visual Analog Scale/Sedation

1Pre-dose assessments had a window of 60 min before drug administration.

2U DS on day of discharge was not performed ³ E If the subject did not experience somnolence (RASS score -1) at or before 90 min postdose, the procedure was performed in 5-min increments until 90 min postdose, then in 15-min increments until 120 min postdose. There was a 3-min window for RASS.

Appropriate studies were repeated if any abnormal vital signs, clinical laboratory tests, physical examination findings, or ECG parameters were determined by the investigator to be clinically significant, including test results obtained on the last day of the single-blind study or at early termination of the study. For any test result abnormality determined to be clinically significant, reanalysis was performed during the observation period and until the value returned to baseline (or within normal limits) or until the investigator deemed the abnormality to be no longer clinically significant.

Inclusion Criteria

1. Healthy men and non-pregnant/non-breastfeeding women aged 18 to 65 years inclusive.

2. Subjects who were capable of giving written informed consent for the study

3. Subjects with body weight > 50 kg and body mass index (BMI) in the range of 19-30 kg/ ^m2 inclusive

4. Subjects who have undergone a physical examination and whose vital signs are determined by the PI or designee to be within normal limits.

5. Subjects whose clinical laboratory tests (complete blood count, blood chemistry, and urinalysis) were within normal limits or were clinically acceptable in the opinion of the PI or designee.

6. Subjects who were physically fit enough to receive the SL dose of dexmedetomidine sublingual film and tolerated somnolence well, as judged by the PI or designee.

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7. Subjects who are fluent in English and able to understand written and oral protocol requirements in English.

8. Subjects who were willing and able to be placed in a CRU for approximately 4-5 days for each dose cohort and were compliant with the procedural schedule and study requirements.

9. Subjects who had reliable intravascular access for blood sampling.

10. Male subjects, unless they have had a vasectomy, must agree to use a condom with spermicide or abstain from sexual intercourse during the study and for 3 months after stopping the drug.

11. Male subjects must not donate semen starting from screening and throughout the study period, as well as for 90 days after the last administration of the study drug.

12. For women of childbearing potential, the female subject must be willing to practice a clinically acceptable method of birth control for at least 30 days prior to the first dose of study drug, during the study, and for at least 30 days after the last dose of study drug.

13. For women of infertility, the subject must be surgically sterile (i.e., have had a hysterectomy, bilateral oophorectomy, or tubal ligation) or be in menopause (at least 1 year without menses) as determined by follicle-stimulating hormone (FSH) levels.

Exclusion criteria

1. Subjects with a history of allergic reaction or intolerance to the study drug or related compounds and additives.

2. Subjects with a history of major surgery within 4 weeks prior to screening.

3. Subjects with a history of severe traumatic brain injury.

4. Subjects with a history of alcohol or drug dependence according to Diagnostic and Statistical Manual of Mental Disorders IV criteria during the 6-month period prior to study inclusion.

5. Subjects with a history or presence of clinically significant mental illness with mental retardation, borderline personality disorder, anxiety disorder or organic brain syndrome.

6. Subjects with a history of orthostatic hypotension (i.e., a sustained decrease in systolic BP (SBP) of at least 20 mmHg or diastolic BP (DBP) of 10 mmHg, or both, within 3 min of standing or tilting the head upward at least 60° on a tilt table) and with high vagal tone.

7. Subjects who regularly consume large amounts of xanthine-containing substances (i.e. more than 5 cups of coffee or equivalent amount of xanthine-containing substances per day).

8. Subjects taking maintenance medications that could inhibit or induce the CYP2A6 enzyme.

9. Subjects who received dexmedetomidine or other alpha-2-agonists within 1 week prior to study entry.

10. Subjects with a history of clinically significant sleep apnea or chronic obstructive pulmonary disease or asthma.

11. Subjects who have suicidal tendencies, in the opinion of the PI or authorized person.

12. Subjects with clinical and laboratory abnormalities (including positive results for hepatitis B, hepatitis C, HIV), if treatment has not been carried out until the onset of remission.

13. Subjects with abnormal vital signs in the opinion of the PI or designee, if remission has not been achieved.

14. Subjects who were enrolled in another clinical trial (e.g. laboratory or clinical study) or received investigational drug within the last 30 days (or within 5 half-lives of investigational drug if > 30 days).

15. Subjects with a resting heart rate <65 bpm or SBP <110 mmHg or >140 mmHg or DBP <70 mmHg or >100 mmHg at Screening and pre-dose. There is evidence of clinically significant abnormalities on a 12-lead ECG. Subjects who previously did not meet the eligibility criteria at the Screening visit or pre-dose on Day 1 due to the presence of exclusion item 15 with a resting heart rate <70 bpm but not <65 bpm may be re-screened.

16. Subjects with altered oral/cheek anatomical structure, inflammation or pathology that, in the opinion of the PI, may affect SL administration and absorption of the drug.

17. Subjects with hepatic impairment or hepatic dysfunction, defined as a history of hepatic dysfunction and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than 2 times normal within the last 6 months prior to administration

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18. Subjects who donated blood within 30 days prior to screening or who donated plasma within 7 days prior to screening.

19. A subject who was a member of the research staff or a family member of any of the research staff.

Duration of the study: 39-42 days.

Treatment carried out

On Day 1 the following treatment was administered:

Active: dexmedetomidine hydrochloride SL film in doses of: 10 mcg (1 film x 10 mcg), 20 mcg (2 films x 10 mcg) and 40 mcg (1 film x 40 mcg)

Placebo: SL film placebo

Cohort 1 and Cohort 2 received 10 and 20 mcg (2 films of 10 mcg), respectively, Cohort 3 and Cohort 4 received 40 mcg dexmedetomidine as a sublingual film. All cohorts received an accompanying placebo. With the exception of the first dose cohort (10 mcg dose), each subsequent dose level was approved after a safety analysis in the cohort with the previous dose level. The dexmedetomidine hydrochloride sublingual film was dotted and had a different appearance from placebo.

Results:

Analysis of the data set

Patient population for safety assessment

The safety population included all randomized subjects who received at least 1 dose of the drug in the single-blind study (n=42).

Patient population for pharmacokinetic evaluation

The PK population included 28 subjects receiving dexmedetomidine sublingual film. Fourteen subjects receiving placebo were not included in the PK analysis. For subjects receiving placebo alone, the following parameters are presented over time: visual analog scale/sedation (VAS/S), Richmond Agitation-Sedation Scale (RASS), and vital signs (diastolic blood pressure, systolic blood pressure, pulse rate, respiratory rate, and oxygen saturation).

Population of patients for PD assessment

The PD evaluable population included all randomized subjects who received at least 1 dose of treatment in the single-blind study and who had post-baseline PD assessments (n=42).

Demographic and other baseline characteristics

Overall, the majority of healthy subjects in the study (59.5%) were white (not of Hispanic or Latino origin), with a minority (31.8%) being black (African American). There was 1 (2.4%) subject of Hispanic or Latino origin and 1 (2.4%) subject of Asian origin.

Overall, the number of men and women in the study was comparable: 22 (52.4%) of all subjects were men and 20 (47.6%) were women. The mean age was 44.8 years; subjects ranged in age from 20 to 65 years; 22 (52.4%) subjects were aged 20 to 49 years and 20 (47.6%) subjects were aged > 49 to 65 years.

The majority of subjects in the placebo group were male (64.3%).

Among subjects who received dexmedetomidine sublingual film, the proportions of men (46.4%) and women (53.6%) were comparable.

Physical parameters were also comparable in the placebo and dexmedetomidine sublingual film groups: the mean body mass index (BMI) was 25.50 kg/ ^m2 in subjects who received dexmedetomidine sublingual film and 25.83 kg/ ^m2 in the placebo group.

Pharmacokinetic Results: Dexmedetomidine was rapidly absorbed with measurable concentrations observed at 10 min for all dose levels and up to 8 h post-dose for the 10 mcg dose levels and up to 10 and 12 h post-dose for the 20 and 40 mcg dose levels, respectively, with short mean t1/2 values that ranged from 1.82 to 2.16 h. The mean±SD plasma DEX concentration-time profiles for each dose (semi-log scale) plotted with sampling times up to 8 h post-dose are shown in Fig. 8. Dose proportionality assessment demonstrated that Cmax and AUC values increased proportionally with dose, with mean Cmax ranging from 29.21 to 122.84 ng/L and mean AUC _0-inf ranging from 130.62 to 561.57 ng/L. Similar trends were observed for AUClast and AUC0-24 (Tables 30–32; Figs. 9A–9C).

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Table 30. Summary of pharmacokinetic parameters of 10 mcg dexmedetomidine in sublingual film in healthy volunteers

Sublingual film with dexmedetomidine, 10 mcg Subject ID Stakh (ng/l) Ttah (h) tl/2 (h) AUClast (h*ng/l) AUC0-INF (h*ng/l) 1001 37.94 1,5 2.06 179,19 201,32 1002 18,27 1,00 1,17 49.45 58.27 1005 33.28 2,00 1.86 116.63 140.07 1007 35.74 2,00 2.95 142.22 168.59 1009 24.15 3.02 2.70 102.76 1011 30.87 1,00 2.75 114.35 138.82 1012 24.53 1.50 2.58 98.28 1016 35.19 2,00 1.24 119.28 129.17 N 8 8 8 8 6 Average value 30 1,752 2,163 115,271 139.37 SD 6,930 0.66 0,693 37.05 47.69 CV% 23.1 37,62 32,0 32.1 34.22 min. 18,27 1,00 1,17 49.45 58.27 Median 32.08 1.75 2.32 115.49 139.45 Max. 37.94 3.02 2.95 179,19 201,32 Geometric mean 29,214 1.65 2,051 109.22 130.62 Geometric CV% 25.79 39.08 37.61 38,59 44.75

Table 31. Summary of pharmacokinetic parameters of 20 mcg dexmedetomidine in sublingual film in healthy volunteers

Sublingual film with dexmedetomidine, 20 mcg Subject ID Stakh (ng/l) Ttah (h) tl/2 (h) AUClast (h*ng/l) AUC0-INF (h*ng/l) 2001 0,00 0,00 0,00 2003 83.08 1,00 2,2 359,59 389.48 2004 65.17 2,00 1.72 259,50 279,49 2007 84.90 1.50 1.60 401,79 416.92 2011 70,76 2,00 1.85 309.75 337,01 2013 85.92 1,00 1.85 307,97 330,48 2016 42.34 3.00 1.97 198.79 225.81 2106 66.75 1.50 1.57 283.34 301,60 N 8 7 7 8 8 Average value 62.37 1.71 1,824 265,092 285,10 SD 28,982 0,70 0.221 123,337 129.91 CV% 46,47 40.75 12.1 46.5 45,57 min. 0,00 1,00 1.57 0,00 0,00 Median 68,76 1.50 1.85 295,66 316,04 Max. 85.92 3.00 2.20 401,79 416.92 Geometric mean - 1,601 1,813 - - Geometric CV% - 41.30 11.95 - -

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Table 32. Summarized pharmacokinetic parameters of 40 mcg dexmedetomidine in film for _______sublingual administration in healthy volunteers_______

Sublingual film with dexmedetomidine, 40 mcg Subject ID Stakh (ng/l) Ttah (h) tl/2 AUClast (h*ng/l) AUC0-INF (h*ng/l) 3011 140.25 1,00 1.78 685,15 709,61 3012 78,69 2,00 2,00 427.97 461,18 3013 97,01 1.07 1.76 292.84 310.29 3023 126.60 1,00 1.86 493.89 508,98 3026 135,02 1.50 1.38 482,44 499.41 3032 78,06 2,00 378,67 3114 167.99 1,00 2.05 777,66 806,08 3131 123.52 2.02 2.42 600,88 627,60 4001 109.62 1,00 1.82 419,51 446,40 4022 204.03 1,00 1.82 664,47 704,50 4026 123.68 2,00 1.83 507.83 534,00 4130 143.95 2,00 1.97 772.97 798,78 N 12 12 AND 12 AND Average value 127.37 1.47 1.88 542,02 582.24 SD 35.79 0.49 0.25 157,144 158.70 CV% 28,10 33.75 13.44 28.99 27,25 min. 78,06 1,00 1.38 292.84 310.29 Median 125,14 1.28 1.83 500,86 534,00 Max. 204.03 2.02 2.42 777,66 806,08 Geometric mean 122.84 1.39 1.87 520,58 561,57 Geometric CV% 28,87 35.22 13.7 30.84 29.65

Pharmacodynamic results:

The sedative effect of dexmedetomidine sublingual film was assessed using the RASS and visual analogue scale/sedation (VAS/S) on the day of administration of dexmedetomidine sublingual film.

The reported assessment included the time in minutes and seconds from administration of the dexmedetomidine sublingual film to achievement of the RASS-1 score;

time in minutes and seconds from reaching a RASS score of -1 until the disappearance of drowsiness on the day of taking dexmedetomidine sublingual film;

time in minutes and seconds from a single administration of sublingual film of dexmedetomidine until its complete dissolution or up to 30 min.

Richmond Sedation-Agitation Scale

All RASS scores assessed during the study ranged from -2 (mild sedation) to 0 (alert and calm). The baseline score for all subjects was 0 (alert and calm). Overall, somnolence (RASS score -1) was achieved in 14 subjects across all procedures. Of these, 2 received the 10 mcg dose, 4 received the 20 mcg dose, 5 received the 40 mcg dose, and 3 received placebo. Two subjects also achieved mild sedation (RASS score -2), one receiving the 10 mcg dose and the other receiving placebo.

The mean time to somnolence from baseline for subjects receiving dexmedetomidine sublingual film and placebo are summarized in Table 33. Overall, the time to somnolence was variable across treatment groups, ranging from 19 to 85 minutes in the dexmedetomidine sublingual film groups and from 19 minutes 17 seconds to 107 minutes 29 seconds in the placebo group. No statistically significant between-group differences were observed for either the 10 mcg or 40 mcg treatment groups.

The time from the onset of sleepiness (RASS -1 score) to its resolution in subjects who received sublingual dexmedetomidine film and placebo is summarized in Table 34. Overall, the time from the onset of sleepiness (RASS -1 score) to its resolution was variable across treatment groups and ranged from 05 min 05 sec to 91 min. The mean time in subjects who received sublingual dexmedetomidine film was

- 141 047684 was 48 min 24 sec, while in subjects given placebo the average duration was 37 min 25 sec.

Table 33. Achievement of sleepiness (in minutes: seconds) compared to the initial ________________ level with a score on the RASS-1 scale_________________

Statistical Sublingual Cohort 1 in film Cohort with dexmedetomidine Cohort 3 YUM Cohort Cohort 3+4 data (10 mcg) 2 (20 mcg) (40 mcg) 4 (40 mcg) (40 mcg) Active treatment (N=8) Placebo (N=4) Active Treatment (No. 8) Active Treatment (No. 8) Placebo (N=4) Active Treatment (No. 4) Active treatment (N=12) Placebo (N=6) η 2 2 4 3 1 2 5 1 Mean (SD) 31:30 (3:32) 65:47 (58:58) 59:16 (18:16) 47:30 (10:27) 19:17 24:00 (7:40) 38:60 (15:15) 19:17 Median 31:30 65:47 54:20 44:20 19:17 24:00 39:00 19:17 Minimum, maximum 29:00, 34:00 24:50, 107:29 44:00, 85:00 39:00, 59:10 19:17, 19:17 19:00, 29:00 19:00, 59:10 19:17, 19:17 Value compared to placebo 1,000 0,5000 0,6667

P-value is based on the nonparametric two-tailed (exact) Wilcoxon test. n is the number of subjects achieving a RASS score of at least -1 at any time during the first 2 h.

Table 34. Duration from reaching the RASS-1 score to the disappearance of drowsiness ___________________________(in minutes:seconds)___________________________

Statistical data Sublingual film with dexmedetomidine Cohort 1 10 mcg (N=8) Cohort 2 20 mcg (N=8) Cohort 3 40 mcg (N=8) Cohort 4 40 mcg (N=4) Cohort Zi4 40 mcg (N=12) Total, active treatment ³ (N=28) Pooled placebo ³ (N=14) Total ³ (N=42) η 2 4 3 2 5 11 2 13 Mean value (SD) 84:30 (9:12) 53:49 (10:56) 28:00 (30:29) 32:03 (38:07) 29:37 (28:52) 48:24 (28:45) 37:25 (10:38) 46:43 (26:44) Median 84:30 52:39 15:01 32:03 15:01 59:00 37:25 45:12 Minimum, maximum 78:00 ,91:00 44:00, 66:00 6:10, 62:50 5:05, 59:00 5:05, 62:50 5:05, 91:00 29:54, 44:56 5:05, 91:00

aThe Total, Active Treatment, Pooled Placebo, and Total columns include estimate counts, not subject-level counts.

n - number of subjects achieving a RASS score of at least -1 at any time during the first 2 h

Visual analogue scale/sedation

The subjective sedative effect of dexmedetomidine was assessed using the VAS. Subjects were asked to rate how they felt on a 100-mm horizontal scale, with 0 indicating very drowsy and 100 indicating very alert. Overall, VAS scores were variable, with the lowest scores generally occurring at 1.0 and 1.5 h in subjects receiving dexmedetomidine sublingual film. The mean scores observed at predose and at 0.5, 1, 1.5, and 2 h after administration of dexmedetomidine sublingual film or placebo and the P values are presented in Table 35 and Fig. 10. There were no statistically significant differences between groups (ac

- 142 047684 (effective treatment versus placebo) was not observed in Cohort 1 (10 mcg), Cohort 2 (20 mcg), or combined Cohorts 3 and 4 (40 mcg dose). Statistically significant differences were observed only in Cohort 3 (40 mcg). However, statistical significance was also reported for the predose assessment in this cohort (P<0.05; Table 35), indicating that study conditions and score variability may have influenced the outcome.

Dissolution time of sublingual film with dexmedetomidine

A single dose of dexmedetomidine sublingual film was administered sublingually. For the 20 mcg dose cohort, two (2) 10 mcg films were administered simultaneously. The film was left in the sublingual cavity until it dissolved. Assessments were made every 5 min for the first 15 min and then every 15 min to determine the time to film dissolution. The mean, median, and minimum and maximum dissolution times for each treatment group in minutes:seconds are presented in Table 36. Overall, the time from a single administration of dexmedetomidine sublingual film or placebo film until complete dissolution was variable, ranging from 3 min to 44 min 11 s. The mean (SD) and median dissolution times were similar for dexmedetomidine sublingual film (14:09 (11:33); 11:11, minutes:seconds) and placebo (13:32 (12:49); 8:28, minutes:seconds). During examination of the buccal mucosa for irritation, no abnormal oral/cheek anatomical structure or signs of inflammation were detected in any subject.

Safety assessment

Based on the results of this study, the following safety conclusions can be drawn:

There were no deaths or serious TEAEs reported in the study. One subject receiving dexmedetomidine 10 mcg sublingual film experienced a decrease in heart rate >30 bpm (exclusion criterion) and was therefore unable to continue in Cohort 3. A summary of AEs is presented in Table 37.

A total of 52 TEAEs were reported in 25 of 28 subjects (89%) who received dexmedetomidine sublingual film and 20 TEAEs were reported in 10 of 14 subjects (71%) who received placebo. All TEAEs resolved by the end of the study.

In subjects administered dexmedetomidine sublingual film, TEAEs were reported at a rate of 75% for the 10 mcg dose group, 88% for the 20 mcg dose group, and 100% for the 40 mcg dose group. Drug-related TEAEs were reported at a rate of 75% following administration in the 10 mcg dose group, 88% following administration in the 20 mcg dose group, 92% following administration in the 40 mcg dose group, and 64% following administration of placebo.

The most common TEAE during the study was somnolence, which was reported at slightly higher frequencies at the 20 mcg and 40 mcg doses (75% each) compared with the 10 mcg dose and placebo (50% each) (Table 38).

Most TEAEs were mild in severity across all treatment groups, with only a few moderate TEAEs reported. Moderate TEAEs were observed after the 10 mcg dose (1/12; 8%), the 40 mcg dose (2/30; 7%), and placebo (4/20; 20%). No serious TEAEs were reported in this study.

No subject dosed in this study required hemodynamic/medical interventions to maintain BP, cardiac interventions to maintain heart rate, or respiratory interventions to maintain oxygen saturation. No subject discontinued the study due to TEAE. Data are further summarized in Figs. 11–15.

Two subjects experienced symptomatic vital sign changes that were considered clinically significant and reported as vital sign related TEAEs. One subject receiving placebo experienced decreases in DBP and SBP that were considered moderate and mild drug related TEAEs, respectively, and one subject receiving the 40 mcg dose experienced decreases in heart rate that were considered 2 mild drug related TEAEs. All TEAEs resolved within 1 day of onset.

There were no clinically significant changes in laboratory parameters or ECG data. None of the physical examination findings were considered clinically significant by the investigators. The results of all neurological examinations performed during the study were normal, and no subject demonstrated abnormal oral/cheek anatomical structure or inflammation during examination for irritation of the buccal mucosa.

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Table 35. Summary of visual analogue scale/sedation examination results

Mo- Statistics- Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort All- ment of time ical data (10 mcg) Active (N=4) Smooth cebo treatment (N=8) (20 mcg) Active (N=4) Smooth cebo treatment (N=8) (40 mcg) Active (N=4) Smooth cebo treatment (N=8) (40 mcg) Active (N=2) Smooth cebo treatment (N=4) 3+4 [40 mc Active treatment (N=12) d) Placebo (N=6) go (N= 42) Tso η 8 4 8 4 8 4 4 2 12 6 60 introduction Average 95.5 97.8 97.4 86.5 74.8 100 86.8 70.5 78.8 90.2 87.5 valuation of tsozy value (SD) P-value (12.73) 1 (4.50) (6.25) 0.2384 (21,30) (35.29) (0.00) 0.0485 * (25.84) 0.8 (41.72) (31.78) 0.139 (24.09) (24.1 8) 0.5 h η 8 4 8 4 8 4 4 2 12 6 60 Average 78.8 90,0 74.4 55.8 73.0 93.0 75,0 64.5 73.7 83.5 76.3 value (SD) P-value (23.50) 0.4788 (11.52) (20.87) 0.2788 (35.61) (25.72) (12.68) 0.0465 * (22.67) 0.8 (48.79) (23.71) 0.2203 (28.09) (24.2 4) 1.0 h η 5 4 8 4 8 4 4 2 12 6 57 Average 67.6 93.8 43,0 48,5 42.8 94.3 71,5 64,0 52.3 84.2 61.7 value (SD) P-value (33.30) 0.3175 (6.65) (38.26) 0.9737 (48,50) (32.98) (10.18) 0.0121 * (22.61) 0.8 (49,50) (32.13) 0.0691 (28,22) (34.9 7) 1.5 h η 8 4 8 4 7 3 4 2 AND 5 56 Average 63,0 80.3 43.8 53.5 53.0 99.7 78.8 70,0 62.4 87.8 65,0 value (SD) P-value (29.69) 0.4586 (30,18) (40.02) 0.4869 (48,64) (41.68) (0.58) 0.0167 * (25.59) 0.9333 (42,43) (37.52) 0.0627 (26.72) (36.0 6) 2.0 h η 8 4 8 4 7 3 3 2 10 5 54 Average 81.8 74.5 54.9 59,0 50.9 99.7 73,0 72.5 57.5 88.8 67.9 value (SD) P-value (25.97) 0.9253 (42,19) (38.92) 0.8848 (47.79) (36.22) (0.58) 0.0167 * (24.88) 0.8 (37,48) (33.56) 0.0513 (23.93) (34.2 8)

P-values are calculated for active treatment and placebo for each cohort. P-value is based on the nonparametric two-tailed (exact) Wilcoxon test. *Statistically significant difference between groups (active treatment and placebo)

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Table 36. Time from SL administration (in minutes-seconds) of dexmedetomidine sublingual film to its complete dissolution (PD total)

Statistical data Sublingual film with dexmedetomidine Cohort 1 10 mcg (N=8) Cohort 2 20 mcg (N=8) Cohort 3 40 mcg (N=8) Kogorg 4 40 mcg (N=4) Cohort 3 and Cohort 4 40 mcg (No. 12) Total, active baking* (No. 28) Pooled placebo* (No. 14) Total* (No. 42) η 8 8 8 4 12 28 13 41 Mean (SD) 9:03 (7:52) 23:49 (12:36) 14:26 (10:04) 4:26 (2:24) 11:06 (9:30) 14:09 (11:33) 13:32 (12:49) 13:58 (11:49) Median 5:11 29:01 14:05 3:23 8:09 11:11 8:28 8:28 Minimum, maximum 3:00, 24:30 8:00, 44:01 3:18, 29:01 3:00, 8:00 3:00, 29:01 3:00, 44:01 3:00, 44:11 3:00, 44:11

*The Total, Active Treatment, Pooled Placebo, and Total columns include estimate counts, not subject-level counts.

Table 37. Summary of adverse events

Sublingual film with dexmedetomidine Cohort 1 10 mcg (No. 8) n(%) Cohort 2 20 mcg (No. 8) n(%) Cohort 3 40 mcg (No. 8) n(%) Cohort 4 40 mcg (No. 4) n(%) Cohort 3 and Cohort 4 40 mcg (No. 12) n(%) Total (No. 28) n(%) Placebo (No. 14) n(%) Total (No. 12) n(%) Messages about AE 75 Messages about TEAE 12 10 24 6 30 52 20 72 Patients with at least one TEAE ^a 6 (75.0) 7 (87.5) 8 (100.0) 4 (100.0) 12 (100.0) 25 (89.3) 10 (71.4) 35 (83.3) Patients with at least one 6 (75.0) 7 (87.5) 8 3 (75.0) AND 24 9 (64.3) 33

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TEAE associated with drug ³ (100,0) (91.7) (85.7) (78.6) TELE ¹³ Interconnection Possibly related 4(33.3) 2 (20.0) 5 (20.8) 0 5 (16.7) And (21.2) 4 (20.0) 15 (20.8) Probably related 2(16.7) 0 7 (29.2) 1 (16.7) 8 (26.7) 10 (19.2) 3 (15.0) 13 (18.1) Definitely related 3 (25.0) 8 (80.0) 12 (50.0) 3 (50.0) 15 (50.0) 26 (50.0) 10 (50.0) 36 (50.0) Related 0 0 0 0 0 0 1 (5.0) 1 (1.4) Not related/unlikely 3 (25.0) 0 0 2 (33.3) 2 (6.7) 5 (9.6) 2 (U,0) 7 (9.7) Severity of TEAE ^Ь Light And (91.7) 10 (100.0) 22 (91.7) 6 (100.0) 28 (93.3) 49 (94.2) 16 (80.0) 65 (90.3) Average 1 (8.3) 0 2 (8.3) 0 2 (6.7) 3 (5.8) 4 (20.0) 7(9.7) Heavy 0 0 0 0 0 0 0 0 Messages about STEAE ^b 0 0 0 0 0 0 0 0 Patients with at least one STEAE ³ 0 0 0 0 0 0 0 0 Patients with at least one drug-related STEAE ³ 0 0 0 0 0 0 0 0 Subjects with at least one TEAE leading to study discontinuation ³ 0 0 0 0 0 0 0 0 Death ³ 0 0 0 0 0 0 0 0

AE: adverse event; N: number of subjects; n (%): number and percentage of subjects included; SAE: serious adverse event; STEAE: serious treatment-emergent adverse event; TEAE: treatment-emergent adverse event

Notes: The Total, Active Treatment, Pooled Placebo, and Total columns include assessment counts, not subject-level counts. The categories Possibly Related, Probably Related, Related, or Definitely Related are considered drug-related.

Percentages are based on the number of subjects in the Safety Assessment Population in each treatment group.

Percentages are based on the total number of treatment-emergent adverse events reported in each treatment group

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Table 38. Treatment-emergent adverse events reported in two or more subjects overall

Class of systems Sublingual film with dexmedetomidine organs Whom- Whom- Whom- Whom- Whom- All- Pla- All- Preferrer mouth 1 mouth 2 mouth 3 mouth 4 mouth 3 go cebo go term 10 20 40 40 And (N=2 (N=14) (N=4 mcg (N=8) n(%) mcg (N=8) n(%) mcg (N=8) n(%) mcg (N=4) n(%) Cohort 4 40 mcg (N=12) n(%) 8) η (%) n(%) 2) η (%) Patients from 6 7 8 4 12 25 10 35 at least one TEAE (75.0) (87.5) (100,0) (100,0) (100,0) (89.3) (71.4) (83.3) Violations with 5 7 7 2 9 21 8 29 parts of the nervous system (62.5) (87.5) (87.5) (50,0) (75.0) (75.0) (57.1) (69,0) Drowsiness 4 6 7 2 9 19 7 26 (50,0) (75.0) (87.5) (50,0) (75.0) (67.9) (50,0) (61.9) Dizzy 1 1 6 0 6 8 2 10 nie (12.5) (12.5) (75.0) (50,0) (28.6) (14.3) (23.8) Headache 1 (12.5) 1 (12.5) 0 0 0 2 (7,1) 3 (21.4) 5 (11.9) Violations with 2 1 3 1 4 7 2(143) 9 sides of the gastrointestinal tract (25,0) (12.5) (37.5) (25,0) (33.3) (25,0) (21.4) Nausea 1(12.5) 0 2(25.0) 0 2(16.7) 3 (10.7) 0 3(7,1) Dry mouth 0 0 1(12.5) 1(25.0) 2(16.7) 2(7,1) 1(7,1) 3(7,1) Vomit 1(12.5) 0 1(12.5) 0 1(8,3) 2(7,1) 1(7,1) 3(7,1) General disorders and administration site conditions 1(12.5) 0 2(25.0) 1(25.0) 3(25.0) 4 (143) 1 ( ⁷ -1) 5 (11.9) Fatigue 1(12.5) 0 2(25.0) 0 2(16.7) 3 (10.7) 0 3(7,1)

Conclusion: Overall, the PK, PD, and safety results presented in this study support the need for further development of dexmedetomidine sublingual film for the acute treatment of agitation associated with dementia, schizophrenia, and bipolar disorders as a minimally invasive formulation with rapid delivery of dexmedetomidine.

Example 8. Clinical study of the efficacy (sedative and anti-agitation effect), pharmacokinetics and safety of intravenous dexmedetomidine in subjects suffering from schizophrenia

The primary objective of the study was to determine the optimal intravenous (IV) dose of dexmedetomidine hydrochloride in the target population in terms of efficacy and safety to achieve sedation with arousability (RASS score -1) that could be reversed by verbal stimulation. When this goal was achieved in each participant, IV dexmedetomidine hydrochloride was discontinued. A secondary key objective of the study was to determine the reduction in agitation, as measured by the RES score, at doses that achieved a RASS score of -1.

In addition, the following secondary objectives were set:

1. Determine how quickly the drug can be administered to achieve the total dose required to achieve a RASS-1 score.

2. To determine how long the sedative effect lasts after the administration of the study drug is stopped.

3. Determine whether any adverse effects on blood pressure, heart rate, or respiratory rate occur prior to or simultaneously with the achievement of the primary objective. Blood pressure and heart rate values that indicate a clinically significant event and at which the drug should be discontinued are:

- 147 047684 drop in systolic BP < 90 mmHg;

drop in diastolic BP < 60 mmHg;

a drop in heart rate below 50 beats per minute.

Participants were asked to read and sign written informed consent prior to any study-related procedures. All participants were screened for inclusion and exclusion criteria. Participants were admitted to the study center for screening (Day -1) the day before infusion. Baseline assessments were performed on Day -1 and the day of infusion (Day 1). On Day 1, participants were prepared for infusion, infused for up to 3 h, and monitored for resolution of sedation and any decrease in blood pressure or heart rate that met criteria for discontinuation. Participants were discharged from the study center only 3 h after resolution of any decrease in arousal level (e.g., RASS-1 score) and/or resolution of any decrease in blood pressure or heart rate that would warrant discontinuation of the drug. The principal investigator had the discretion to keep the participant overnight at the center on the evening of Day 1 for extended observation and then discharge the participant home on Day 2 if the principal investigator or designee determined that the participant's condition had returned to baseline.

The study population included 14 participants: 10 who received active treatment and 4 who received placebo. Patients 5, 7, 8, and 9 received placebo. Patients 1, 2, 3, 4, 11, 12, 14, 16, 17, and 18 received intravenous dexmedetomidine hydrochloride, starting at 0.2 mcg/kg/h and increasing by 0.1 mcg/kg/h every 30 min until discontinuation criteria were reached or to a maximum of 3 h (Table 39). Participants randomized to placebo received a corresponding intravenous infusion of placebo solution.

Table 39. Treatment methods studied

Treatment Compound Frequency Dexmedetomidine hydrochloride PRECEDEX® Continuous infusion, increase every 30 minutes Placebo Physiological solution Continuous infusion

Once the participant felt drowsy (RASS score -1), the infusion was stopped. The maximum total dose administered was 1.6 mcg/kg/h, when either the desired level of sedation was achieved or the maximum acceptable decrease in systolic or diastolic blood pressure or heart rate occurred.

During the study, participants were closely monitored by center staff with blood pressure and heart rate monitoring. Electrocardiograms were recorded periodically from the start of the infusion until sedation and/or any adverse effects on blood pressure or heart rate had ceased.

Whenever the patient's parameters met the above discontinuation criteria, center staff discontinued the infusion and continued to monitor the participant's vital signs every 15 minutes until the participant's parameters returned to baseline or until the participant achieved stable and acceptable blood pressure and pulse, as determined by the principal investigator. Return to baseline was defined as a decrease in BP within 15 mm Hg from the pre-infusion baseline or a decrease in HR within 10 beats per minute from the pre-infusion baseline.

If the investigator deems the decrease in blood pressure or heart rate to be clinically significant, in addition to discontinuing the dexmedetomidine hydrochloride infusion, appropriate medications may be administered based on the investigator's judgment.

Adverse events (AEs), including serious adverse events (SAEs), were assessed, recorded, and reported in accordance with FDA guidance. If any SAE occurred, the study was stopped until the cause of the SAE was determined.

Efficacy assessment (1) Richmond Agitation-Sedation Scale (RASS): The desired endpoint was how quickly somnolence could be achieved (RASS-1 score) without inducing changes in heart rate or blood pressure greater than those specified in the protocol. The study also tracked how long the participant remained at this level of sedation; sedation was considered resolved when the participant was awake and responsive to spontaneous stimuli.

(2) PANSS: change from baseline for patients with mild agitation (3) Clinical Global Impression of Improvement (CGI-I)

- 148 047684 (National Institute of Mental Health, 1976) ranging from 1 (very much improved) to 7 (very much worse) compared with baseline. Each participant was rated for agitation severity at 15 and 30 min after each dose, at the time of the efficacy assessment, and when the participant returned to baseline (in terms of level of arousal). The CGI-I scale focuses on the severity of agitation rather than the severity of illness.

(4) After the infusion was stopped, participants were assessed for fitness for discharge by the principal investigator or designee, as evidenced by a return to their baseline level of alertness and awareness without deterioration in balance, gait, and reaction time, as determined by the principal investigator or designee.

Results (A) RASS (Richmond Sedation-Agitation Scale) efficacy study 9 of 10 patients in the treatment group (subjects 1-3, 11, 12, 14, and 16-18) achieved a RASS score of at least -1, while no patient in the placebo group (subjects 5 and 7-9) experienced significant sedation (see Fig. 16 and Table 40).

Table 40. RASS scores in patients with schizophrenia treated with dexmedetomidine hydrochloride and saline infusion

Infusion (minutes) RASS scores after infusion start Patient No. 1 T 2 T T 4 t 5 R 7 R 8 R 9 R and so on 12 t 14 t 16 t 17 t 18 t 0 1 3 1 1 1 1 1 1 1 1 1 1 1 0 15 -2 -1 30 0 0 0 1 1 1 1 0 0 0 0 0 45 0 -1 60 0 -1 0 1 1 0 1 0 0 0 0 75 -1 -1 -1 -1 90 0 1 0 0 1 0 105 120 0 0 0 0 1 -1 135 0 150 0 0 0 1 165 180 0 0 0 1

T - treatment group;

P - placebo group

RES (PANSS Emotional Arousal Rating Component)

In 9 of 10 patients in the treatment group (subjects 1-4, 11, 12, 14, 16, and 17), agitation was reduced to a minimum (RES score of 7 or less) (see Table 41 and Fig. 17).

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Table 41. The RES scale score is presented in patients with schizophrenia who received an infusion of dexmedetomidine hydrochloride and saline solution.

Time (min) RES points after infusion start Patient No. 1 T 2 T 3 t 4 T 5 R 7 R 8 R 9 R And t 12 T 14 T 16 t 17 T 18 T 0 9 16 12 9 AND 12 9 13 13 13 10 10 10 15 5 13 12 9 10 12 9 13 13 13 9 9 8 30 12 10 8 9 9 8 12 11 13 6 6 7 45 11 7 8 9 8 8 12 9 10 6 6 5 60 9 6 7 8 8 8 13 9 10 5 7 75 7 7 8 8 7 AND 7 8 5 5 90 7 7 9 7 AND 6 105 7 8 8 7 10 5 120 7 8 8 7 10 135 7 8 7 7 9 150 8 7 7 9 165 8 8 7 9 180 8 8 7 10

T- treatment group;

P - placebo group (B) Pharmacokinetic study: (PK study)

Plasma dexmedetomidine levels in patients were also measured during the infusion period. The results are shown in Table 42. Maximum dexmedetomidine concentrations in patients with schizophrenia (Cmax) ranged from about 22.45 to about 406.3 pg/mL. The time to reach Cmax ranged from about 15 to about 105 min. The mean infusion rate was 0.36 mcg/kg/hr with the maximum rate ranging from about 0.2 to about 0.6 mcg/kg/hr (see Figs. 18–20).

Table 42. Plasma concentrations (pg/mL) of patients with schizophrenia at various time points during infusion of dexmedetomidine hydrochloride and saline solution are presented

Time (min) Plasma concentration (picogram/mL) 1 T 2 T 3 G 4 T 5 R 7 R 8 R 9 R I T 12 T 14 G 16 G 17 T 18 T 0 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ 15 22.45 BLQ BLQ BLQ BLQ BLQ 41,01 BLQ BLQ 2.56 15.87 48.36 30 14.72 BLQ BLQ BLQ BLQ BLQ BLQ BLQ 62.91 44.87 52,66 15.59 BLQ 54,53 45 BLQ BLQ BLQ BLQ BLQ BLQ 124.07 50,51 46.53 41,17 39.93 60 BLQ BLQ BLQ BLQ BLQ 150.47 108.6 406.3 67,88 75 BLQ BLQ BLQ BLQ BLQ 158.5 4 72.26 90 44.3 BLQ BLQ BLQ BLQ 237.8 105 BLQ BLQ BLQ BLQ 267.3 120 BLQ BLQ BLQ BLQ 135 BLQ BLQ BLQ BLQ 150 BLQ BLQ BLQ BLQ 165 BLQ BLQ BLQ BLQ 180 BLQ BLQ BLQ BLQ Total duration of infusion (min) 19 75 60 149 180 180 180 179 68 103 64 66 36 30

*BLQ means below limit of quantification T - treatment; P - placebo

Discussion: Administration of intravenous dexmedetomidine hydrochloride resulted in a >= 50% reduction in PEC score in a total of 7 of 10 subjects, with one subject (Patient 1) responding to treatment at a Cmax of 22 pg/mL. Five of 10 subjects (Patients 1, 2, 3, 16, and 17) demonstrated a 40% reduction in PEC score at a Cmax of <72 pg/mL. Good response rates at these exposure levels in

- 150 047684 plasma data indicate that sublingual administration of dexmedetomidine hydrochloride at similar or higher Cmax exposure levels results in good anti-agitation effects. As demonstrated above in Example 7, sublingual administration of dexmedetomidine hydrochloride to healthy volunteers provided good plasma exposure levels at doses of 10, 20, and 40 mcg, indicating that such doses were suitable for producing good anti-agitation effects (e.g., as measured by reduction in PEC score) in agitated subjects, including patients with schizophrenia, without causing clinically significant adverse effects on blood pressure and/or heart rate.

Example 9. A multicenter, randomized, double-blind, placebo-controlled, phase III study to determine the efficacy and safety of dexmedetomidine hydrochloride sublingual film in dementia-associated agitation

Goals

Main objective:

To determine whether a single dose of dexmedetomidine sublingual film was effective in reducing symptoms of acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder, as assessed by change from baseline in the agitation component of the Positive and Negative Syndrome Scale (PEC) compared with placebo.

Key Secondary Goal:

To determine the earliest time at which an effect on agitation was evident, as measured by the change in total RES score from baseline compared with placebo.

Other search targets:

1. Overall clinical improvement after drug administration according to the Clinical Global Impression of Improvement (CGI-I) scale.

2. Agitation-Calmness Evaluation Scale (ACES) score at 2, 4 and 8 hours after dosing.

3. Change from baseline in the total RES score over time, measured from 10 min to 24 h after dosing.

4. RES responders and CGI-I responders 2 hours after administration of dexmedetomidine sublingual film compared with placebo:

a) RES responders were defined as subjects who achieved at least a 40% reduction in total RES score from baseline at or before 2 hours post-dose.

b) CGI-I responders were defined as subjects with a CGI-I score of 1 or 2 (CGI-I non-responders were defined as subjects with a score of 3 to 7 at 2 h).

5. Time to rescue drug intake during the entire 24-hour post-treatment assessment period for subjects receiving dexmedetomidine sublingual film compared with placebo.

6. Proportion of subjects in the treatment group who received rescue medications at 4 h and within 24 h after dosing.

7. Duration of the calming effect, described by the change in the total RES score and the ACES score from baseline at 2, 4, and 8 hours after dosing.

8. Description of the effect on general psychotic symptoms and on the subscale scores (general, positive, negative subscales, as well as the general psychopathology subscale of the PANSS)

9. To determine the safety profile of dexmedetomidine sublingual film as measured by vital signs and treatment-emergent adverse event reports, as well as vital signs.

10. Description of general tolerability taking into account reports of adverse events and local (oral/sublingual) tolerability of the oral film.

11. Description of the pharmacokinetics of dexmedetomidine sublingual film in patients.

12. Determining the acceptability, taste and attractiveness of the study drug to the patient using a Likert scale to collect information on the subject's acceptability of the drug, opinions on taste and issues related to attractiveness.

Study design:

This was a randomized, double-blind, placebo-controlled, dose-ascending phase III study evaluating the efficacy, safety, and tolerability of sublingual dexmedetomidine film in adult (18-75 years) men and women with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder. In this clinical trial, subjects were randomized 1:1:1 to receive dexmedetomidine sublingual film (180 or 120 mcg DEX dose) or matching placebo film. Randomization was stratified by age; age < 65 years and age > 65 years.

Suitable subjects (subjects with acute agitation due to schizophrenia, schizoaffective disorder

- 151 047684 or schizophreniform disorder) were identified in outpatient clinics, mental health facilities, psychiatric clinics, or emergency medical services, including medical/psychiatric observation units, and patients could be recently admitted to the hospital with acute agitation or already hospitalized for chronic comorbidities. Subjects resided at the clinical trial center or were hospitalized to remain under medical supervision during eligibility screening procedures.

After eligibility was confirmed, subjects were randomized to receive 180 or 120 mcg dexmedetomidine sublingual film or matching placebo. During administration, patients were instructed on how to administer the study product sublingually and that they were to retain the study product in the sublingual cavity until it dissolved. The patient self-administered the drug under the supervision of a trained staff member at the center. If the patient was unable to self-administer the drug, this was recorded and the subject was discontinued. In case of persistent or recurrent agitation, the investigators may decide to administer a repeat dose of 90 or 60 mcg (half of a 180 or 120 mcg film) after 2 hours, as measured by a change in PEC score from baseline of <40%, but in the absence of safety concerns. Patients could only be re-dosed if they were hemodynamically stable, were not hypotensive (diastolic/systolic pressure should be greater than 90/60), and were not bradycardic (must be greater than 60 bpm). Patients also could not be re-dosed if they were orthostatically hypotensive (drop in SBP or DBP of 20 units) or if they experienced an AE that, in the opinion of the PI, precluded re-dosing. The maximum number of re-doses per subject was 2 within 12 hours of the first dose. Doses could not be given sooner than 2 hours after the previous dose. If the change in PEC score from baseline was >40%, re-dosing was not allowed.

Participants were also assessed for local irritation around the area where the film was placed. Efficacy and safety assessments were performed periodically before and after dosing. Every effort was made to complete all patient assessments according to protocol. Vital sign measurements, pulse oximetry, and ECG with rhythm strip were performed according to the assessment schedule (Table 43) prior to any PK assessments. Participants were allowed to drink water ad libitum 15 min after completion of dosing. Safety and tolerability assessments were performed at various time points.

Appropriate studies were repeated if any abnormal vital signs, clinical laboratory tests, physical examination findings, or ECG parameters were determined by the investigator to be clinically significant, including test results obtained on the last day of the study or at early study termination. For any test result abnormality determined to be clinically significant, reanalysis was performed during the observation period and until the value returned to baseline (or within normal limits) or until the abnormality was judged by the investigator to be stable and no longer of clinical concern.

Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mL of plasma) was collected into K2-EDTA tubes at scheduled intervals to determine plasma study drug (or placebo) concentrations. Plasma PK samples were collected within 10 minutes of the scheduled sample collection time on Day 1.

Number of subjects (planned): Approximately 375 subjects were enrolled at 30 study sites in the United States.

Diagnosis and main eligibility criteria

Inclusion criteria:

(1) Male and female patients aged 18 to 75 years inclusive.

(2) Patients who met DSM-5 criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder.

(3) Patients who exhibit clinical agitation at baseline with a total score > 14 on 5 items (impaired impulse control, tension, hostility, uncooperativeness, and agitation), including the PANSS agitation component (PEC).

(4) Patients with a score > 4 on at least 1 of 5 items on the PEC scale or a PEC score at baseline (5) Patients who have read, understood, and provided written informed consent.

(6) Patients in good general health prior to study entry, as determined by detailed medical history, physical examination, 12-lead ECG with rhythm strip, blood chemistry profile, hematology data, urinalysis, and the principal investigator's opinion.

- 152 047684 (7) Female participants if they were of childbearing potential and sexually active, and male participants if they were sexually active with a partner of childbearing potential, who agreed to use a medically acceptable and effective method of birth control throughout the study and for one week thereafter. Medically acceptable methods of contraception that the participant and/or his/her partner could use included abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppositories, surgical sterilization, and progestin-only implant or injection. Prohibited methods included the calendar method, withdrawal, condom only, or diaphragm only.

Exclusion criteria:

(1) Patients with agitation due to acute intoxication, including positive detection of alcohol vapor in exhaled air or drugs of abuse (except THC) during urine screening.

(2) Patients treated with benzodiazepines, other hypnotics, or short-acting oral or intramuscular neuroleptics within 4 hours prior to study drug administration.

(3) Treatment with alpha-1-noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin or prazocin) or other prohibited drugs.

(4) Patients at significant risk of suicide or homicide as assessed by the investigator or any patient with a yes answer to items 4 or 5 on the CSSRS.

(5) Female patients who have had a positive pregnancy test on screening or who are breastfeeding.

(6) Patients with a history of hydrocephalus, seizure disorder, or severe head injury, stroke, transient ischemic attack, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal neurologic manifestations.

(7) History of syncope or other syncopal attacks, existing signs of hypovolemia, orthostatic hypotension (mean of 1, 3, and 5 min measurements), screening and baseline heart rate < 55 beats per minute or systolic blood pressure < 110 mmHg or diastolic blood pressure < 70 mmHg.

(8) Patients with laboratory or ECG abnormalities deemed clinically significant by the investigator or designee [progressive heart block (second-degree atrioventricular block or higher without pacemaker), diagnosed sick sinus syndrome] that could have had clinical consequences while the patient was in the study.

(9) Patients with serious or unstable medical conditions. These include pre-existing hepatic (moderate to severe liver failure), renal, gastrointestinal, respiratory, cardiovascular (including coronary artery disease, congestive heart failure), endocrinological, or hematological diseases.

(10) Patients who received study drug within 30 days prior to the current episode of agitation.

(11) Patients who, for any reason, are considered by the investigator to be unsuitable candidates for dexmedetomidine; for example, patients with a history of allergic reactions to dexmedetomidine.

Treatment under investigation

Study drug, dose and route of administration:

Dexmedetomidine hydrochloride was a thin film formulation of DEX for sublingual (SL) administration. The delivered dose was 180 mcg or 120 mcg DEX sublingually. The product is formulated in a small solid film dosage form, approximately 193.6 ^mm2 in area and 0.7 mm thick, designed to dissolve completely in the SL space within 1-3 min.

Reference therapy, dose and route of administration:

Appropriate placebo films for sublingual administration as described above. Duration of treatment 1 day

Research procedures

Subjects provided written informed consent prior to any study-related procedures, including discontinuation of prohibited concomitant medications.

The schedule of procedures to be performed during the study is given in Table 43.

- 153 047684

Table 43. Schedule of procedures

Treatment Evaluation, Day 1 Activity Screening Dose administration time ¹ Time after administration of dose ¹ Day 2, observation (+1) Day 3, discharge Day 7 (+2) Moment in time Ts of treatment -1 hour from time 0 10 min 20 min 30 min 45 min 1 h 1.5 h 2 h 4 h 6 h 8 h 24 h (-9/+12 h) End of study Informed consent X Medical history X Demographics X data Body weight X X Height X BMI X Alcohol in exhaled air X MINI X Physical examination X X Lab. safety research 2 X X X ECG with rhythm strip ³ X X X X Pulse oximeter X X X X X X Resting vital signs ⁴ X X X X X X X X X X X Vital signs in orthostatic position ⁴ X X X X X X X X

- 154 047684

Hospitalization in department X Inclusion/exclusion criteria X X Randomization X Administration of study drug ¹⁰ PANSS ⁹ PCRS ⁵ RES ⁵ ACES ⁵ CGI severity ⁶ CGI improvement ⁶ C-SSRS Score of buccal mucosa (SL) for local irritation ⁷ Likert scale X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Question about the attractiveness of the drug X Taking samples for RK ⁸ X X X Concomitant drug therapy X X X X X X Adverse events X X X X X X

Notes on the procedure schedule:

¹ Pre-dose assessments had a window of 60 min before dose administration, except for PEC and ACES, which were conducted within 15 min after dose administration (15 to 0 min). All post-dose assessments had a window of -5/+15 min for 1.5 h assessments, -5/+25 min for 2 h assessments (except for the PEC scale, which had a window of +/-5 min), and ±30 min for 4, 6, and 8 h assessments.

² Laboratory parameters for safety analyses included biochemistry, hematology, urinalysis, UDS (local lab, tested at screening only), breath alcohol (tested at screening only), and urine pregnancy test (tested at screening only). Laboratory assessments at screening/enrollment: specimens collected at the local lab within 7 days before screening were acceptable, with the exception of urine drug screening. If same-day results were not available, a benchtop or non-CLIA test could be performed for confirmation; results from a CLIA-certified lab must be reported when available. Central lab specimens were collected at screening, Day 3, and Day 7.

³ There was no need to repeat the pre-dose ECG if a screening ECG was recorded on the day of dosing. Post-treatment ECGs should be performed before pharmacokinetic assessment.

- 155 047684 ⁴ Resting (supine) vital signs (SBP, DBP, and HR) were measured after the subject had been lying down for 5 min at Screening, pre-dose, and at 30 min, 1, 2, 4, 6, 8, and 24 h after the first dose, and on Day 3 and Day 7. Triplicate measurements were taken if systolic BP<90 mmHg, diastolic BP<60 mmHg, or pulse <60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate, and temperature) were taken after the subject had stood for 1, 3, and 5 min at Screening, pre-dose, 2, 4, 8, and 24 h after the first dose, and on Day 3 and Day 7.

⁵ The PEC assessment was performed at screening, predose (within 15 min before dose), and 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, 8, and 24 h after the first dose. The PCRS assessment was to be performed before the PEC assessment, if appropriate. The PEC assessment was to be performed at 6 and 24 h before the PANSS interview. The ACES assessment was performed predose (within 15 min before dose) and 2, 4, and 8 h after dose ⁶ The CGI Severity assessment was performed at screening and predose. The CGI Improvement assessment was performed 30 min, 1, 2, and 4 h after the first dose.

^7. Examination of the buccal mucosa 30 min, 2, 4 and 24 h after administration of the dose for local irritation.

⁸ Blood PK samples were collected at 1, 4, and 8 h (while awake) post-dose. A sample could be withheld if the physician indicated in the initial documentation that the patient was in a mental state that did not support the collection of a PK sample. Non-consent or refusal of all or any PK sample collections was not restrictive and did not result in ET. Vital signs were to be assessed prior to PK sample collection when they were performed at the same time points.

⁹ Pre-dose PANSS assessments could be performed at any time before dosing on the day of dosing and at 6 and 24 h (-1/+2 h) post-dose. At 6 and 24 h after the PEC assessment, a PANSS interview was required. The PANSS assessments at 6 and 24 h were relative to the pre-dose PANSS.

¹⁰ The investigator could decide to re-dose a patient with half of the film after the 2-hour post-dose assessments were performed if the change in PEC score from baseline was <40%. Patients could be re-dosed up to 2 times within 12 hours of the first dose. All assessments listed in this procedure schedule were performed 2 hours after the first dose and repeated 2 hours after each re-dose.

Evaluation criteria

Efficiency rating:

The drug effects on acute agitation were assessed using the Positive and Negative Syndrome, Excitation Component (PEC) scale. The PEC scale includes 5 items related to agitation: decreased impulse control, tension, hostility, uncooperativeness, and agitation; each item can be scored from 1 (minimum) to 7 (maximum) points. Thus, the total score on the PEC scale, consisting of 5 subscales, could range from 5 to 35 points.

General agitation and sedation were assessed using the Agitation and Serenity Scale (ACES), in which 1 = marked agitation; 2 = moderate agitation; 3 = mild agitation; 4 = normal behavior; 5 = mild calm; 6 = moderate calm; 7 = marked calm; 8 = deep sleep; and 9 = sleep without awakening.

Change in agitation in response to treatment was also measured using the Clinical Global Impression of Improvement (CGI-I) scale. CGI-I scores range from 1 to 7: 0 = not rated (absent), 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse.

Safety and Tolerability Assessments: AEs, clinical laboratory test results, ECG with rhythm strip, pulse oximetry, and vital signs were monitored to assess tolerability. All observed and self-reported AEs were recorded. The relationship of AEs to study drugs was defined by the investigators as unrelated, unlikely/remotely related, possibly related, probably related, or definitely related. Vital signs, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate, were monitored. The SL application site (buccal mucosa) was also observed for signs of local irritation.

Additional ratings:

Demographic data, medical and psychiatric history, psychotic symptoms (PANSS), smoking history, previous and concomitant medications, physical examination, pregnancy

Pharmacokinetics: Random PK sampling of plasma concentrations has been reported in certain

- 156,047,684 divided time points. Population PK/PD analysis of plasma drug concentration relative to clinical response was presented using a separate SAP and report. Graphical assessment of PK relative to vital signs and other potential PD parameters is presented.

Statistical Analysis Efficiency Analysis

The primary efficacy endpoint in this study was the absolute change from baseline in PEC total score at 120 minutes. The intention-to-treat set, consisting of all patients who received any study drug and had both a baseline assessment and at least 1 postdose efficacy assessment, was analyzed. Key secondary endpoints were the change from baseline in PEC score at 90, 60, 45, 30, 20, and 10 minutes. Other exploratory endpoints were the same as those listed in the Exploratory Objectives section.

Security Analysis:

Safety data were analyzed for all subjects who received at least 1 dose of study drug. The number and percentage of subjects with 1 or more AEs were summarized by treatment, relationship to study drug, and severity. AEs were coded using the Medical Dictionary of Terminology for Regulatory Activities (Med DRA). Subjects who discontinued study drug due to AEs, serious AEs, and/or death are listed. Laboratory parameters were summarized by treatment using descriptive statistics and fact sheets of clinically significant abnormalities. Vital signs and ECG data were summarized by change from baseline using descriptive statistics.

Pharmacokinetic analyses

Plasma concentrations and concentration-time data for dexmedetomidine were used to calculate pharmacokinetic parameters; these data and results are reported separately. All pharmacokinetic parameters were calculated using noncompartmental analysis with WinNonlin software version 5.2 or higher. Actual sampling times were included in all pharmacokinetic analyses. Protocol times were included in the calculation of mean plasma concentrations for graphical display. Other PK analyses were performed as needed.

Summary of Results Demographic Data

Demographic and baseline characteristics are presented below in Table 44.

_____________Table 44. Demographic data_____________

Sublingual film with dexmedetomidine Placebo (N=126) Total (N=381) 180 mcg (N=126) 120 mcg (N=129) Average age (years) 46.0(11.91) 45.7 (11.32) 45.1 (11.13) 45.6 (11.43) Women, η (%) 44 (34.9) 52 (40.3) 44 (34.9) 140 (36.7) Race (% white/% non-white) 16.7/83.3 25.6/74.4 16.7/83.3 19.7/80.3 BMI 32.53 (7.8) 31.24 (7.6) 32.56 (7.4) 32.10(7.6) Diagnosis of schizophrenia 85.70% 87.60% 80.20% 84.50% Schizophrenia 14.30% 12.40% 19.80% 15.50% RES at baseline, average 17.6 17,5 17.6 ND

3. Efficiency

Dexmedetomidine sublingual film significantly reduced the severity of agitation from baseline as measured by the PEC, ACES, and CGI-I scores. Key efficacy data at 2 hours post-dose are presented below.

(a) Primary efficacy endpoint (PEC score reduction): There was a reduction in PEC (PANSS or Positive and Negative Syndrome Scale, agitation component) score for agitation with rapid reassurance without excessive sedation at the clinical index time point and earlier time points. The primary efficacy endpoint was the mean change from baseline in PEC total score at 2 h (120 min) compared with placebo. There were 2 dose cohorts (120 mcg (N=129) and 180 mcg (N=126)) and 126 patients receiving placebo. Active patients in each of the 2 dose cohorts receiving placebo were compared with patients receiving placebo. Change from baseline in PEC score at 2 h

- 157 047 684 levels in patients receiving dexmedetomidine sublingual film were compared with placebo using a mixed-effects model for repeated measures (MMRM) analysis with baseline PEC score, treatment group, time, the interaction between treatment group and time, and the interaction between baseline PEC score and time taken as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film, as measured by RES score reduction, is dose-dependent and robust. The reduction in RES score from baseline in the 180 mcg dose group demonstrated a significant response, with a mean change from baseline in RES total score (CFB) of -10.3 at 2 h post-dose compared with placebo (Table 45 and Figs. 21A and 21B). Mean changes from baseline were 8.5 points for the 120 mcg treatment groups compared with placebo (mean change -4.8). Furthermore, because early onset of action is an important attribute of therapy to reduce agitation, the 180 mcg group demonstrated a statistically significant difference from placebo as early as 20 min post-dose (Figs. 21A and 21B). Furthermore, the reduction in RES score from baseline in the 180 mcg and 120 mcg dose groups demonstrated a significant response at 6 hours post-dose compared with placebo (Fig. 21B).

Analysis of RES responders: The proportion of responders, defined as those with a 40% reduction in total RES score from baseline at 2 hours post-dose, was greatest in the 180 mcg group (87% for 180 mcg, 67% for 120 mcg) compared with placebo (34%) (Table 45). The duration of the sedative effect of the 180 mcg dose was markedly prolonged, with a sustained, statistically significant reduction in RES score evident at 24 hours.

Table 45. Summary of changes from baseline in PANSS-PEC total score at 2 h and percentage of responders at 2 h for PEC score by treatment group

Moment of time (120 min) N Placebo Sublingual film with dexmedetomidine Total RES score 120 mcg (N=126) 180 mcg (N=126) Change from baseline (LSM) N=126 (180 µg) N=129 (120 µg) -4.8 -8 5 *** -10 3 *** Answer ° 126 34% 67% 87%

Proportion of patients achieving a reduction in RES score by > 40%; * P < 0.025; *** P < 0.0001 Secondary efficacy endpoints

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at 2 hours post-dose were consistent with the PEC total score results and indicated improvement in agitation symptoms following treatment with dexmedetomidine sublingual film.

ACES scores: The secondary objective of this study was to evaluate the duration of the calming effect of sublingual dexmedetomidine thin film using the Agitation and Calmness Evaluation Scale (ACES) at pre-dose, 2 hours, and 4 hours after the first dose. The ACES score was consistent with the analysis of the primary efficacy endpoint and was statistically significant for calming, as measured by the ACES at two hours, compared with placebo at doses of 120 and 180 mcg (120 mcg; p=0.0001) and (180 mcg; p<0.0001). At 2 hours post-dose, subjects in the 120 and 180 mcg treatment groups demonstrated significantly greater improvements compared with placebo on the ACES scale (+ about 2.8 [P<0.0001] for 120 mcg; + about 3.75 [P<0.0001] for 180 mcg compared with placebo + about 1.0). Improvements at 4 hours post-dose were similar (+ about 2.8 [P<0.0001] for 120 mcg; + about 3.2 [P<0.0001] for 180 mcg compared with placebo + about 1.0). (Fig. 22).

CGI Scores: The percentage of subjects achieving a CGI-I score of 1 or 2 (very much improved or much improved) at 2 hours post-dose was significantly higher in the 120 mcg group (about 65% [p<0.0001]) and the 180 mcg group (about 90% [p<0.0001]) compared with placebo (about 35%). Significant improvements were also observed at 30 min, 1, and 4 hours post-dose in both treatment groups [in the 180 mcg group (p<0.0001) and the 120 mcg group (p<0.0075)] (Fig. 23).

Conclusion: Dexmedetomidine sublingual film significantly reduced the severity of agitation from baseline as measured by the PEC, CGI-I, and ACES scales in patients with schizophrenia. The primary endpoint was met in the 120 and 180 mcg treatment groups as there was a significant improvement in PEC total scores from baseline to 2 hours post-dose, with mean changes of -8.5 and -10.3 points, respectively.

- 158,047,684 venously, versus -4.8 for placebo. A decrease in agitation was observed as early as 20 min compared with placebo. In addition, changes in secondary efficacy endpoints (i.e., ACES and CGI-I scores) at 2 h post-dose were consistent with the PEC total score results and indicated improvement in agitation symptoms following treatment with dexmedetomidine sublingual film.

Example 10. A multicenter, randomized, double-blind, placebo-controlled phase III study to determine the efficacy and safety of dexmedetomidine hydrochloride sublingual film in subjects with agitation associated with bipolar disorder (SEREN ITY II)

Goals

The main parameter to be determined

The primary efficacy endpoint in this study was the absolute change from baseline in RES total score at 2 hours. The intention-to-treat set, consisting of all patients who received any study drug and had both a baseline assessment and at least 1 post-dose efficacy assessment, was analyzed. Observations recorded after administration of rescue medications were reviewed.

Secondary outcome measures included:

A secondary efficacy outcome measure was the earliest time at which an effect on agitation was evident, as measured by the change from baseline in RES total score compared with placebo.

The search parameters evaluated included:

1. Overall clinical improvement after drug administration according to the Clinical Global Impression of Improvement (CGI-I) scale.

2. Agitation-Calmness Evaluation Scale (ACES) score at 2, 4 and 8 hours after dosing.

3. Change from baseline in the total RES score over time, measured from 10 min to 24 h after dosing.

4. RES responders and CGI-I responders 2 hours after dexmedetomidine hydrochloride administration, compared with placebo:

a) RES responders were defined as those who achieved at least a 40% reduction in total RES score from baseline at or before 2 hours post-dose.

b) CGI-I responders were defined as subjects with a CGI-I score of 1 or 2 (CGI-I non-responders were defined as subjects with a score of 3 to 7 at 2 h).

5. Time to rescue medication administration during the entire 24-hour post-treatment assessment period for subjects receiving dexmedetomidine hydrochloride compared with placebo.

6. Proportion of subjects in the treatment group who received rescue medications at 4 h and within 24 h after dosing.

7. Duration of the calming effect, described by the change in the total RES score and the ACES score from baseline at 2, 4, and 8 hours after dosing.

8. To determine the safety profile of dexmedetomidine hydrochloride as measured by vital signs and treatment-emergent adverse event reports.

9. Description of general tolerability taking into account reports of adverse events and local (oral/sublingual) tolerability of the oral film.

10. Description of the pharmacokinetics of dexmedetomidine hydrochloride in patients.

11. Determining the acceptability, taste and attractiveness of the study drug to the patient using a Likert scale to collect information on the subject's acceptability of the drug, opinions on taste and questions regarding attractiveness.

12. Characterization of the patient population using the Young Mania Rating Scale (YMRS).

Study design

The study included approximately 381 subjects randomized in a 1:1:1 ratio to doses of 180, 120 mcg dexmedetomidine hydrochloride, or placebo, stratified by age < 65 and > 65 years. Doses were selected based on the results of a previous phase Ib clinical trial.

The study included adult men and women with acute agitation associated with bipolar I or II disorder.

Eligible subjects (subjects with acute agitation due to bipolar I or II disorder, typically with hypomanic, manic, or mixed episodes) were identified from outpatient clinics, mental health settings, psychiatric clinics, or emergency medical services, including medical/psychiatric observation units,

- 159 047684 and patients could be newly admitted to hospital with acute agitation or already hospitalized for chronic comorbidities. Subjects resided at the clinical trial center or were hospitalized to remain under medical supervision while undergoing eligibility screening procedures.

After eligibility was confirmed, subjects were randomized to receive 180 mcg dexmedetomidine hydrochloride sublingual film or 120 mcg dexmedetomidine hydrochloride sublingual film or matching placebo. Efficacy and safety assessments were performed periodically before and after dosing.

Vital sign measurements, pulse oximetry, and rhythm strip ECG were performed according to the assessment schedule prior to any PK assessments. Participants were allowed to drink water ad libitum 15 min after completion of dosing. Safety and tolerability assessments were performed at various time points. Please see Table 46 for the procedure schedule.

Appropriate studies were repeated if any abnormal vital signs, clinical laboratory tests, physical examination findings, or ECG parameters were determined by the investigator to be clinically significant, including test results obtained on the last day of the study or at early study termination. For any test result abnormality determined to be clinically significant, reanalysis was performed during the observation period and until the value returned to baseline (or within normal limits) or until the abnormality was judged by the investigator to be stable and no longer of clinical concern.

Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mL of plasma) was collected into K2-EDTA tubes at scheduled intervals to determine plasma study drug (or placebo) concentrations. Plasma PK samples were collected within 10 min of the scheduled sample collection time on Day 1. Blood samples were collected according to Table 46 Procedure Schedule.

Discussion of study design

This is a definitive, confirmatory study to evaluate the safety and efficacy of dexmedetomidine hydrochloride sublingual film for the acute treatment of agitation in bipolar disorder. The study was designed to characterize the efficacy, safety, and tolerability of dexmedetomidine hydrochloride sublingual film in agitation associated with bipolar disorder. The dose of dexmedetomidine hydrochloride was selected based on results that demonstrated rapid onset of efficacy in a large proportion of subjects, good tolerability, and an acceptable safety profile. In cases of persistent or recurrent agitation, the investigators may decide to administer an additional reduced dose of 90 or 60 mcg (half of a 180 or 120 mcg film) after 2 hours, as measured by a change in RES score from baseline <40%, but in the absence of safety concerns. Patients could only be re-dosed if they were hemodynamically stable, did not have hypotension (systolic/diastolic pressure should be greater than 90/60), and did not have bradycardia (must be greater than 60 bpm). Patients also could not be re-dosed if they had orthostatic hypotension (drop of > 20 mm Hg in systolic pressure or 10 mm Hg in diastolic pressure) or if they had an adverse event (AE) that, in the opinion of the PI, precluded re-dosing. The maximum number of re-doses per subject was 2 within 12 hours after the first dose. Doses could not be given sooner than 2 hours after the previous dose. If the change in PEC score from baseline was > 40%, re-dosing was not allowed.

Placebo was chosen as the comparator to more accurately assess efficacy as well as safety and tolerability. The randomized, double-blinded, parallel-group design ensured that treatment assignment and outcomes were masked to the sponsor, all subjects, and involved site personnel, thereby minimizing any potential bias. The randomization ratio provided an additional tool to ensure blinding by reducing the likelihood of guessing between treatment groups.

Diagnosis and main eligibility criteria:

Inclusion Criteria

1. Male and female patients aged 18 to 75 years inclusive.

2. Patients who met DSM-5 criteria for bipolar I or II disorder, typically with hypomanic, manic, or mixed episodes.

3. Patients who exhibit clinical agitation at screening and at baseline with a total score > 14 on 5 items (impaired impulse control, tension, hostility, uncooperativeness, and agitation), including the PANSS agitation component (PEC).

4. Patients who had a score > 4 on at least 1 of 5 items on the RES scale at baseline.

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5. Patients who have read, understood and provided written informed consent.

6. Patients in good general health prior to study entry, as determined by detailed medical history, physical examination, 12-lead ECG with rhythm strip, blood chemistry profile, hematology data, urinalysis, and the principal investigator's opinion.

7. Female participants if they are of childbearing potential and sexually active, and male participants if they are sexually active with a partner of childbearing potential, who agreed to use a medically acceptable and effective method of birth control throughout the study and for one week after the end of the study. Medically acceptable methods of contraception that the participant and/or his/her partner could use included abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppositories, surgical sterilization, and progestin-only implant or injection. Prohibited methods included the calendar method, withdrawal, condom only, or diaphragm only.

Exclusion criteria

1. Patients with agitation due to acute intoxication, including positive detection of alcohol vapor in exhaled air or drugs of abuse (except THC) during urine screening.

2. Use of benzodiazepines or other hypnotics or antipsychotic drugs within 4 hours before study treatment.

3. Treatment with alpha-1-noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin or prazosin) or other prohibited drugs.

4. Patients with serious risk of suicide were also excluded.

5. Female patients who have had a positive pregnancy test on screening or who are breastfeeding.

6. Patients with a history of hydrocephalus, seizure disorder, or severe head injury, stroke, transient ischemic attack, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal neurologic manifestations.

7. History of syncope or other syncopal attacks, existing signs of hypovolemia, orthostatic hypotension (mean of 1, 3, and 5 min measurements), screening and baseline heart rate < 55 beats per minute or systolic blood pressure < 110 mmHg or diastolic blood pressure < 70 mmHg.

8. Patients with laboratory or ECG abnormalities deemed clinically significant by the investigator or designee [progressive heart block (second-degree atrioventricular block or higher without pacemaker), diagnosed sick sinus syndrome] that could have had clinical consequences while the patient was in the study.

9. Patients with serious or unstable medical conditions. These include pre-existing hepatic (moderate to severe liver failure), renal, gastrointestinal, respiratory, cardiovascular (including coronary artery disease, congestive heart failure), endocrinological, or hematological diseases.

10. Patients who received study drug within 30 days prior to the current episode of agitation.

11. Patients who for any reason are considered by the investigator to be unsuitable candidates for dexmedetomidine hydrochloride; for example, patients with a history of allergic reactions to dexmedetomidine hydrochloride.

Treatment under investigation

Methodology for assigning subjects to treatment groups

After eligibility was confirmed, subjects were randomized to sublingual 180 mcg dexmedetomidine hydrochloride film or 120 mcg dexmedetomidine hydrochloride film or matching placebo. The randomization ratio was 1:1:1 (180 mcg or 120 mcg dexmedetomidine hydrochloride or placebo stratified by age < 65 years, age > 65 years) with 125 patients assigned to each group in a block design. Study randomization was computer generated.

Study drug, dose and route of administration:

Dexmedetomidine hydrochloride was formulated as a film for sublingual (SL) administration. The delivered dose was 180 or 120 mcg dexmedetomidine hydrochloride sublingually. The product is formulated in a small solid film dosage form, approximately 193.6 ^mm2 in area and 0.7 mm thick, designed to dissolve completely

- 161 047684 rhenium in SL space for about 1-3 min.

Administration of the drug

During the administration of the drug, patients were instructed on how to take the dexmedetomidine hydrochloride film sublingually and that they should keep the film of dexmedetomidine hydrochloride in the sublingual cavity until it dissolved. The patient self-administered the drug under the supervision of a trained staff member at the center. If the patient was unable to self-administer the drug, this was recorded and the subject's participation was terminated.

In case of persistent or recurrent agitation, investigators may decide to administer a repeat dose of 90 mcg or 60 mcg (dividing the 180 or 120 mcg film in half) 2 hours later, as measured by a change in RES score from baseline of <40%, but in the absence of safety concerns.

Research procedures

Subjects provided written informed consent prior to any study-related procedures, including discontinuation of prohibited concomitant medications.

The schedule of procedures to be performed during the study is given in Table 46.

Table 46. Schedule of procedures

Treatment Evaluation, Day 1 Activity Screening Before Dose ¹ Time after administration of dose ¹ Day 2, observation (+1) Day 3, discharge Day 7 (+2) Moment in time Before treatment -1 hour TO time 0 10 m i n 20 m i n 30 m and and 45 m i n 1 h 1.5 h 2 h 4 h 6 h 8 h 24 h (-9/+12 h) End of study Informed consent X Medical history X Demographic data X Body mass X X

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Height X NML X Alcohol in exhaled air X MINI X Physical examination X X Lab. safety research ² X X X ECG with rhythm strip ³ X X X X Pulse oximetry X X X X X X Resting vital signs ⁴ X X X X X X X X X X X Vital Signs in Orthostatic Position ⁴ X X X X X X X X Hospitalization in the department X Inclusion/exclusion criteria X X Randomization X Administration of study drug ⁹ YMRS PCRS ⁵ RES ⁵ ACES ⁵ CGI severity ⁶ CGI improvement ⁶ C-SSRS Score of buccal mucosa (SL) for local irritation ⁷ Likert scale Question about the attractiveness of the drug Sampling for RK ⁸ X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X II 1 1 1xSh 1 1 1 II 1 X X X X X X X Accompanying drugs X X X X X X Adverse events X X X X X X

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Notes on the procedure schedule:

1. Predose assessments had a window of 60 min before dose administration, except for PEC and ACES, which were performed within 15 min after dose administration (15 to 0 min). All postdose assessments had a window of -5/+15 min for 1.5 h assessments, -5/+25 min for 2 h assessments (except for PEC, which had a window of +/-5 min), and ±30 min for 4, 6, and 8 h assessments, and YMRS assessment could be performed at any time.

2. Laboratory parameters for safety analysis included biochemistry, hematology, urinalysis, UDS (local lab, tested at screening only), breath alcohol (tested at screening only), and urine pregnancy test (tested at screening only). Laboratory assessments at screening/enrollment: specimens collected in the local lab within 7 days before screening were acceptable, with the exception of urine drug screening. If same-day results were not available, a benchtop or non-CLIA test could be performed for confirmation; however, results from a CLIA-certified lab must be reported when available. Central lab specimens were collected at screening, Day 3, and Day 7.

3. There was no need to repeat the pre-dose ECG if a screening ECG was recorded on the day of dosing. Post-treatment ECGs should be performed before pharmacokinetic assessment.

4. Resting (supine) vital signs (SBP, DBP, and HR) were measured after the subject had been lying down for 5 minutes at Screening, pre-dose, and at 30 minutes, 1, 2, 4, 6, 8, and 24 hours after the first dose, and on Day 3 and Day 7. Triplicate measurements were taken if systolic BP<90 mmHg, diastolic BP<60 mmHg, or pulse <60 bpm. Orthostatic measurements (SBP, DBP, HR, respiratory rate) were taken after the subject had stood for 1, 3, and 5 minutes, and temperature was measured at Screening, pre-dose, 2, 4, 8, and 24 hours after the first dose, and on Day 3 and Day 7.

5. The PEC assessment was performed at screening, predose (within 15 min before dose), and 10, 20, 30, 45 min; 1, 1.5, 2, 4, 6, 8, and 24 h postdose. The PCRS assessment was to be performed before the PEC assessment if appropriate. The ACES assessment was performed predose (within 15 min before dose), 2, 4, and 8 h postdose.

6. CGI severity was assessed at screening and predose. CGI improvement was assessed at 30 min, 1, 2, and 4 h after the first dose.

7. Examination of the mucous membrane of the cheeks 30 minutes, 2, 4 and 24 hours after administration of the dose for local irritation.

8. Blood PK samples were collected at 1, 4, and 8 h (while awake) post-dose. A sample could be withheld if the Physician indicated in the original documentation that the patient was in a mental state that was not conducive to collection of a PK sample. Non-consent or refusal of all or any PK sample collections was not restrictive and did not result in ET. Vital signs were to be assessed prior to PK sample collection when they were performed at the same time points.

9. The investigator could decide to re-dose a patient after the 2-hour post-dose assessments were completed if the change in PEC score from baseline was < 40%. Patients could be re-dose 2 hours after completion of the first dose assessment. The re-dose was one-half film. Patients could be re-dose twice within a 12-hour period after the first dose. All assessments listed in this Procedure Schedule were performed 2 hours after the first dose and were repeated 2 hours after each re-dose. Assessments at 4, 6, or 8 hours after the first dose that fell within a 1-hour period after the re-dose assessment were not required.

Estimates in the study

Efficiency

The effect of the study drug was assessed using several validated instruments as described below.

PANSS - Excitement Component (PEC) Agitation and Calmness Evaluation Scale (ACES) CGI-S and CGI-I

The Clinical Global Impression of Severity (CGI-S) is assessed based on the severity of agitation at screening and pre-dose (immediately before dosing).

The severity of the condition was assessed using the following scale:

= not rated = not ill at all = on the verge of mental disorder = slightly ill = moderately ill

- 164 047684 = noticeably ill = seriously ill = one of the most seriously ill subjects

The effect of the drug on agitation was assessed using the Clinical Global Impression-Improvement (CGI-I) scale. This assessment was performed at 30 min, 1, 2, and 4 h after dosing. Scores on the CGI-I scale range from 1 to

7:0 = not rated (absent), 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse

The CGI-I and CGI-S scales focus on the severity of agitation rather than the overall severity of bipolar disorder.

Young Mania Rating Scale (YMRS)

The YMRS was an 11-item scale assessing manic symptoms based on patients' subjective reports of their clinical state. This scale was used to characterize the population of patients included in the study.

Placebo Control Reminder Script (PCRS)

The Placebo Control Reminder Script (PCRS) © Hassman and Cohen, 2019, version 5.0 informs clinical trial participants about the primary reasons for placebo and nocebo effects, namely, to reduce participants’ expectations by reminding subjects what a placebo is and how it relates to their reports of symptoms and potential adverse effects, and how interactions with study site staff differ from their previous experiences with healthcare professionals. To achieve this, the PCRS informs subjects that they were expected to be honest about their symptoms; that site staff do not expect symptoms to improve or worsen and will not be disappointed if subjects feel better, worse, or the same; and that the PCRS asks participants to explain the content of their symptoms in their own words to ensure full understanding. The PEC assessor read the study PCRS source prior to administering the PEC assessment to each subject at each visit (time point) specified in the specific study PCRS, typically taking approximately 2 min to read.

Likert scale

After taking the study drug, subjects rated their preference for the study drug by responding to the statements I like the taste of the drug and The drug is acceptable using a five-level Likert scale as shown below:

Not completely satisfied

Not satisfied

Neither satisfied nor dissatisfied

Satisfied

Completely satisfied

The drug is attractive

Subjects answered open-ended questions about their experiences with the product.

Additional comments about aftertaste, odor, dissolution time, etc. were asked as Yes/No questions, and Yes answers required an explanation field.

Safety

Safety was assessed during the study by monitoring and recording adverse events, clinical laboratory results (hematology, biochemistry, and urinalysis), vital sign measurements (systolic and diastolic blood pressure, heart rate measured as pulse, respiratory rate, and temperature), ECG, and physical examination results. If a known safety concern is identified (eg, high incidence of severe hypotension or bradycardia in the 180 mcg active dose group or in the 120 mcg group), the DSMB will notify the sponsor. If this occurs, the sponsor will notify the FDA, and the sponsor may decide to continue giving patients a lower dose.

Pharmacokinetics

Blood samples (4 mL) were collected according to Table 46 - Schedule of Procedures. For each subject, up to 3 blood samples (12 mL of blood) were collected for PK analysis during the study. In addition, approximately 30 mL of blood was collected at Screening, approximately 15 mL of blood was collected on Day 3 Discharge, and approximately 15 mL of blood was collected on Day 7 (+2) for clinical laboratory testing. The total volume of blood collected during the study was expected to be approximately 72 mL. For each subject, up to 3 blood samples (12 mL of blood) were collected for PK analysis during the study. In addition, approximately 30 mL of blood was collected at Screening, approximately 15 mL of blood was collected on Day 3 Discharge, and approximately 15 mL of blood was collected on Day 7 (+2) for clinical laboratory testing. The total volume of blood collected during the study was expected to be approximately 72 mL.

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Statistical analysis Pharmacokinetic analyses

Plasma concentrations and concentration-time data for dexmedetomidine were used to calculate pharmacokinetic parameters; these data and results were reported separately. Details of the PK data analysis were described in a separate PK SAP. A separate SAP for PK analysis was prepared and completed prior to database lock.

Safety analyses

All safety analyses were performed in the safety set. All subjects who received at least one dose of study drug were included in the safety set. Adverse events (AEs) were characterized by type, severity, seriousness, and relationship to treatment. AEs were coded by preferred term and system organ class using MedDRA version 20.0.

Efficiency analyses

The primary efficacy endpoint in this study was the absolute change from baseline in RES total score at 120 minutes. The intention-to-treat set, consisting of all patients who received any study drug and had both a baseline assessment and at least 1 post-dose efficacy assessment, was analyzed.

Summary of Results Demographic Data

Demographic and baseline characteristics are presented below in Table 47.

Table 47. Demographic data

Sublingual film with dexmedetomidine Placebo (N-126) Total (N=381) 180 mcg (N=126) 120 mcg (N=129) Average age (years) 46.0(11.91) 45.7(11.32) 45.1 (11.13) 45.6 (11.43) Women, η (%) 44 (34.9) 52 (40.3) 44 (34.9) 140 (36.7) Race (% white/% non-white) 38.9/61.1 44.4/55.6 39.7/60.3 41.0/59 BMI 32.53 (7.8) 31.24 (7.6) 32.56 (7.4) 32.10 (7.6) Diagnosis: depression 22% 16% 21% 20% Diagnosis: Hypomania 4% 11% 8% 8% Diagnosis: Mania 47% 46% 50% 47% Diagnosis: mixed episodes 24% 21% 17% 21% Diagnosis: unspecified 3% 6% 4% 4% RES at baseline, average 18 18 17.9 nd

3. Efficiency

Dexmedetomidine sublingual film significantly reduced the severity of agitation from baseline as measured by the PEC, ACES, and CGI-I scores. Key efficacy data at 2 hours post-dose are presented below.

(a) Primary efficacy outcome measure (PEC score reduction): There was a reduction in PEC (PANSS or Positive and Negative Syndrome Scale, arousal component) score for

- 166,047,684 agitation with rapid calming without excessive sedation at the clinical target time point and earlier time points. The primary efficacy endpoint was mean change from baseline in RES total score at 2 h (120 min) compared with placebo. There were 2 dose cohorts (120 mcg (N=129) and 180 mcg (N=126)) and 126 patients receiving placebo. Active patients in each of the 2 dose cohorts receiving placebo were compared with patients receiving placebo. Change from baseline in RES score at 2 hours in patients receiving dexmedetomidine sublingual film was compared with placebo using a mixed-effects model for repeated measures (MMRM) analysis with baseline RES score, treatment group, time, the interaction between treatment group and time, and the interaction between baseline RES score and time as covariates.

The efficacy of dexmedetomidine hydrochloride sublingual film, as measured by RES score reduction, is dose-dependent and robust. The reduction in RES score from baseline in the 180 mcg dose group demonstrated a significant response, with a mean change from baseline in RES total score (CFB) of -10.4 at 2 h post-dose compared with placebo (Table 48 and Figs. 24A and 24B). Mean changes from baseline were 9.1 points for the 120 mcg treatment groups compared with placebo (mean change -5). Furthermore, because early onset of action is an important attribute of therapy to reduce agitation, the 180 mcg group demonstrated a statistically significant difference from placebo as early as 20 min post-dose (Figs. 24A and 24B). Furthermore, the reduction in RES score from baseline in the 180 and 120 μg dose groups demonstrated a significant response at 6 h post-dose compared with placebo (Fig. 24B).

Table 48. Summary of changes from baseline in PANSS-PEC total score at 2 h and percentage of responders at 2 h for PEC score by treatment group

Moment of time (120 min) N Placebo Sublingual film with dexmedetomidine 120 mcg 180 mcg Total Score RES Change from Baseline (LSM) 126 (180 mcg) 129 (120 mcg) -5.0 _| 0 4*** Answer ° 126 37% 69% 85%

Proportion of patients achieving a reduction in RES score by > 40%; * P < 0.025; *** P < 0.0001

Analysis of RES responders: The proportion of responders, defined as those with a 40% reduction in total RES score from baseline at 2 hours post-dose, was greatest in the 180 mcg group (85% for 180 mcg, 69% for 120 mcg) compared with placebo (37%) (Table 48). The duration of the sedative effect of the 180 mcg dose was markedly prolonged, with a sustained, statistically significant reduction in RES score evident at 24 hours.

Secondary performance metrics

Changes in secondary efficacy measures (i.e., ACES and CGI-I scores) at 2 hours post-dose were consistent with the PEC total score results and indicated improvement in agitation symptoms following treatment with dexmedetomidine sublingual film.

ACES scores: The secondary objective of this study was to evaluate the duration of the calming effect of sublingual dexmedetomidine thin film using the Agitation and Calmness Evaluation Scale (ACES) at pre-dose, 2 h, and 4 h after the first dose. The ACES score was consistent with the analysis of the primary efficacy endpoint and was statistically significant for calming as measured by the ACES at 2 h compared with placebo at doses of 120 and 180 mcg (120 mcg; p<0.0001) and (180 mcg; p<0.0001). At 2 hours post-dose, subjects in the 120 and 180 mcg treatment groups demonstrated significantly greater improvements compared with placebo on the ACES scale (+ about 3.0 [P<0.0001] for 120 mcg; + about 3.7 [P<0.0001] for 180 mcg compared with placebo + about 1.0. Improvements at 4 hours post-dose were similar (+ about 2.8 [P<0.0001] for 120 mcg; + about 3.2 [P<0.0001] for

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180 mcg compared with placebo + about 1.0). (Fig. 25).

CGI Scores: The percentage of subjects achieving a CGI-I score of 1 or 2 (very much improved or much improved) at 2 hours post-dose was significantly higher in the 120 mcg group (about 70% [P<0.0001]) and the 180 mcg group (about 90% [P<0.0001]) compared with placebo (about 38%). Significant improvements were also observed at 30 min, 1, and 4 hours post-dose in both treatment groups (Fig. 26).

Safety and tolerability

Dexmedetomidine sublingual film (Example 2 formulations) was well tolerated in patients with schizophrenia and bipolar I disorder and had a favorable safety profile in subjects with agitation. Table 49 summarizes the subjects who experienced at least 1 treatment-emergent adverse event (TEAE) by treatment group for the safety population.

Table 49. Summary of adverse events in the phase III study (patient with schizophrenia and bipolar disorder I_____

Phenomenon Sublingual film with dexmedetomidine Placebo (N=252) 180 mcg (N=252) 120 mcg (N=255) Drowsiness Light 40(15.9) 43 (16.9) 15 (6.0) Average 16 (6.3) 11(4.3) 1 (0.4) Dizziness Light 13 (5.2) 7(2,7) 2 (0.8) Average 2 (0.8) 3 (1,2) 0 Hypotension Light 10 (4.0) 10 (3.9) 0 Average 3 (1,2) 4(1.6) 0 Orthostatic hypotension Light 9 (3.6) 7(2,7) 1 (0.4) Average 4 (1.6) 0 0 Hypesthesia of the oral cavity 12 (4.8) 7 (2.7) 1 (0.4) Dry mouth 11 (4.4) 19 (7.5) 3 (1,2) Nausea 7 (2.8) 6(2,4) 4(1.6) Headache 6 (2.4) 12 (4.7) 12 (4.8) Oral paresthesia 6 (2.4) 7 (2.7) 1 (0.4)

Conclusion: Dexmedetomidine sublingual film significantly reduced the severity of agitation from baseline as measured by the PEC, CGI-I, and ACES scales in patients with schizophrenia. The primary efficacy endpoint was met in the 120 and 180 mcg treatment groups, as there was a significant improvement in PEC total scores from baseline to 2 hours post-dose, with mean changes of -9.1 and -10.4 points, respectively, versus -5.0 for placebo. Reductions in agitation were observed as early as 20 minutes compared with placebo. In addition, changes in secondary efficacy endpoints (i.e., ACES and CGI-I scores) at 2 hours post-dose were consistent with the results of PEC total scores and indicated improvement in agitation symptoms following treatment with dexmedetomidine sublingual film.

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Example 11.

Table 50. Composition for a tablet formulation used for delivery through the oral mucosa (with mucoadhesive properties)

Active ingredient(s) Quantity % w/v. Dexmedetomidine hydrochloride 180 mcg (equivalent to dexmedetomidine) 0.36% Lactose monohydrate 44.27 mg 88.54% G ipromellose (or) Hydroxypropyl cellulose (or) Polyethylene oxide (or) Xanthan gum (or) Sodium alginate 2.5 mg 5.0% Croscarmellose sodium (or) sodium starch glycolate 2.5 mg 5.0% Sucralose 0.05 mg 0.1% Magnesium stearate 0.5 mg 1.0% Weight of the tablet 50.0 mg 100%

Manufacturing process:

1. Dexmedetomidine, a binder (hypromellose (or) hydroxypropyl cellulose (or) polyethylene oxide (or) xanthan gum (or) sodium alginate) and sucralose are dissolved or dispersed in water to prepare a solution or dispersion.

2. The remaining ingredients, except magnesium stearate, are mixed in a suitable mixer and sifted through an appropriate sieve.

3. The mixture obtained in step 2 is granulated using a suitable granulator.

4. The granules are dried in a suitable fluid bed dryer or any other suitable dryer and classified accordingly in a quadruple joint mill or multi mill.

5. The granules are loaded into a suitable blender, such as a V-blender, and lubricated with magnesium stearate.

6. The lubricated mixture obtained in step 5 is pressed into tablets of specified sizes using appropriate tools.

Table 51. Composition for a tablet formulation used for delivery through the buccal mucosa (with mucoadhesive properties)

Active ingredient(s) Quantity % w/v. Dexmedetomidine hydrochloride 180 mcg (equivalent to dexmedetomidine) 0.36% Lactose monohydrate 43.77 87.54% Hypromellose (or) Hydroxypropyl cellulose (or) Polyethylene oxide (or) Xanthan gum (or) Sodium alginate 5.0 mg 10.0% Sucralose 0.05 mg 0.1% Magnesium stearate 0.5 mg 1.0% Talc 0.5 mg 1.0% Weight of the tablet 50.0 mg 100%

Manufacturing process:

1. Dexmedetomidine hydrochloride, binder (hypromellose (or) hydroxypropyl cellulose (or) polyethylene oxide (or) xanthan gum (or) sodium alginate) and sucralose are dissolved

- 169 047684 or dispersed in water to prepare a solution or dispersion.

2. The remaining ingredients, except magnesium stearate and talc, are mixed in a suitable mixer and sifted through an appropriate sieve.

3. The mixture obtained in step 2 is granulated using a suitable granulator.

4. The granules are dried in a suitable fluid bed dryer or any other dryer and classified accordingly in a quadruple joint mill or multi mill.

5. The granules are loaded into a suitable blender, such as a V-blender, and lubricated with magnesium stearate and talc.

6. The lubricated mixture obtained in step 5 is pressed into tablets of specified sizes using appropriate tools.

Table 52. Dexmedetomidine hydrochloride spray composition for sublingual delivery

Ingredients Quantity % w/v. Dexmedetomidine hydrochloride 180 mcg (equivalent to dexmedetomidine) 0.18% N-methylpyrrolidone (or) propylene glycol (or) polyethylene glycol (or) glycerol 10 µl 10% Ethanol 5 µl 5% Sucralose 0.1 mg 0.1% Peppermint oil 1 µl 1.0% Purified water q.s. 100 µl q.s. 100%

Manufacturing process:

1. The polymer (N-methylpyrrolidone (or) propylene glycol (or) polyethylene glycol) or glycerin is dissolved or dispersed in a portion of the total amount of water.

2. Dexmedetomidine hydrochloride is mixed with the remaining excipients and the solution or dispersion obtained in step 1.

3. Bring to the final volume with water in a suitable vessel.

4. The resulting solution is poured into appropriate aerosol cans using appropriate tools such as metering nozzles.

Table 53. Composition of dexmedetomidine hydrochloride drops for sublingual delivery

Active ingredient(s) Quantity % w/v. Dexmedetomidine hydrochloride 180 mcg (equivalent to dexmedetomidine) 0.18% Povidone or hypromellose or carbopol 5 mg 5.0% N-methylpyrrolidone (or) propylene glycol (or) polyethylene glycol (or) glycerol (or) ethanol 10 µl 10.0% Sucralose 0.1 mg 0.1% Peppermint oil 1 µl 1.0% Purified water q.s. 100 µl q.s. 100%

Production process: simple mixing process

1. The polymer (N-methylpyrrolidone (or) propylene glycol (or) polyethylene glycol) or glycerin is dissolved or dispersed in a portion of the total amount of water.

2. Dexmedetomidine hydrochloride is mixed with the remaining excipients and the solution or dispersion obtained in step 1.

3. Bring to the final volume with water in a suitable vessel.

4. The resulting solution is poured into appropriate bags or bottles.

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Claims (11)

Table 54. Composition of dexmedetomidine hydrochloride gel for sublingual delivery Active ingredient(s) Dexmedetomidine Carbopol or hypromellose or HPC or CMC N-methylpyrrolidone (or) propylene glycol (or) polyethylene glycol (or) glycerol (or) ethanol Amount 180 mcg 10 mg 10 mcl % w/v 0.18% 10.0% 10.0% Sucralose 0.1 mg 0.1% Peppermint oil 1 µl 1.0% Purified water q.s. 100 µl q.s. 100% Manufacturing process: 1. The polymer (N-methylpyrrolidone (or) propylene glycol (or) polyethylene glycol) or glycerin) is dissolved or dispersed in a portion of the total amount of water. 2. The remaining ingredients are dissolved or dispersed in another portion of water. 3. The solutions or dispersions obtained in step 1 and step 2 are mixed to obtain the final volume. 4. The mixture obtained in step 3 is packed into appropriate packaging or containers. Inclusion via link All references, articles, publications, patents, patent publications and patent applications cited in this document are incorporated by reference in their entirety and for all purposes. However, mention of any references, articles, publications, patents, patent publications and patent applications cited in this document does not constitute and should not be taken as an admission or any form of suggestion that they constitute actual prior art or form part of the general public knowledge in any country in the world. CLAUSE OF THE INVENTION 1. A method of treating agitation associated with schizophrenia or bipolar disorder in a human subject with agitation, comprising administering a composition comprising a single active agent to the oral mucosa of a human subject with agitation, wherein the active agent consists of dexmedetomidine or a pharmaceutically acceptable salt thereof; wherein the human subject has a Fridericia corrected QT interval (QTcF) of less than 470 ms and wherein the subject is administered a first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof equal to 120 to 180 mcg. 2. The method according to claim 1, characterized in that the first dose of dexmedetomidine is 120 mcg of dexmedetomidine or its pharmaceutically acceptable salt. 3. The method according to claim 1, characterized in that the first dose of dexmedetomidine is 180 mcg of dexmedetomidine or its pharmaceutically acceptable salt. 4. The method according to claim 2, characterized in that the treatment includes a reduction in agitation that is statistically significant 30 minutes after administration. 5. The method according to claim 3, characterized in that the treatment includes a reduction in agitation, which is statistically significant 20 minutes after administration. 6. The method according to claim 1, characterized in that the composition is presented in the form of a film. 7. The method according to claim 6, characterized in that dexmedetomidine or its pharmaceutically acceptable salt is administered sublingually. 8. The method according to claim 6, characterized in that dexmedetomidine or its pharmaceutically acceptable salt is administered buccally. 9. The method according to claim 1, characterized in that the first dose of dexmedetomidine is 120 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is presented in the form of a sublingual film and wherein the treatment includes a reduction in agitation that is statistically significant 30 minutes after administration. 10. The method according to claim 1, characterized in that the first dose of dexmedetomidine is 180 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is presented in the form of a sublingual film and wherein the treatment includes a reduction in agitation that is statistically significant 20 minutes after administration. 11. The method according to claim 1, characterized in that the subject has a QTcF less than 450 ms. - 171 -