EA041383B1 - INTRANASAL COMPOSITION INCLUDING BETAHISTINE - Google Patents

Description

Cross-references to related applications

The present application claims priority over U.S. Provisional Application No. 62/453931, filed Feb. 2, 2017, the contents of which are hereby incorporated by reference in their entirety.

Region

The present disclosure relates generally to pharmaceutical compositions comprising betahistine or a pharmaceutically acceptable salt thereof, and methods of using the same, for example in the treatment of otological or neurological disorders.

Level

Drugs useful for treating vestibular disorders or ameliorating the symptoms of vestibular disorders, such as histamine, are known to act through the histaminergic system. Histamine is a potent bioactive that has been studied for almost a century, acting as an aminergic neurotransmitter in the nervous system and as a local mediator in the gut, skin and immune system peripherally and in the brain. Betahistine is a structural analogue of histamine with similar pharmacological properties but without the potentially serious side effects of histamine such as anaphylactic reactions.

Betahistine is known to have therapeutic effects in the treatment of vestibular vertigo, such as benign paroxysmal positional vertigo, vestibular neuritis, or Meniere's disease. The therapeutic effects of betahistine in Meniere's disease, a condition characterized by dizziness, tinnitus, hearing loss, and a sensation of pressure or pain in the affected ear, have been evaluated in a large number of clinical trials. However, the trial results are inconsistent and the general opinion of the reviewers is that there is still not enough evidence to say whether betahistine has any effect on Ménière's disease or not. It is also known that betahistine has therapeutic effects in vestibular rehabilitation, for example, it significantly reduces the recovery time of postural stability and subjective visual vertical and head orientation in patients with Meniere's disease after vestibular neurectomy.

Betahistine is also known to have therapeutic effects in the treatment of neurological disorders such as obesity, attention deficit hyperactivity disorder, cerebrovascular disease/dementia, narcolepsy/sleep disorder, parkinsonism, drug addiction, schizophrenia, Gilles de la Tourette syndrome, or Alzheimer's disease.

In humans, betahistine is usually administered orally as a tablet or solution, usually two to three times a day, up to 6 times a day. Betahistine is known for its short plasma half-life (3-4 hours), which requires frequent dosing and may lead to regimen failure, especially in elderly patients. In addition, after oral administration, betahistine is readily and almost completely absorbed from all parts of the gastrointestinal tract. After absorption, the drug is rapidly and almost completely metabolized to 2-pyridylacetic acid (2-PAA; which has no pharmacological activity) by the action of monoamine oxidase. Due to the very high first pass metabolism, the absolute bioavailability of orally administered betahistine is approximately 1% (SmPC). Accordingly, plasma levels of betahistine are very low.

Thus, the strong first pass metabolism following oral administration of betahistine limits the efficacy of the compound in clinical practice, and significantly higher doses may indeed be required to achieve greater results. Therefore, there is a need for improved pharmaceutical compositions comprising betahistine and routes of administration thereof for the treatment of otological and/or neurological disorders, including inner ear dysfunctions, which provide increased efficacy and allow reduction in the frequency and/or daily dosage, as well as to achieve more fast and long lasting effect.

The essence of the invention

In various embodiments, the present invention relates to pharmaceutical compositions for intranasal delivery to a human patient, comprising a solution or suspension of a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt thereof and a viscosity increasing agent.

In specific embodiments, the present invention relates to pharmaceutical compositions as described herein, wherein, after a single intranasal administration to a human, C _max is in the range of 80-125%: about 640 pg/ml for a 5 mg dose of betahistine; approximately 2000 pg/ml for a 10 mg dose of betahistine; about 4000 pg/ml for a 20 mg betahistine dose or about 10,500 pg/ml for a 40 mg betahistine dose.

In specific embodiments, the present invention relates to pharmaceutical compositions as described herein, wherein, after a single intranasal administration to a human, the AUC ₀ _ _last is in the range of about 80-125%: about 210 pg-h/ml for a 5 mg dose of betahistine; about 500 pg-h/ml for a dose of betahistine 10 mg; about 1600 pg-h / ml for a dose of betahistine 20 mg; or about 3500 pg-h/ml for a dose of betahistine 40 mg.

- 1 041383

In specific embodiments, the present invention relates to pharmaceutical compositions as described herein, wherein, after a single intranasal administration to a human, the AUC _0-inf is in the range of about 80-125%: about 275 pg-h/ml for a 5 mg dose of betahistine; about 700 pg-h/ml for a dose of betahistine 10 mg; about 1630 pg-h/ml for the 20 mg betahistine dose or about 3940 pg-h/ml for the 40 mg betahistine dose.

In still other embodiments, the present invention relates to methods of treating an inner ear dysfunction or inner ear disorder, or treating or alleviating the symptoms of an inner ear disorder, or increasing cochlear blood flow or cerebral blood flow in a subject, comprising intranasally administering any of the compositions disclosed herein to said subject.

Brief description of the figures

In FIG. 1 shows plasma concentrations of betahistine in 6 beagle dogs following intranasal administration of a single dose of betahistine dihydrochloride 4, 20, or 80 mg over time.

In FIG. 2 shows the plasma concentration of 2-pyridylacetic acid (2-PAA) from 6 beagle dogs following intranasal administration of a single dose of betahistine dihydrochloride 4, 20, or 80 mg over time.

In FIG. 3 shows the maximum plasma concentration C _max of betahistine in 24 healthy volunteers after intranasal administration of a single dose of betahistine dihydrochloride 5, 10, 20 or 40 mg (whisker=standard deviation).

In FIG. 4 shows the maximum C _max plasma concentration of 2-pyridylacetic acid (2-PAA) in 24 healthy volunteers after intranasal administration of a single dose of betahistine dihydrochloride 5, 10, 20 or 40 mg (whisker'-standard deviation).

In FIG. 5 shows the median plasma concentration of betahistine over time in 8 beagle dogs following intranasal administration of a single dose of betahistine dihydrochloride at 40, 80, or 120 mg.

In FIG. 6 shows the mean plasma concentration of betahistine over time in 8 beagle dogs following intranasal administration of a single dose of betahistine dihydrochloride at 40, 80, or 120 mg.

In FIG. 7 shows the median plasma concentration of betahistine over time in 8 beagle dogs following oral administration of betahistine.

In FIG. 8 shows the mean plasma concentration of betahistine over time in 8 beagle dogs following oral administration of betahistine.

In FIG. 9 shows the median plasma concentration of betahistine over time in 8 beagle dogs following intravenous administration of betahistine.

In FIG. 10 shows the mean plasma concentration of betahistine over time in 8 beagle dogs following intravenous administration of betahistine.

Detailed description

While the following terms are believed to be well understood by those skilled in the art, the following definitions are provided to facilitate the explanation of the present invention.

Throughout this description, the terms about and/or approximately may be used in conjunction with numerical values and/or ranges. The term approximately refers to values close to the specified value. For example, about 40 [units] can mean within ±25% of 40 (e.g., 30 to 50), within ±20%, ±15%, ±10%, ±9%, ±8%, ±7% , ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, or any other value or range of values therein or specified below. In other contexts, the term may roughly refer to a value intermediate between adjacent values in a numerical sequence. In addition, the phrases less than about [values] or more than about [values] should be understood in accordance with the definition of the term approximately given in this document. The terms approximately and approximately may be used interchangeably.

In the present description, the numerical ranges are given for given values. These ranges are to be understood to include all subranges therein. Thus, the range from 50 to 80 includes all possible ranges in it (eg 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). In addition, all values within a given range may be the endpoint of the range thus covered (eg, the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

The singular form refers to one or more of that object; for example, a kinase inhibitor refers to one or more kinase inhibitors or at least one kinase inhibitor. Thus, the terms one or more and at least one are used interchangeably herein. Furthermore, reference to an inhibitor in the singular does not preclude the possibility that more than one inhibitor is present, unless the context clearly indicates that there is one and only one of the inhibitors.

- 2 041383

As used here, the verb include, as used in the present specification and claims, and its conjugations are used in its non-limiting sense to mean that elements following the word are included, but elements not specifically mentioned are not excluded. The present invention may appropriately include, consist of, or consist essentially of, steps, elements and/or reagents described in the claims.

In addition, it should be noted that the claims may be drafted in such a way as to exclude any optional element. As such, this wording is intended to serve as an a priori basis for exclusive terms such as sole, only, etc., in connection with the enumeration of the constituent parts of the claims or the use of negative features.

The term to treat, to be treated, treatment or therapy includes the reduction or amelioration of at least one symptom associated with or caused by the condition, disorder or disease being treated. Treatment may be the reduction of one or more symptoms of a disorder, or the complete elimination of the disorder or disease. Similarly, the term prophylaxis refers to the partial or complete prevention of symptoms by administering the active agent before such symptoms are expected to occur.

As used herein, the term subject, individual, or patient is used interchangeably and refers to a vertebrate, preferably a mammal. Non-limiting examples include mice, dogs, rabbits, farm animals, sport animals, pets, and humans.

Used in the present description, the term therapeutically effective amount or effective amount means the amount that leads to the desired pharmacological and/or physiological effect for the condition. The effect may be prophylactic in terms of completely or partially preventing the condition or symptom thereof and/or may be therapeutic in terms of partially or completely curing the condition and/or side effect associated with the condition.

The term pharmaceutically acceptable salt of betahistine as used herein refers to pharmaceutically acceptable acid addition salts of betahistine, especially those known to be non-toxic and commonly used in the field of pharmaceutical formulation. In one embodiment, the betahistine salt is an acid addition salt, where a non-limiting example of the acid is selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid ( hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glyceroph osphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid acid, naphthalene-1,5disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p) or undecylenic acid. In another embodiment, suitable betahistine salts also include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, tartrate, mesylate, citrate, phosphate, acetate, pamoate/embonate, nitrate, lactate, sulfate, methyl sulfate, fumarate, oxalate, phthalate, maleate and succinate. In addition, betahistine salts may be a monosalt or a bis-salt. In one embodiment, betahistine hydrochloride may be betahistine monohydrochloride or betahistine bis-hydrochloride.

In one embodiment of the present invention, betahistine or a pharmaceutically acceptable salt thereof may be formulated in any form suitable for administration by a variety of routes, including nasal (e.g., solution, spray, drops, aerosol, gels, dry powders), oral (e.g., tablets , capsules, granules, syrups, elixirs, or powders) sublingually, buccally, parenterally (eg, subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injections) or infusion methods (eg, as sterile injectable aqueous or non-aqueous solutions or suspensions), topically ( e.g., a drug-releasing skin patch, cream, or ointment), intravaginally, by wetting, transdermally, intradermally, pulmonary, intrauterine, aerosolized, or rectally (e.g., suppositories, dosage

- 3 041383 unit preparations containing non-toxic, pharmaceutically acceptable carriers or diluents). In one embodiment, betahistine or a pharmaceutically acceptable salt thereof is formulated in any form suitable for nasal or intranasal administration.

In one embodiment, the present invention provides a pharmaceutical composition comprising betahistine hydrochloride. In another embodiment, a pharmaceutical composition is provided comprising betahistine monohydrochloride. In another embodiment, a pharmaceutical composition is provided comprising betahistine dihydrochloride.

In one embodiment, the pharmaceutical composition comprises a particular polymorph of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises a particular polymorph of betahistine or a pharmaceutically acceptable salt thereof, formulated in any form suitable for nasal or intranasal administration.

In one embodiment, the present invention provides a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof. In specific embodiments, the pharmaceutical compositions of the present invention comprise solutions or suspensions of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition is provided comprising betahistine or a pharmaceutically acceptable salt thereof and one or more viscosity adjusting agents or one or more pharmaceutically acceptable viscosity increasing agents. Non-limiting examples of suitable viscosity adjusting agents or viscosity increasing agents include polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, carboxymethylcellulose-Na, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, carbopol, polyethylene glycol, propylene glycol, glycerin, alginate, alginates, carrageenan, pectins, maltodextrin, sodium starch glycolate, gum tragacanth, gum arabic, microcrystalline cellulose and their derivatives. In one embodiment, the viscosifying agent is polyvinylpyrrolidone.

In another embodiment, the present invention relates to a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof and one or more viscosity adjusting agents, which is an intranasal pharmaceutical composition. In one embodiment, the one or more viscosity adjusting agents in the intranasal dosage form allow the dosage form to remain at the site of application long enough for absorption of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, the presence of one or more viscosity-adjusting agents in the intranasal dosage form does not prevent the drug from being sprayed into the nasal cavity.

In one embodiment, the pharmaceutical compositions of the present invention have a viscosity in the range of about 0.1 to about 1000 centipoise, or about 1 to about 100 centipoise. In one embodiment, the viscosity of the pharmaceutical composition of the present invention is about 0.1 cP, about 0.5 cP, about 1 cP, about 5 cP, about 10 cP, about 15 cP, about 20 cP, about 25 cP, about 30 sp. about 40 cP, about 45 cP, about 50 cP, about 55 cP, about 60 cP, about 65 cP, about 70 cP, about 75 cP, about 80 cP, about 85 cP, about 90 cP, about 95 cP, about 100 cP, approximately 105 cP, approximately 110 cP, approximately 115 cP, approximately 120 cP, approximately 125 cP, approximately 130 cP, approximately 135 cP, approximately 140 cP, approximately 145 cP, approximately 150 cP, approximately 175 cP, approximately 200 cP, about 250 cP, about 300 cP, about 350 cP, about 400 cP, about 450 cP, about 500 cP, about 550 cP, about 600 cP, about 650 cP, about 700 cP, about 750 cP, about 800 cP , about 850 cps, about 900 cps, about 950 cps, or about 1000 cps. In one embodiment, the viscosity of the pharmaceutical compositions described herein can be measured using the USP <911> viscosity measurement method.

In one embodiment, the pharmaceutical compositions of the present invention for nasal delivery have a viscosity of about 0.5 to about 10.5 centipoise, about 1 to about 10 centipoise, or about 1 to about 7 centipoise. In one embodiment, the pharmaceutical composition of the present invention for nasal delivery has a viscosity of about 0.5 cP, about 0.6 cP, about 0.7 cP, about 0.8 cP, about 0.9 cP, about 1.0 cP , about 1.1 cP, about 1.2 cP, about 1.3 cP, about 1.4 cP, about 1.5 cP, about 1.6 cP, about 1.7 cP, about 1.8 cP, about 1.9 cP, about 2.0 cP, about 2.1 cP, about 2.2 cP, about 2.3 cP, about 2.4 cP, about 2.5 cP, about 2.6 cP, about 2, 7 cP, approximately 2.8 cP, approximately 2.9 cP, approximately 3.0 cP, approximately 3.1 cP, approximately 3.2 cP, approximately 3.3 cP, approximately 3.4 cP, approximately 3.5 cP , about 3.6 cP, about 3.7 cP, about 3.8 cP, about 3.9 cP, about 4.0 cP, about 4.1 cP, about 4.2 cP, about 4.3 cP, about 4.4 cP, about 4.5 cP, about 4.6 cP, about 4.7 cP, about 4.8 cP, about 4.9 cP, about 5.0 cP, about 5.1 cP, about 5, 2 cP, approx. 5.3 cP, approx. 5.4 cP, approx. 5.5 cP, example but 5.6 cP, about 5.7 cP, about 5.8 cP, about 5.9 cP, about 6.0 cP, about 6.1 cP, about 6.2 cP, about 6.3 cP, about 6 .4 cP, about 6.5 cP,

- 4 041383 about 6.6 cP, about 6.7 cP, about 6.8 cP, about 6.9 cP, about 7.0 cP, about 7.1 cP, about 7.2 cP, about 7.3 cP , about 7.4 cP, about 7.5 cP, about 7.6 cP, about 7.7 cP, about 7.8 cP, about 7.9 cP, about 8.0 cP, about 8.1 cP, about 8.2 cP, about 8.3 cP, about 8.4 cP, about 8.5 cP, about 8.6 cP, about 8.7 cP, about 8.8 cP, about 8.9 cP, about 9, 0 cP, approximately 9.1 cP, approximately 9.2 cP, approximately 9.3 cP, approximately 9.4 cP, approximately 9.5 cP, approximately 9.6 cP, approximately 9.7 cP, approximately 9.8 cP , about 9.9 cP, about 10.0 cP, about 10.1 cP, about 10.2 cP, about 10.3 cP, about 10.4 cP, about 10.5 cP, or any range between any of these values . In one embodiment, the pharmaceutical compositions of the present invention for nasal delivery are presented in an intranasal composition. In one embodiment, the viscosity of the pharmaceutical compositions described herein can be measured using the USP <911> viscosity measurement method.

In one embodiment, the pharmaceutical compositions of the present invention include one or more pharmaceutically acceptable wetting agents. Non-limiting examples of such moisturizing agents include glycerin, ethylene glycol, propylene glycol, propylene glycol 400, hexalene glycol, butylene glycol, dextrose, glyceryl triacetate, polydextrose, glycerol, glyceryl triacetate, sorbitol, and mannitol. In various embodiments, the implementation of the pharmaceutical compositions of the present invention may include mixtures of pharmaceutically acceptable wetting agents.

In one embodiment, one or more wetting agents are selected from glycerin, polyethylene glycol 400, and propylene glycol. In one embodiment, the pharmaceutical compositions of the present invention include glycerin. In another embodiment, the pharmaceutical composition of the present invention comprises polyethylene glycol 400. In other embodiments, the pharmaceutical composition of the present invention comprises propylene glycol. In some embodiments, the implementation of the pharmaceutical compositions of the present invention include glycerin, polyethylene glycol 400 and propylene glycol.

In one embodiment, the pharmaceutical compositions of the present invention, comprising one or more pharmaceutically acceptable wetting agents, are intranasal pharmaceutical compositions. In one embodiment, one or more wetting agents in the intranasal pharmaceutical composition for intranasal administration moisturize the nasal mucosa, nasal tissues, and/or nasal membrane. In one embodiment, one or more wetting agents in the intranasal pharmaceutical composition for intranasal administration reduce irritation in the nasal cavity after administration. In some embodiments, the intranasal pharmaceutical composition of the present invention includes glycerin, polyethylene glycol 400, and propylene glycol.

In another embodiment, a pharmaceutical composition is provided comprising betahistine or a pharmaceutically acceptable salt thereof, one or more viscosity adjusting agents, and one or more wetting agents. In one embodiment, the pharmaceutical composition is an intranasal pharmaceutical composition.

In one embodiment, the pharmaceutical compositions of the present invention include one or more pharmaceutically acceptable carriers and/or one or more pharmaceutically acceptable excipients.

In one embodiment, the pharmaceutical compositions of the present invention further comprise one or more additives, including, but not limited to, preservatives, osmolarity agents, complexing agents (such as, for example, sodium edetate), surfactants, agents , which affect pH and tonicity, and sensory masking agents. In one embodiment, the pharmaceutical composition of the present invention for intranasal delivery further comprises one or more additives, including, but not limited to, preservatives, osmolarity agents, complexing agents (such as, for example, sodium edetate), surfactants substances, agents that affect pH and tonicity, and sensory masking agents.

Non-limiting examples of additives and/or excipients include benzyl alcohol, benzalkonium chloride, sodium carboxymethylcellulose/microcrystalline cellulose, propylparaben, methylparaben, phenethyl alcohol, chlorobutanol, EDTA, ethanol, ascorbic acid, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium phosphate, sodium phosphate , sodium citrate, sodium chloride, dextrose anhydrous, butylated hydroxyanisole, butylated, hydroxytoluene, PEG 400, PEG 3500, polyoxyl 400 stearate, polysorbate 20, polysorbate 80, glycerin, propylene glycol, glyceryl triacetate, glycerin, ethylene glycol, sorbitol, mannitol and alginates, carrageenan , pectins, gum tragacanth, gum arabic.

For the purposes of the present invention, a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof may be formulated for administration by various routes, including oral, parenteral, inhalational spray, topically or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and diluents. The term parenteral

- 5 041383 ny, as used in the present description, includes subcutaneous, intravenous, intramuscular and intra-arterial injections using various methods of infusion. Intra-arterial and intravenous injections, as used herein, include administration through catheters.

The pharmaceutical composition disclosed in the present description may be formulated in accordance with routine procedures adapted to the desired route of administration. Accordingly, the pharmaceutical composition herein may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain adjuvants such as suspending, stabilizing and/or dispersing agents. Alternatively, betahistine or a pharmaceutically acceptable salt thereof may be in powder form for reconstitution with a suitable solvent, eg sterile, pyrogen-free water, prior to use. Suitable formulations for each of these routes of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

In one embodiment, pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, buffer solutions, saline, and water. In one embodiment, the pharmaceutically acceptable carrier comprises about 0.01 to about 0.1 M phosphate buffer or saline (eg, 0.8% saline). In one embodiment, the buffer solution includes dibasic sodium phosphate and monobasic sodium phosphate. In such embodiments, the buffering agent adjusts the pH of the composition in a suitable range to allow rapid absorption of betahistine through the nasal mucosa and to minimize irritation. For example, the pH can be adjusted to be in the range of about 4 to about 9, including pH values of about 4, about 4.2, about 4.4, about 48, about 5, about 5.2, about 5.4 , about 5.6, about 5.8, about 6, about 6.2, about 6.4, about 6.8, about 7, about 7.2, about 7.4, about 7.6, about 7, 8, about 8, about 8.2, about 8.4, about 8.6, about 8.8, or about 9, including all ranges between any of these values. In one embodiment, the pharmaceutical composition of the present invention has a pH value of about 5. In another embodiment, the pharmaceutical composition of the present invention, having a pH value of about 5, shows improved solubility and stability of betahistine or its pharmaceutically acceptable salt compared to a composition with a higher pH value.

Such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use in this application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

Aqueous carriers suitable for use in this application include, but are not limited to, water, alcoholic/aqueous solutions (such as ethanol/water), glycerin and/or glycerol/aqueous mixtures, emulsions or suspensions, including saline and buffered medium. . Oral carriers may be elixirs, syrups, capsules, tablets, and the like.

Liquid carriers suitable for use in this application can be used in the preparation of solutions, suspensions or emulsions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier may include other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity regulators, stabilizers or osmoregulators.

Liquid carriers suitable for use in this application include, but are not limited to, water (partially containing additives as noted above, for example, cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example, glycols) and their derivatives and oils (e.g. fractionated coconut oil and peanut oil). When the compositions of the present invention are administered from pressurized containers (e.g., pressurized, metered dose dispensers), the liquid carrier for the pressurized compositions disclosed herein may be a halogenated hydrocarbon, hydrocarbon, carbon dioxide, or other pharmaceutically acceptable propellant.

Solid carriers suitable for use in this application (for example, when the compositions are presented as an intranasal dry powder) include, but are not limited to, inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. similar.

Flavoring agents and flavor enhancers can make the dosage form more palatable to the patient if some nasal compositions are swallowed. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition and/or combination of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.

The sensory masking agent can be used to mask taste and/or mask

- 6 041383 smell perception in connection with the introduction of a pharmaceutical composition. In one embodiment, the odor masking agent may include an aromatic masking agent. In one embodiment, any known sensory masking agents that are known in the pharmaceutical literature can be considered.

The compositions of the present invention may also include a coloring agent, using any pharmaceutically acceptable coloring agent to improve their appearance and/or facilitate patient identification of the product and unit dose level, in liquid pharmaceutical compositions of the present invention, where the components are dissolved or suspended in a liquid carrier such as as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

For example, formulations for parenteral administration may include, as common excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes, and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer or polyoxyethylene polyoxypropylene copolymers can be useful excipients to control the release of active compounds. Compositions for inhalation administration include, for example, lactose as excipients, or may be aqueous solutions, including, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops or as a gel for intranasal use. Compositions for parenteral administration may also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

Liquid pharmaceutical compositions and/or combinations may include emulsifying agents to distribute evenly throughout the composition and/or combination of the active ingredient or other excipient that is insoluble in the liquid carrier.

Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, carrageenan, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

Sweeteners such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to enhance the taste.

Preservatives and chelating agents such as alcohol, quaternary ammonium compounds such as benzethonium chloride, benzoxonium chloride, benzododecinium bromide, alkyltrimethylammonium bromide, cetrimonium bromide, benzalkonium chloride, phenylethyl alcohol, benzoic acid and their esters and salts, for example C ₁ -C ₇ -alkyl esters of 4-hydroxybenzoic acid such as methyl 4-hydroxybenzoate, sodium methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, butylated hydroxyltoluene, butylated hydroxyanisole, cetylpyridinium chloride, cetrimide; parabens and derivatives such as propylparaben or methylparaben; alkyl acids such as potassium sorbate, sorbic acid, calcium sorbate, sodium sorbate; biguanides, eg chlorhexidine or nasally acceptable salts thereof, eg chlorhexidine digluconate, chlorhexidine acetate or chlorhexidine chloride, 2-phenoxyethanol; boric acids; phenols such as 4-chlorocresol, 4-chloroxylenol, dichlorophene or hexachlorophene, and chelators such as ethylenediaminetetraacetic acid (EDTA) or ethylenediamine-N,N'disuccinic acid (ED) may be added at safe levels to administer to improve stability during storage.

The liquid composition and/or combination may also include additives or excipients such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The choice of excipients and the amounts to be used can be readily determined by one of ordinary skill in the formulation of drugs based on experience and consideration of standard procedures and manuals in the art.

The pharmaceutical compositions and/or pharmaceutical combinations of the invention may be in the form of an aqueous or oily suspension. In one embodiment, the pharmaceutical composition and/or pharmaceutical combinations of the invention may be in the form of a sterile aqueous or oily suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile solution or suspension may be dissolved or dispersed in a non-toxic pharmaceutically acceptable diluent or solvent such as a solution in 1,3-butanediol, or formulated as a lyophilized powder for delivery as a dry powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can usually be used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides.

Dosage forms include powders or liquids capable of being administered by evaporation or aerosol, or as a dry powder. Dosing can be controlled using a dosing device with a dosing pump, known from the prior art.

- 7 041383

In one embodiment of the present invention, betahistine or a pharmaceutically acceptable salt thereof may be formulated in any manner suitable for nasal or intranasal administration. In one embodiment, the present invention provides an intranasal pharmaceutical composition comprising betahistine hydrochloride. In another embodiment, an intranasal pharmaceutical composition is provided comprising betahistine monohydrochloride. In another embodiment, an intranasal pharmaceutical composition is provided comprising betahistine dihydrochloride.

In another embodiment, the intranasal pharmaceutical composition comprises betahistine free base. In another embodiment, the intranasal pharmaceutical composition comprises pharmaceutically acceptable betahistine salts selected from betahistine hydrochloride, betahistine dihydrochloride, betahistine fumarate, betahistine maleate, betahistine tartrate, betahistine citrate, betahistine succinate, betahistine phthalate and betahistine mesylate, betahistine hydrobromide, betahistine hydroiodide, betahistine mesylate , betahistine phosphate, betahistine acetate, betahistine pamoate/embonate, betahistine nitrate, betahistine lactate, betahistine sulfate, betahistine methyl sulfate, betahistine oxalate, or any other pharmaceutically acceptable salt of betahistine as disclosed herein or known in the art.

In one embodiment, to improve nasal delivery and retention, betahistine or a pharmaceutically acceptable salt thereof may be encapsulated with cyclodextrins or formulated with other agents that are expected to improve delivery and retention in the nasal mucosa.

In one embodiment, the present invention relates to sustained or controlled release formulations of betahistine. For example, bioadhesive polymers have shown good performance in a nasal formulation and can control the rate and extent of drug release. In addition, the increased contact time afforded by bioadhesive polymers at the site of absorption may improve drug bioavailability. Thus, nasal formulations are contemplated herein, including bioadhesive polymers, eg, chitosan microspheres. Various biocompatible and biodegradable polymers that can be used to formulate sustained release nasal formulations include polyvinyl alcohol, chitosan, carbopol, alginate, hydroxypropylmethylcellulose, hydroxypropylcellulose, starch and gellan gum. In some embodiments, liposome formulations can also be used to provide sustained release. In other embodiments, nasal microparticles or microspheres comprising albumin, starch, dextran and/or chitosan can be used to provide sustained release. These and other sustained release nasal drug delivery systems are reviewed by Ghori et al. (American Journal of Pharmacological Sciences, 2015, Vol. 3, No. 5, 110-119), which is hereby incorporated by reference in its entirety in all respects.

In some embodiments, the nasal controlled release delivery systems disclosed in U.S. Patent No. 8574622, which is incorporated herein in its entirety by reference in all respects, may be used to provide sustained release of the active agent.

In some embodiments, formulations including absorption enhancers may be used to provide sustained release. The goal of improved absorption in intranasal drug delivery is to facilitate or increase drug absorption. This can be achieved either by increasing the retention time to obtain a longer period of time for absorption, or by increasing the permeability of the mucosal tissue. Enhancing uptake is achieved through mucoadhesion or in situ gelation for long retention times, sometimes a combination of the two, or enhanced penetration by loosening cellular junctions or increasing the fluidity of membrane bilayers. Accordingly, compositions comprising mucoadhesive excipients and/or in situ gelling agents may be used for intranasal delivery of betahistine. For example, in one embodiment, sustained release formulations comprising mucoadhesive excipients such as carbomers, cellulose derivatives, starch derivatives or chitosan may be used in the present invention.

In another embodiment, sustained release formulations are in the form of in situ nasal gelling systems comprising stimulus-responsive polymers. Stimulus responsive polymers include polymers that change the rheological characteristics of gelling formulations in situ upon contact with the nasal mucosa due to changes in temperature, pH or ions. Examples of stimulus-responsive polymers or in situ gelling agents include, but are not limited to, poloxamers, pectin, and chitosan-based polymers. In one embodiment, in situ gelling systems may further include mucoadhesive excipients such as carbopol 934P, chitosan, sodium carboxymethyl cellulose (NaCMC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, and methylcellulose. In some embodiments,

Nasal compositions comprising stimulus-responsive polymers, which may optionally include mucoadhesive excipients, such as those disclosed in Chonkar et al., Indian J Pharm Sci., 2015 Jul-Aug; 77(4):367-375, incorporated herein by reference in its entirety in all respects, may be used as sustained release formulations for the practice of the present invention. In other embodiments, mucoadhesive microspheres comprising betahistine dihydrochloride as disclosed in Pilicheva et al. (International Journal of Drug Delivery, 2013, 5(4):389-401), incorporated herein by reference in its entirety in all respects, may be adapted for intranasal delivery of betahistine in accordance with the present invention.

In some embodiments, formulations comprising absorption enhancers such as alkyl glycosides disclosed in patent applications published 18 months after the priority date, nos. soy derived as absorption enhancers (Ando et al., Biological and Pharmaceutical Bulletin, 21(8), 862-865) can be used to provide sustained release, each of these documents is incorporated herein by reference in all respects . In some other embodiments, formulations comprising sodium glycocholate micelles or sodium glycocholate micelles mixed with a fatty acid (eg, linoleic acid) as absorption enhancers can be used as sustained release formulations. Other examples of absorption enhancers include cyclodextrins, phospholipids and chitosans.

Exemplary nasal formulations based on thermogelling polymers such as poloxamers are disclosed by Sharma et al. (Drug Dev Ind Pharm. 2014 Jul; 40(7):869-78); Cho et al. (J Pharm Sci. 2011 Feb;100(2):681-91); Choi et al. (Int Forum Allergy Rhinol. 2017 Jul;7(7):705-711); and Balakrishnan et al. (Molecules. 2015 Mar 4;20(3):4124-35), each of these documents is incorporated herein by reference in its entirety in all respects. The formulations disclosed in these references can be adapted for intranasal delivery of betahistine in accordance with the present invention.

In one embodiment, the implementation of the pharmaceutical composition of the present invention includes the ingredients disclosed in table. 1. In another embodiment, the pharmaceutical composition of the present invention is essentially the same as the composition disclosed in table. 1. In one embodiment, the implementation of the pharmaceutical composition of the present invention includes the ingredients disclosed in table. 1, with different amounts of each ingredient.

_______________Table 1. Sample composition of betahistine __________

Ingredient Quantity Concentration (mg/ml) betahistine dihydrochloride 5 g* 50.0 benzalkonium chloride 2 0 mg 0.2 Glycerol 100 mg 1.0 edetate disodium 2 0 mg 0.2 polyvinylpyrrolidone 1.25 g 12.5 polyethylene glycol 400 3.75 g 37.5 dibasic sodium phosphate 97.5 mg 0.975 propylene glycol 2 g 20 monobasic sodium phosphate 552.5 mg 5,525 1M sodium hydroxide 4.38 ml* pH 5.0 water for injections Up to 100 ml

For the 200 mg/ml betahistine dihydrochloride formulation, *20 g betahistine dihydrochloride and **9.3 ml 1M sodium hydroxide can be substituted.

Pharmacokinetics

In one embodiment, the implementation of the pharmaceutical composition of the present invention provides a detectable concentration C _max betahistine in human plasma after administration of a single dose of the pharmaceutical composition of the present invention. In one embodiment, _Cmax of betahistine in human plasma after a single administration of the pharmaceutical composition of the present invention is at least about 0.2 ng/mL, or at least about 0.5 ng/mL. In one embodiment, C _max is measured after administration of a single dose of about 1 g to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, C _max is measured after administration of a single dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt. In other embodiments, C _max for a 5 mg intranasal dose of betahistine is in the range of about 80% to about 125% of about 640 pg/mL; about 80% to about 125% of about 2000 pg/mL for a dose of betahistine 10

- 9 041383 mg administered intranasally; about 80 to about 125% of about 4000 pg/ml for a dose of betahistine 20 mg administered intranasally; and about 80% to about 125% of about 10,500 pg/ml for a 40 mg intranasal dose of betahistine. In other embodiments, C _max for a 5 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 230 to about 1260 pg/ml; about 80 to about 125% about 790 to about 3470 pg/ml for a dose of betahistine 10 mg administered intranasally; about 80 to about 125% about 1900 to about 8300 pg/ml for a dose of betahistine 20 mg administered intranasally; and about 80 to about 125% of about 8,000 to about 16,000 pg/ml for a 40 mg dose of betahistine administered intranasally.

In one embodiment, the C _max for a 5 mg intranasal dose of betahistine is between about 80% and about 125% about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300 .

In other embodiments, the C _max for a 5 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 600 to about 3000 pg/mL, about 600 to about 2800 pg/mL, about 600 to about 2600 pg/mL. ml, about 600 to about 2400 pg/ml, about 600 to about 2200 pg/ml, about 600 to about 2000 pg/ml, about 600 to about 1800 pg/ml, about 600 to about 1600 pg/ml, about 600 to about 1400 pg/mL, about 600 to about 1200 pg/mL, about 600 to about 1000 pg/mL, about 500 to about 2500 pg/mL, about 500 to about 2300 pg/mL, about 500 to about 2100 pg/mL , about 500 to about 1900 pg/ml, about 500 to about 1700 pg/ml, about 500 to about 1500 pg/ml, about 500 to about 1300 pg/ml, or about 500 to about 1100 pg/ml.

In one embodiment, the Cmax for a 10 mg intranasal dose of betahistine is in the range of about 80% to about 125%, 4200, 4400, 4600, 4800, 5000, 5200, 5400, 5600, 5800, 6000, 6200, 6400, 6600, 6800, 7000, 7200, 7400, 7600, 7800 or about 8000 pg/ml.

In other embodiments, the C _max for a 10 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 1800 to about 4500 pg/mL, about 2000 to about 5000 pg/mL, about 2200 to about 5500 pg/mL. ml, about 2500 to about 5500 pg/ml, about 1600 to about 3000 pg/ml, about 1600 to about 3300 pg/ml, or about 1600 to about 3500 pg/ml. In one embodiment, the C _max for a 20 mg intranasal dose of betahistine is in the range of about 80% to about 125% about 3600, 3800, 4000, 4200, 4400, 4600, 4800, 5000, 5200, 5400, 5600, 5800 pg/ml

In other embodiments, the Cmax for a 20 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 3000 to about 8000 pg/mL, about 3000 to about 7700 pg/mL, about 3000 to about 7500 pg/mL , about 3000 to about 7300 pg/mL, about 3000 to about 7100 pg/mL, about 3000 to about 6900 pg/mL, about 3000 to about 6700 pg/mL, about 3000 to about 6500 pg/mL, about 3000 to about 6300 pg/ml, about 3000 to about 6100 pg/ml, about 3000 to about 5800 pg/ml, about 3000 to about 5600 pg/ml, about 3000 to about 5400 pg/ml, about 3000 to about 5200 pg/ml, about 3000 to about 5000 pg/mL, about 3250 to about 8000 pg/mL, about 3250 to about 7750 pg/mL, about 3250 to about 7500 pg/mL, about 3250 to about 7250 pg/mL, about 3250 to about 7000 pg/ml, about 3250 to about 6800 pg/ml, about 3250 to about 6600 pg/ml, about 3250 to at about 6400 pg/mL, about 3250 to about 6200 pg/mL, about 3250 to about 6000 pg/mL, about 3250 to about 5800 pg/mL, about 3250 to about 5600 pg/mL, about 3250 to about 5400 pg/mL , about 3250 to about 5200 pg/mL, about 3250 to about 5000 pg/mL, about 3250 to about 4800 pg/mL, about 3500 to about 8000 pg/mL, about 3500 to about 7800 pg/mL, about 3500 to about 7600 pg/ml, about 3500 to about 7400 pg/ml, about 3500 to about 7200 pg/ml, about 3500 to about 7000 pg/ml, about 3500 to about 6800 pg/ml, about 3500 to about 6600 pg/ml, about 3500 to about 6400 pg/mL, about 3500 to about 6200 pg/mL, about 3500 to about 6000 pg/mL, about 3500 to about 5800 pg/mL, about 3500 to about 5600 pg/mL, about 3500 to about 5300 pg/mL, about 3500 to about 5100 pg/mL, about 3700 to about 7500 pg/mL, about 3700 to about 7200 pg/mL, about 3700 to about 7000 pg/mL g/mL, about 3700 to about 6800 pg/mL, about 3700 to about 6500 pg/mL, about 3700 to about 6300 pg/mL, about 3700 to about 6100 pg/mL, about 3700 to about 5900 pg/mL, about 3700 to about 5700 pg/ml, about 3700 to about 5500 pg/ml, about 3700 to about 5300 pg/ml, or about 3700 to about 5100 pg/ml.

In one embodiment, the Cmax for a 40 mg intranasal dose of betahistine is in the range of about 80% to about 125%, 11750, 12000, 12250, 12500, 12750, 13000, 13250, 13500, 13750,

- 10 041383

pg/ml

In other embodiments, the C _max for a 40 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 8000 to about 20000 pg/mL, about 8000 to about 19000 pg/mL, about 8000 to about 18500 pg/mL. ml, about 8000 to about 18000 pg/ml, about 8000 to about 17500 pg/ml, about 8000 to about 17000 pg/ml, about 8000 to about 16500 pg/ml, about 8000 to about 16000 pg/ml, about 8000 to about 15,500 pg/mL, about 8,000 to about 15,000 pg/mL, about 8,000 to about 14,500 pg/mL, about 8,000 to about 14,000 pg/mL, about 8,000 to about 13,500 pg/mL, about 8,000 to about 13,000 pg/mL , about 8000 to about 12500 pg/ml, about 9000 to about 19500 pg/ml, about 9000 to about 19000 pg/ml, about 9000 to about 18500 pg/ml, about 9000 to about 18000 pg/ml, about 9000 to about 17500 pg/ml, about 9000 to about 17000 pg/ml, about 9000 to about 16500 pg/m l, about 9000 to about 16000 pg/ml, about 9000 to about 15500 pg/ml, about 9000 to about 15000 pg/ml, about 9000 to about 15000 pg/ml, about 9000 to about 14500 pg/ml, about 9000 to about 14,000 pg/mL, about 9,000 to about 13,500 pg/mL, about 9,000 to about 13,000 pg/mL, about 10,000 to about 18,500 pg/mL, about 10,000 to about 18,000 pg/mL, about 10,000 to about 17,500 pg/mL , about 10,000 to about 17,000 pg/mL, about 10,000 to about 16,500 pg/mL, about 10,000 to about 16,000 pg/mL, about 10,000 to about 15,500 pg/mL, about 10,000 to about 15,000 pg/mL, about 10,000 to about 14,500 pg/ml or about 10,000 to about 14,000 pg/ml.

In one embodiment, the C _max for a 60 mg intranasal dose of betahistine is in the range of about 80% to about 125% about 14000, 14250, 14500, 14750, 15000, 15250, 15500, 15750, 16000, 16250, 16500, 16750 , 17000, 17250, 17500, 17750, 18000, 18250, 18500 or 19000 pg/ml.

In other embodiments, the C _max for a 60 mg intranasal dose of betahistine is in the range of about 80 to about 125%, about 13,500 to about 19,000 pg/ml, about 13,500 to about 18,500 pg/ml, about 13,500 to about 18,250 pg/ml. ml, about 13500 to about 18000 pg/ml, about 13500 to about 17750 pg/ml, about 13500 to about 17500 pg/ml, about 13500 to about 17250 pg/ml, about 13500 to about 17000 pg/ml, about 13500 to about 16,500 pg/mL, about 13,500 to about 16,000 pg/mL, about 14,000 to about 19,000 pg/mL, about 14,000 to about 18,500 pg/mL, about 14,000 to about 18,250 pg/mL, about 14,000 to about 18,000 pg/mL , about 14,000 to about 17,750 pg/mL, about 14,000 to about 17,500 pg/mL, about 14,000 to about 17,250 pg/mL, about 14,000 to about 17,000 pg/mL, about 14,000 to about 16,500 pg/mL, about 14,000 to about 16,000 pg/ml, about 14,500 to about 18,500 pg/ml, about 14,500 up to about 18250 pg/ml, about 14500 to about 18000 pg/ml, about 14500 to about 17750 pg/ml, about 14500 to about 17500 pg/ml, about 14500 to about 17250 pg/ml, about 14500 to about 17000 pg/ml ml or about 14500 to about 16500 pg/ml.

In one embodiment, C _max for an intranasal dose of betahistine 80 mg is in the range of about 80% to about 125% about 18000, 18500, 19000, 19250, 19500, 19750, 20000, 20250, 20500, 20750, 21000, 21250 , 21500, 21750, 22000, 22250, 22500, 22750, 23000, 23250, 23500, 23750 or 24000 pg/ml.

In other embodiments, C _max for an intranasally administered dose of betahistine 80 mg is in the range of about 80% to about 125%, about 18,000 to about 25,000 pg/mL, about 18,000 to about 24,500 pg/mL, about 18,000 to about 24,000 pg/mL. ml, about 18,000 to about 23,750 pg/ml, about 18,000 to about 23,500 pg/ml, about 18,000 to about 23,250 pg/ml, about 18,000 to about 23,000 pg/ml, about 18,000 to about 22,750 pg/ml, about 18,000 to about 22,500 pg/mL, about 18,000 to about 22,250 pg/mL, about 18,000 to about 22,000 pg/mL, about 18,500 to about 25,000 pg/mL, about 18,500 to about 24,500 pg/mL, about 18,500 to about 24,000 pg/mL , about 18500 to about 23750 pg/mL, about 18500 to about 23500 pg/mL, about 18500 to about 23250 pg/mL, about 18500 to about 23000 pg/mL, about 18500 to about 22750 pg/mL, about 18500 to about 22500 pg/ml, about 18500 to about 222 50 pg/ml, about 18500 up to about 22,000 pg/ml, about 19,000 to about 25,000 pg/ml, about 19,000 to about 24,500 pg/ml, about 19,000 to about 24,250 pg/ml, about 19,000 to about 24,000 pg/ml, about 19,000 to about 23,750 pg/ml ml, about 19,000 to about 23,500 pg/ml, about 19,000 to about 23,250 pg/ml, about 19,000 to about 23,000 pg/ml, about 19,000 to about 22,750 pg/ml, about 19,000 to about 22,500 pg/ml, about 19,000 to about 22,250 pg/mL, about 19,000 to about 22,000 pg/mL, about 19,500 to about 24,500 pg/mL, about 19,500 to about 24,250 pg/mL, about 19,500 to about 24,000 pg/mL, about 19,500 to about 23,750 pg/mL , about 19500 to about 23500 pg/mL, about 19500 to about 23250 pg/mL, about 19500 to about 23000 pg/mL, about 19500 to about 22750 pg/mL, about 19500 to about 22500 pg/mL, about 19500 to about 22250 pg/ml or example

- 11 041383 but 19500 to about 22000 pg/ml.

In one embodiment, the human plasma _Cmax of betahistine after administration of a single dose of the intranasal pharmaceutical composition of the present invention is at least about 0.2 ng/mL, or at least about 0.5 ng/mL. In one embodiment, the C _max of betahistine in human plasma after administration of a single dose of the intranasal pharmaceutical composition of the present invention is at least about 0.2 ng/ml, at least about 0.3 ng/ml, at least about 0, 4 ng/ml, at least about 0.5 ng/ml, at least about 0.6 ng/ml, at least about 0.7 ng/ml, at least about 0.8 ng/ml, at least about 0.9 ng/ml, at least about 1 ng/ml, at least about 1.5 ng/ml, at least about 2 ng/ml, at least about 2.5 ng/ml, at least about 3 ng/ml, at least about 3.5 ng/ml, at least about 4 ng/ml, at least about 4.5 ng/ml, at least about 5 ng/ml, at least about 5.5 ng/ml, at least about 6 ng/ml, at least about 7.5 ng/ml, at least about 8 ng/ml, at least about 8.5 ng/ml, at least about 9 ng/mL, at least at least about 9.5 ng/ml, or at least about 10 ng/ml.

In one embodiment, the _Cmax of betahistine in human plasma following single dose administration of the intranasal pharmaceutical composition of the present invention is at least about 10 ng/mL, at least about 11 ng/mL, at least about 12 ng/mL, at least about 13 ng/ml, at least about 14 ng/ml, at least about 15 ng/ml, at least about 16 ng/ml, at least about 17 ng/ml, at least about 18 ng /ml, at least about 19 ng/ml, at least about 20 ng/ml, at least about 21 ng/ml, at least about 22 ng/ml, at least about 23 ng/ml, at least at least about 24 ng/ml, at least about 25 ng/ml, at least about 26 ng/ml, at least about 27 ng/ml, at least about 28 ng/ml, at least about 29 ng/ml ml or at least about 30 ng/ml. In one embodiment, _Cmax of betahistine in human plasma following single dose administration of the intranasal pharmaceutical composition of the present invention is at least about 3.5 ng/mL. In one embodiment, the human plasma C _max of betahistine was measured following administration of a single dose of an intranasal pharmaceutical composition comprising about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, C _max was measured after intranasal administration of a single dose of about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, approx. black 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg or about 100 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, Cmax was measured following intranasal administration of a single dose of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, C _max was measured after intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the intranasal pharmaceutical composition of the present invention exhibits good tolerability and a dose-dependent increase in betahistine plasma concentrations, higher than what can be found after oral administration of betahistine.

In one embodiment, the implementation of the pharmaceutical composition of the present invention provides t _max betahistine in human plasma after administration of a single dose of the pharmaceutical composition of the present invention. In one embodiment, the tmax of betahistine in human plasma after administration of a single dose of a pharmaceutical composition of the present invention is about 0.05 hour or more, 0.06 hour or more, 0.07 hour or more, about 0.08 hour or more,

- 12 041383 about 0.09 hour or more, about 0.1 hour or more, about 0.11 hour or more, about 0.12 hour or more, about 0.13 hour or more, about 0.14 hour or more , about 0.15 hours or more, about 0.16 hours or more, about 0.17 hours or more, about 0.18 hours or more, about 0.19 hours or more, about 0.2 hours or more, about 0.25 hours or more, or about 0.3 hours or more. In one embodiment, t _max is measured after administration of a single dose of about 1 to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t _max is measured after a single dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg , about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the t _max of betahistine in human plasma after administration of a single dose of the intranasal pharmaceutical composition of the present invention is about 0.05 hour or more, 0.06 hour or more, 0.07 hour or more, about 0.08 hour, or more, about 0.09 hour or more, about 0.1 hour or more, about 0.11 hour or more, about 0.12 hour or more, about 0.13 hour or more, about 0.14 hour or more, about 0.15 hour or more, about 0.16 hour or more, about 0.17 hour or more, about 0.18 hour or more, about 0.19 hour or more, about 0.2 hour or more, about 0, 25 hours or more, or about 0.3 hours or more. In one embodiment, the t _max of betahistine in human plasma after administration of a single dose of the intranasal pharmaceutical composition of the present invention is about 0.09 hours or more, about 0.1 hours or more, about 0.11 hours or more, or about 0. 12 hours or more. In one embodiment, the t _max of betahistine in human plasma is determined following administration of a single dose of an intranasal pharmaceutical composition comprising about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, tmax was determined after intranasal administration of a single dose of about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg , about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg , about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, approximately 62 mg, approximately 63 mg, approximately 64 mg, approximately 65 mg, approximately 66 mg, approximately 67 mg, approximately 68 mg, approximately 69 mg, approximately 70 mg, approximately 71 mg, approximately 72 mg, approximately 73 mg, approximately 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg, of betahistine or a pharmaceutically acceptable salt.

In one embodiment, t _max was determined following intranasal administration of a single dose of about 20 or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, t _max was determined following intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the pharmaceutical composition of the present invention provides a human plasma AUC ₀ _ _last of betahistine after administration of a single dose of the pharmaceutical composition of the present invention of at least about 50 h-pg/mL, at least about 100 h-pg/mL , at least about 200 h-pg/ml, at least about 250 h-pg/ml, at least about 300 h-pg/ml, at least about 400 h-pg/ml, at least about 500 h-pg/ml, at least about 600 h-pg/ml, at least about 700 h-pg/ml, at least about 800 h-pg/ml, at least about 900 h-pg/ml, at least about 1000 h-pg/ml, at least about 1100 h-pg/ml, at least about 1200 h-pg/ml, at least about 1300 h-pg/ml, at least about 1400 h -pg/ml, at least about 1500 h-pg/ml, at least about 1600 h-pg/ml, at least about 1700 h-pg/ml, at least about 1800 h-pg/ml, at least about 1900 h-pg/mL, at least about 2000 h-pg/mL, at least about 2100 h-pg/mL, at least about 2200 h-pg/mL, at least about 2300 h -pg/ml, at least about 2400 h-pg/ml, at least about 2500 h-pg/ml, at least about 2600 h-pg/ml, at least about 2700 h-pg/ml, at least about 2800 h-pg/ml, at least about 2900 h-pg/ml, at least about 3000 h-pg/ml, at least about 3100 h-pg/ml, at least about 3200

- 13 041383 h-pg/ml, at least about 3300 h-pg/ml, at least about 3400 h-pg/ml, or at least about 3500 h-pg/ml. In one embodiment, AUC0-iast is measured following administration of a single dose of about 1 to about 250 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the AUC0-last of betahistine in human plasma after administration of a single dose of the intranasal pharmaceutical composition of the present invention is at least about 0.05 h-ng/mL, at least about 0.1 h-ng/mL, according to at least about 0.2 h-ng/mL, at least about 0.25 h-ng/mL, at least about 0.3 h-ng/mL, at least about 0.4 h-ng/mL , at least about 0.5 h-ng/ml, at least about 0.6 h-ng/ml, at least about 0.7 h-ng/ml, at least about 0.8 h-ng /ml, at least about 0.9 h-ng/ml, at least about 1.0 h-ng/ml, at least about 1.1 h-ng/ml, at least about 1.2 h -ng/ml, at least about 1.3 h-ng/ml, at least about 1.4 h-ng/ml, at least about 1.5 h-ng/ml, at least about 1, 6 h-ng/ml, at least about 1.7 h-ng/ml, at least about 1.8 h-ng/ml, at least about 1.9 h-ng/ml, at least pe about 2.0 h-ng/ml, at least about 2.1 h-ng/ml, at least about 2.2 h-ng/ml, at least about 2.3 h-ng/ml, at least about 2.4 h-ng/ml, at least about 2.5 h-ng/ml, at least about 2.6 h-ng/ml, at least about 2.7 h-ng/ml ml, at least about 2.8 h-ng/ml, at least about 2.9 h-ng/ml, at least about 3.0 h-ng/ml, at least about 3.1 h- ng/mL, at least about 3.2 h-ng/mL, at least about 3.3 h-ng/mL, at least about 3.4 h-ng/mL, at least about 3.5 h-ng/ml, at least about 3.6 h-ng/ml, at least about 3.7 h-ng/ml, at least about 3.8 h-ng/ml, at least about 3 .9 h-ng/ml, at least about 4.0 h-ng/ml. In one embodiment, the human plasma AUC0-last of betahistine after administration of a single dose of the intranasal pharmaceutical composition of the present invention is at least about 1.5 h ng/mL, or at least about 3.0 h ng/mL.

In one embodiment, the human plasma AUC _0-last of betahistine was determined following administration of a single dose of an intranasal pharmaceutical composition comprising about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, AUC0-last was determined after a single intranasal dose of about 5.6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, approximately one of mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, about mg, about mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, about about about about about about about about about about about about about about about about about mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, about about about about about about about about about about about about about about about about about mg, about mg, about mg, about mg , approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately mg, approximately about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg, about mg , about mg, about

85 mg, primg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg

100 mg betahistine or pharmaceutically acceptable salt. In embodiments, AUC-last was determined following intranasal administration of a single dose of about 20 or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, AUC _0-last was determined following intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In various embodiments, the AUQ-last is about 80-125% of about 210 pg-h/ml for a 5 mg intranasal dose of betahistine; about 80-125% of about 500 pg-h/ml for a dose of betahistine 10 mg administered intranasally; about 80-125% of about 1600 pg-h/ml for a dose of betahistine 20 mg administered intranasally; and about 80-125% of about 3500 pg-h/ml for a dose of betahistine 40 mg administered intranasally.

In some embodiments, the AUC0-last for a 5 mg intranasal dose of betahistine is in the range of about 80% to about 125% about 200 pg-h/mL, 300 pg-h/mL, 400 pg-h/mL, 500 pg -h/ml, 600 pg-h/ml, 700 pg-h/ml, 800 pg-h/ml, 900 pg-h/ml, 1000 pg-h/ml, 1100 pg-h/ml, 1200 pg- h/ml, 1300 pg-h/ml, 1400 pg-h/ml or 1500 pg-h/ml.

- 14 041383

In some other embodiments, the AUCo _-last for a 5 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 200 to about 500 pg-h/mL, about 200 to about 600 pg-h/mL, about 300 to about 700 pg-h/ml, about 400 to about 800 pg-h/ml, about 500 to about 1000 pg-h/ml, about 600 to about 1100 pg-h/ml, about 750 to about 1250 pg- h/ml or about 800 to about 1400 pg-h/ml.

In some embodiments, the _0-last AUC for a 10 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 500 pg-h/mL, 600 pg-h/mL, 700 pg-h/mL, 800 pg-h/ml, 900 pg-h/ml, 1000 pg-h/ml, 1100 pg-h/ml, 1200 pg-h/ml, 1300 pg-h/ml, 1400 pg-h/ml or 1500 pg -h/ml.

In some other embodiments, the _0-last AUC for a 10 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 400 to about 800 pg-h/mL, about 500 to about 800 pg-h/mL, about 500 to about 900 pg-h/mL, about 500 to about 1000 pg-h/mL, about 500 to about 1200 pg-h/mL, about 600 to about 1000 pg-h/mL, about 600 to about 1100 pg -h/ml, about 600 to about 1200 pg-h/ml, about 700 to about 1100 pg-h/ml, about 700 to about 1200 pg-h/ml, about 800 to about 1300 pg-h/ml, about 800 to about 1200 pg-h/ml, or about 900 to about 1200 pg-h/ml.

In some embodiments, the AUC0-last for a 20 mg intranasal dose of betahistine is in the range of about 80% to about 125% about 1500 pg-h/mL, 1600 pg-h/mL, 1700 pg-h/mL, 1800 pg -h/ml, 1900 pg-h/ml, 2000 pg-h/ml, 2100 pg-h/ml, 2200 pg-h/ml, 2300 pg-h/ml, 2400 pg-h/ml, 2500 pg- h/ml, 2600 pg-h/ml, 2700 pg-h/ml, 2800 pg-h/ml, 2900 pg-h/ml or 3000 pg-h/ml.

In some other embodiments, the AUC0-last for a 20 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 1500 to about 2000 pg-h/mL, about 1500 to about 2200 pg-h/mL, about 1600 to about 2100 pg-h/ml, about 1700 to about 2200 pg-h/ml, about 1700 to about 2400 pg-h/ml, about 1800 to about 2400 pg-h/ml, about 1900 to about 2500 pg- h/ml, about 2000 to about 2500 pg-h/ml, about 2100 to about 2700 pg-h/ml, or about 2200 to about 2900 pg-h/ml.

In some embodiments, the AUC0-last for a 40 mg intranasal dose of betahistine is in the range of about 80% to about 125% about 3300 pg-h/mL, 3400 pg-h/mL, 3500 pg-h/mL, 3600 pg -h/ml, 3700 pg-h/ml, 3800 pg-h/ml, 3800 pg-h/ml, 4000 pg-h/ml, 4100 pg-h/ml, 4250 pg-h/ml, 4500 pg- h/ml, 4750 pg-h/ml, 5000 pg-h/ml, 5250 pg-h/ml, 5500 pg-h/ml, 5750 pg-h/ml, 6000 pg-h/ml, 6250 pg-h /ml, 6500 pg-h/ml or 7000 pg-h/ml.

In some other embodiments, the AUC0-last for a 40 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 3300 to about 3800 pg-h/mL, about 3300 to about 4000 pg-h/mL, about 3300 to about 4200 pg-h/mL, about 3300 to about 4500 pg-h/mL, about 3500 to about 4000 pg-h/mL, about 3500 to about 4200 pg-h/mL, about 3500 to about 4500 pg- h/mL, about 3750 to about 4250 pg-h/mL, about 3750 to about 4500 pg-h/mL, about 3750 to about 4750 pg-h/mL, about 4000 to about 5000 pg-h/mL, or about 4000 to about 5500 pg-h/ml.

In some embodiments, the AUC0-last for a 60 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 5300 pg-h/mL, 5400 pg-h/mL, 5500 pg-h/mL, about 5750 pg-h/ml, 6000 pg-h/ml, 6250 pg-h/ml, 6500 pg-h/ml, 6750 pg-h/ml, 7000 pg-h/ml, 7250 pg-h/ml, 7500 pg -h/ml, 7750 pg-h/ml or about 8000 pg-h/ml.

In some other embodiments, the AUC0-last for a 60 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 5300 to about 5800 pg-h/mL, about 5400 to about 5900 pg-h/mL, about 5500 to about 6000 pg-h/mL, about 5400 to about 6200 pg-h/mL, about 5500 to about 6400 pg-h/mL, about 5500 to about 6700 pg-h/mL, about 5500 to about 6900 pg- h/mL, about 5700 to about 6300 pg-h/mL, about 5700 to about 6500 pg-h/mL, about 5700 to about 6700 pg-h/mL, about 5900 to about 6500 pg-h/mL, about 5900 up to about 6700 pg-h/ml, about 6000 to about 7250 pg-h/ml, about 6000 to about 7000 pg-h/ml, about 6000 to about 7500 pg-h/ml.

In some embodiments, the _0-last AUC for an intranasal dose of betahistine 80 mg is between about 80% and about 125%, about 7500 pg-h/ml, 7750 pg-h/ml, 8000 pg-h/ml, 8250 pg-h/ml, 8500 pg-h/ml, 8750 pg-h/ml, 9000 pg-h/ml, 9250 pg-h/ml, 9500 pg-h/ml, 9750 pg-h/ml or 10000 pg *h/ml.

In some other embodiments, the AUC _0-last for an intranasal dose of betahistine 80 mg is in the range of about 80% to about 125%, about 7300 to about 8000 pg-h/mL, about 7500 to about 8200 pg-h/mL, about 7500 to about 8000 pg-h/mL, about 7500 to about 8500 pg-h/mL, about 7750 to about 8500 pg-h/mL, about 7750 to about 8750 pg-h/mL, about 8000 to about 8500 pg -h/ml, about 8000 to about 8750 pg-h/ml, at

- 15 041383 measured 8000 to about 9000 pg-h/mL, about 8250 to about 9000 pg-h/mL, about 8250 to about 8750 pg-h/mL, about 8250 to about 9250 pg-h/mL, about 8500 to about 9500 pg-h/ml, or about 8500 to about 9000 pg-h/ml.

In one embodiment, the pharmaceutical composition of the present invention provides an AUC0-inf of betahistine in human plasma after administration of a single dose of the pharmaceutical composition of the present invention of at least about 100 h-pg/ml, at least about 200 h-pg/ml, at least about 250 h-pg/ml, at least about 300 h-pg/ml, at least about 400 h-pg/ml, at least about 500 h-pg/ml, at least about 600 h- pg/ml, at least about 700 h-pg/ml, at least about 800 h-pg/ml, at least about 900 h-pg/ml, at least about 1000 h-pg/ml, at least at least about 1100 h-pg/ml, at least about 1200 h-pg/ml, at least about 1300 h-pg/ml, at least about 1400 h-pg/ml, at least about 1500 h-pg /ml, at least about 1600 h-pg/ml, at least about 1700 h-pg/ml, at least about 1800 h-pg/ml, at least about 1900 h-pg/ml, according to at least about 2000 h-pg/ml, at least about 2100 h-pg/ml, at least about 2200 h-pg/ml, at least about 2300 h-pg/ml, at least about 2400 h- pg/ml, at least about 2500 h-pg/ml, at least about 2600 h-pg/ml, at least about 2700 h-pg/ml, at least about 2800 h-pg/ml, at least at least about 2900 h-pg/ml, at least about 3000 h-pg/ml, at least about 3100 h-pg/ml, at least about 3200 h-pg/ml, at least about 3300 h-pg /ml, at least about 3400 h-pg/ml or at least about 3500 h-pg/ml. In one embodiment, AUC0_inf is measured after administration of a single dose of about 1 to about 250 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the human plasma AUC0-inf of betahistine after administration of a single dose of the intranasal pharmaceutical composition of the present invention is at least about 0.1 h ng/mL, at least about 0.2 h ng/mL, at least approximately

0.25 h-ng/mL, at least about 0.3 h-ng/mL, at least about 0.4 h-ng/mL, at least about 0.5 h-ng/mL, at least at least about 0.6 h-ng/ml, at least about 0.7 h-ng/ml, at least about 0.8 h-ng/ml, at least about 0.9 h-ng/ml, at least about 1.0 h-ng/ml, at least about 1.1 h-ng/ml, at least about 1.2 h-ng/ml, at least about 1.3 h-ng/ml ml, at least about 1.4 h-ng/ml, at least about 1.5 h-ng/ml, at least about 1.6 h-ng/ml, at least about 1.7 h- ng/mL, at least about 1.8 h-ng/mL, at least about 1.9 h-ng/mL, at least about 2.0 h-ng/mL, at least about 2.1 h-ng/ml, at least about 2.2 h-ng/ml, at least about 2.3 h-ng/ml, at least about 2.4 h-ng/ml, at least about 2 .5 h-ng/mL, at least about 2.6 h-ng/mL, at least about 2.7 h-ng/mL, at least about 2.8 h-ng/mL , at least about 2.9 h-ng/ml, at least about 3.0 h-ng/ml, at least about 3.1 h-ng/ml, at least about 3.2 h-ng /ml, at least about 3.3 h-ng/ml, at least about 3.4 h-ng/ml, at least about 3.5 h-ng/ml, at least about 3.6 h -ng/ml, at least about 3.7 h-ng/ml, at least about 3.8 h-ng/ml, at least about 3.9 h-ng/ml, at least about 4, 0 h-ng/ml. In one embodiment, the human plasma AUC0-inf of betahistine following single dose administration of the intranasal pharmaceutical composition of the present invention is at least about 1.5 h ng/mL, or at least about 3.0 h ng/mL.

In one embodiment, the human plasma AUC0-inf of betahistine was determined following administration of a single dose of an intranasal pharmaceutical composition comprising about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, determined after a single intranasal dose of about 5.6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about about about about about about about about about about about about about mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, about about about about about about about about about about about about about mg, mg, mg, mg, mg, mg , mg, mg, mg, mg, mg, about about about about about about about about about about about about about about about mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, about about about about about about about about about about about about mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, about about about about about about about about about about about about about

25

43 mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, about about about about about about about about about about about about about about mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg,

- 16 041383 about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg , about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 or about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the implementation of the AUC _0-inf was determined after intranasal administration of a single dose of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, AUC ₀ _ _inf was determined after intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In various embodiments, the AUC ₀ _ _inf of betahistine is in the range of about 80125% of about 275 pg-h/ml for a dose of betahistine 5 mg administered intranasally; about 80-125% of about 700 pg-h/ml for a dose of betahistine 10 mg administered intranasally; about 80-125% of about 1630 pg-h/ml for a dose of betahistine 20 mg administered intranasally; and about 80-125% of about 2940 pg-h/ml for the intranasal dose of betahistine 40 mg.

In some embodiments, the AUC ₀ _ _inf for a 5 mg intranasal dose of betahistine is between about 80% and about 125%, about 250 pg-h/ml, 275 pg-h/ml, 300 pg-h/ml, 350 pg-h/ml, 400 pg-h/ml, 450 pg-h/ml, 500 pg-h/ml, 600 pg-h/ml, 700 pg-h/ml, 800 pg-h/ml, 900 pg -h/ml or 1000 pg-h/ml.

In some other embodiments, the AUC ₀ _ _inf for a 5 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 250 to about 350 pg-h/ml, about 250 to about 500 pgmh/ml, about 275 up to about 375 pg-h/ml, about 275 to about 475 pg-h/ml, about 275 to about 575 pg-h/ml, about 250 to 850 pg-h/ml, about 300 to about 800 pg-h/ml ml, about 300 to about 700 pg-h/ml, about 400 to about 800 pg-h/ml, about 500 to about 1000 pg-h/ml, about 750 to about 1250 pg-h/ml, or about 750 to about 1500 pg-h / ml.

In some embodiments, the AUC ₀ _ _inf for a 10 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 650 pg-h/ml, about 700 pg-h/ml, about 800 pg-h/ml , about 900 pg-h/ml, about 1000 pg-h/ml, about 1250 pg-h/ml, about 1500 pg-h/ml, about 1750 pg-h/ml or about 2000 pg-h/ml.

In some other embodiments, the AUC ₀ _ _inf for a 10 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 650 to about 1000 pg-h/mL, about 650 to about 1250 pg-h/mL, about 700 to about 1400 pg-h/ml, about 700 to about 1200 pg-h/ml, about 700 to 1000 pg-h/ml, about 800 to about 1200 pg-h/ml, about 800 to about 1400 pg- h/ml, about 800 to about 1600 pg-h/ml, about 1000 to about 1500 pg-h/ml, or about 1000 to about 2000 pg-h/ml.

In some embodiments, the AUC ₀ _ _inf for a 20 mg intranasal dose of betahistine is in the range of about 80% to about 125% about 1600 pg-h/ml, about 1700 pg-h/ml, about 1800 pg-h/ml , about 1900 pg-h/ml, about 2000 pg-h/ml, about 2250 pg-h/ml, about 2500 pg-h/ml, about 2750 pg-h/ml, about 3000 pg-h/ml or about 3500 pg-h / ml.

In some other embodiments, the AUC ₀ _ _inf for a 20 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 1600 to about 2000 pg-h/mL, about 1600 to about 2200 pg-h/mL, about 1600 to about 2400 pg-h/mL, about 1600 to about 2600 pg-h/mL, about 1800 to about 2400 pg-h/mL, about 1800 to about 2600 pg-h/mL, about 1800 to about 2800 pg -h/ml, about 2000 to about 3000 pg-h/ml, about 2000 to about 2500 pg-h/ml, about 2000 to about 2800 pg-h/ml, about 2250 to about 3250 pg-h/ml, about 2250 to about 3000 pg-h/ml, about 2500 to about 3500 pg-h/ml, or about 2500 to about 3000 pg-h/ml.

In some embodiments, the AUC ₀ _ _inf for a 40 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 2800 pg-h/ml, about 2900 pg-h/ml, about 2950 pg-h/ml , about 3000 pg-h/ml, about 3100 pg-h/ml, about 3200 pg-h/ml, about 3300 pg-h/ml, about 3400 pg-h/ml, about 3500 pg-h/ml, about 3600 pg-h/ml, about 3700 pg-h/ml, about 3800 pg-h/ml, about 3800 pg-h/ml, about 4000 pg-h/ml, about 4250 pg-h/ml, about 4500 pg -h/ml, about 4750 pg-h/ml, about 5000 pg-h/ml, about 5250 pg-h/ml, about 5500 pg-h/ml, about 5750 pg-h/ml or about 6000 pg*h /ml

In some other embodiments, the AUC ₀ _ _inf for a 40 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 2800 to about 3300 pg-h/mL, about 2800 to about 3500 pg-h/mL, about 2800 to about 3800 pg-h/mL, about 3000 to about 3500 pg-h/mL, about 3500 to about 3750 pg-h/mL, about 3000 to about

- 17 041383

4000 pg-h/mL, about 3250 to about 4250 pg-h/mL, about 3250 to about 4500 pg-h/mL, about 3500 to about 4500 pg-h/mL, about 3500 to about 4000 pg-h/mL , about 3750 to about 4750 pg-h/mL, about 3750 to about 4500 pg-h/mL, about 4000 to about 5000 pg-h/mL, about 4500 to about 5500 pg-h/mL, or about 5000 to about 6000 pg-h/ml.

In some embodiments, the AUC ₀ _ _inf for a 60 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 5300 pg-h/ml, 5400 pg-h/ml, 5500 pg-h/ml, about 5750 pg-h/ml, 6000 pg-h/ml, 6250 pg-h/ml, 6500 pg-h/ml, 6750 pg-h/ml, 7000 pg-h/ml, 7250 pg-h/ml, 7500 pg-h/ml, 7750 pg-h/ml or about 8000 pg-h/ml.

In some other embodiments, the AUC ₀ _ _inf for a 60 mg intranasal dose of betahistine is in the range of about 80% to about 125%, about 5300 to about 5800 pg-h/mL, about 5400 to about 5900 pg-h/mL, about 5500 to about 6000 pg-h/mL, about 5400 to about 6200 pg-h/mL, about 5500 to about 6400 pg-h/mL, about 5500 to about 6700 pg-h/mL, about 5500 to about 6900 pg -h/ml, about 5700 to about 6300 pg-h/ml, about 5700 to about 6500 pg-h/ml, about 5700 to about 6700 pg-h/ml, about 5900 to about 6500 pg-h/ml, about 5900 to about 6700 pg-h/ml, about 6000 to about 7250 pg-h/ml, about 6000 to about 7000 pg-h/ml, about 6000 to about 7500 pg-h/ml.

In some embodiments, the AUC ₀ _ _inf for an intranasal dose of betahistine 80 mg is between about 80% and about 125%, about 7500 pg-h/ml, 7750 pg-h/ml, 8000 pg-h/ml, 8250 pg-h/ml, 8500 pg-h/ml, 8750 pg-h/ml, 9000 pg-h/ml, 9250 pg-h/ml, 9500 pg-h/ml, 9750 pg-h/ml or 10000 pg -h/ml.

In some other embodiments, the AUC ₀ _ _inf for an intranasal dose of betahistine 80 mg is in the range of about 80% to about 125%, about 7300 to about 8000 pg-h/mL, about 7500 to about 8200 pg-h/mL, about 7500 to about 8000 pg-h/mL, about 7500 to about 8500 pg-h/mL, about 7750 to about 8500 pg-h/mL, about 7750 to about 8750 pg-h/mL, about 8000 to about 8500 pg -h/ml, about 8000 to about 8750 pg-h/ml, about 8000 to about 9000 pg-h/ml, about 8250 to about 9000 pg-h/ml, about 8250 to about 8750 pg-h/ml, about 8250 to about 9250 pg-h/ml, about 8500 to about 9500 pg-h/ml, or about 8500 to about 9000 pg-h/ml.

In one embodiment, the absolute bioavailability (%F) of betahistine administered intranasally is about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 6θ, 65, 70, 75, 80, 85, or 90%. In one embodiment, the absolute bioavailability (% F) of intranasally administered betahistine is about 30-80%, about 25-75%, about 20-60%, about 10-50%, about 30-60%, about 40- 60%, about 40-70%, about 40-80% or about 50-80%.

In one embodiment, the relative bioavailability (F _oth ) for 5 mg intranasal betahistine is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 times the oral bioavailability. In one embodiment, the relative bioavailability for 10 mg intranasal betahistine is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 times the bioavailability at oral administration. In one embodiment, the relative bioavailability for 20 mg intranasal betahistine is about 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 40, 41, or 42 times oral bioavailability. In one embodiment, the relative bioavailability for 40 mg intranasal betahistine is about 36, 37, 38, 38, 40, 41, 42, 43, 44, 45, or 46 times the oral bioavailability. In one embodiment, the relative bioavailability for 60 mg intranasal betahistine is about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69 or 70 times the oral bioavailability. In one embodiment, the relative bioavailability for 80 mg intranasal betahistine is about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80 times the oral bioavailability. In one embodiment, the relative bioavailability for 100 mg intranasal betahistine is about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 times the oral bioavailability.

In one embodiment, the relative bioavailability for intranasal betahistine is about 10-25, about 15-30, about 20-40, about 20-30, about 20-50, about 25-40, about 25-45, about 25-50, about 15-45, about 30-60 times the oral bioavailability.

In one embodiment, the t _1/2 (apparent half-life) of betahistine, as determined based on the administration of a single dose of a pharmaceutical composition of the present invention, is about 0.07 hours or more, about 0.08 hours or more, about 0.09 hours or more, about 0.1 hour or more, about 0.2 hour or more, about 0.3 hour or more, about 0.4 hour or more,

- 18 041383 about 0.5 hour or more, about 0.6 hour or more, about 0.6 hour or more, about 0.8 hour or more, about 0.9 hour or more, or about 1.0 hour, or more. In one embodiment, ti/ ₂ was determined based on the administration of a single dose of about 1 to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t _1/2 was determined based on the administration of a single dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg , about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the t _1/2 (apparent half-life) of betahistine, as determined based on the administration of a single dose of an intranasal pharmaceutical composition of the present invention, is about 0.07 hours or more, about 0.08 hours or more, about 0.09 hour or more, about 0.1 hour or more, about 0.2 hour or more, about 0.3 hour or more, about 0.4 hour or more, about 0.5 hour or more, about 0.6 hour, or more, about 0.6 hour or more, about 0.8 hour or more, about 0.9 hour or more, or about 1.0 hour or more. In one embodiment, the t1/2 of betahistine, based on the administration of a single dose of the intranasal pharmaceutical composition of the present invention, is about 0.4 hours or more, or about 0.8 hours or more. In one embodiment, the t _1/2 of betahistine, based on a single dose of the intranasal pharmaceutical composition of the present invention, is about 0.5 or about 0.9 hours.

In one embodiment, the t _1/2 value is determined based on intranasal administration of a single dose of about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t1/2 was determined based on intranasal administration of a single dose of about 5.6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg , about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg , about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 or about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t _1/2 is determined based on intranasal administration of a single dose of about 20 or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, t _1/2 was determined based on intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg , about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the pharmaceutical composition of the present invention provides a detectable C _{max of} 2-PAA (2-pyridylacetic acid) in human plasma after administration of a single dose of the pharmaceutical composition of the present invention. In one embodiment, the C _{max of} 2-PAA in human plasma after administration of a single dose of a pharmaceutical composition of the present invention is at least about 15, or at least about 50 ng/mL. In one embodiment, C _max 2-PAA is measured after administration of a single dose of about 1 g to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, C _max 2-PAA is measured after a single dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg , about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt. In other embodiments, C _max 2-PAA for a 5 mg intranasal dose of betahistine is in the range of about 80% to about 125% of about 65 ng/mL; about 80 to about 125% of about 150 ng/mL for a 10 mg dose of betahistine administered intranasally; about 80 to about 125% of about 370 ng/mL for a 20 mg dose of betahistine administered intranasally; and about 80% to about 125% of about 520 ng/mL for a 40 mg dose of betahistine administered intranasally. In other embodiments, the Cmax of 2-PAA for a 5 mg intranasal dose of betahistine is in the range of about 80 to about 125%, about 16 to about 95 ng/mL; about 80 to about 125% about 115 to about 175 ng/ml per dose

- 19 041383 betahistine 10 mg administered intranasally; about 80 to about 125% about 250 to about 430 g/ml for a dose of betahistine 20 mg administered intranasally; and about 80% to about 125% of about 290 to about 690 ng/mL for a 40 mg intranasal dose of betahistine.

In one embodiment, the C _{max of} 2-PAA in human plasma after administration of a single dose of the intranasal pharmaceutical composition of the present invention is at least about 15 ng/mL, or at least about 50 ng/mL. In one embodiment, C _max 2-PAA in human plasma after administration of a single dose of an intranasal pharmaceutical composition of the present invention is at least about 10 ng/ml, at least about 15 ng/ml, at least about 20 ng/ml , at least about 25 ng/ml, at least about 30 ng/ml, at least about 35 ng/ml, at least about 40 ng/ml, at least about 45 ng/ml, at least about 50 ng/ml, at least about 55 ng/ml, at least about 60 ng/ml, at least about 65 ng/ml, at least about 70 ng/ml, at least about 75 ng/ml, at least about 80 ng/ml, at least about 85 ng/ml, at least about 90 ng/ml, at least about 95 ng/ml, at least about 100 ng/ml, at least about 150 ng/ml, at least about 200 ng/ml, at least about 250 ng/ml, at least about 300 ng/ml, at least pe about 400 ng/ml, at least about 450 ng/ml, at least about 500 ng/ml, or at least about 550 ng/ml.

In one embodiment, the C _{max of} 2-PAA in human plasma following single dose administration of the intranasal pharmaceutical composition of the present invention is at least about 60 ng/mL. In one embodiment, C _max 2-PAA in human plasma is measured following administration of a single dose of an intranasal pharmaceutical composition comprising about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, C _max 2-PAA was measured following intranasal administration of a single dose of about 5 to about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, C _max 2-PAA was measured following intranasal administration of a single dose of about 20 or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, C _max 2-PAA was measured following intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg , about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the implementation of the pharmaceutical composition of the present invention provides t _max 2-PAA in human plasma after administration of a single dose of the pharmaceutical composition of the present invention. In one embodiment, the t _{max of} 2-PAA in human plasma after administration of a single dose of a pharmaceutical composition of the present invention is about 0.6 hours or more, about 0.7 hours or more, about 0.8 hours or more, about 0. 9 hours or more, about 1 hour or more, about 1.1 hours or more, about 1.2 hours or more, about 1.25 hours or more, about 1.3 hours or more, about 1.4 hours or more or about 1.5 hours or more. In one embodiment, t _max is measured after administration of a single dose of about 1 to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t _max is measured after a single dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg , about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the t _{max of} 2-PAA in human plasma after administration of a single dose of the intranasal pharmaceutical composition of the present invention is about 1.0 hours. In one embodiment, the t _{max of} 2-PAA in human plasma after administration of a single dose of the intranasal pharmaceutical composition according to the present invention is about 0.9 hours or more, about 1.0 hours or more, about 1.1 hours or more, or about 1.2 hours or more. In one embodiment, the t _{max of} 2-PAA in human plasma was determined following administration of a single dose of an intranasal pharmaceutical composition comprising about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t _max 2-PAA was determined following intranasal administration of a single dose of about 5 to about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t _max 2-PAA was determined following intranasal administration of a single dose of about 20 or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, t _max 2-PAA was determined after intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg , about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the pharmaceutical composition of the present invention provides AUC ₀ _ _last 2-PAA in human plasma after administration of a single dose of pharmaceutical

- 20 041383 compositions of the present invention at least about 100 h-ng/ml, at least about 200 h-ng/ml, at least about 250 h-ng/ml, at least about 300 h-ng/ml , at least about 400 h-ng/ml, at least about 500 h-ng/ml, at least about 600 h-ng/ml, at least about 700 h-ng/ml, at least about 800 h-ng/ml, at least about 900 h-ng/ml, at least about 1000 h-ng/ml, at least about 1100 h-ng/ml, at least about 1200 h-ng/ml, at least about 1300 h-ng/mL, at least about 1400 h-ng/mL, at least about 1500 h-ng/mL, at least about 1600 h-ng/mL, at least about 1700 h -ng/ml, at least about 1800 h-ng/ml, at least about 1900 h-ng/ml, at least about 2000 h-ng/ml, at least about 2100 h-ng/ml, at least about 2200 h-ng/ml, at least about 2300 h-ng/ml, at least about 2400 h-ng/mL, at least about 2500 h-ng/mL, at least about 2600 h-ng/mL, at least about 2700 h-ng/mL, at least about 2800 h-ng/mL , at least about 2900 h-ng/ml or at least about 3000 h-ng/ml, at least about 3100 h-ng/ml, at least about 3200 h-ng/ml, at least about 3300 h-ng/ml, at least about 3400 h-ng/ml, or at least about 3500 h-ng/ml. In one embodiment, the AUC ₀ _ _last 2-PAA is measured after administration of a single dose of about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the AUC ₀ _ _last 2-PAA in human plasma was determined after administration of a single dose of an intranasal pharmaceutical composition comprising about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the AUC ₀ _ _last 2-PAA was determined after a single intranasal dose of about 5 to about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the implementation of AUC ₀ _ _last 2PAA was determined after intranasal administration of a single dose of about 20 or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, AUC ₀ _ _last 2-PAA was determined after intranasal administration of a single dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In various embodiments, the AUC ₀ _ _last 2-PAA is about 80-125% of about 380 ng-h/ml for a dose of betahistine 5 mg administered intranasally; about 80-125% of about 730 ng-h/ml for a dose of betahistine 10 mg administered intranasally; about 80-125% of about 2000 ng-h/ml for a dose of betahistine 20 mg administered intranasally; and about 80-125% of about 2800 ng-h/ml for the intranasal dose of betahistine 40 mg. In one embodiment, the pharmaceutical composition of the present invention provides an AUC ₀ _ _inf 2-PAA in human plasma after administration of a single dose of the pharmaceutical composition of the present invention of at least about 100 h-ng/ml, at least about 200 h-ng/ ml, at least about 250 h-ng/ml, at least about 300 h-ng/ml, at least about 400 h-ng/ml, at least about 500 h-ng/ml, at least about 600 h-ng/ml, at least about 700 h-ng/ml, at least about 800 h-ng/ml, at least about 900 h-ng/ml, at least about 1000 h-ng/ml , at least about 1100 h-ng/ml, at least about 1200 h-ng/ml, at least about 1300 h-ng/ml, at least about 1400 h-ng/ml, at least about 1500 h-ng/ml, at least about 1600 h-ng/ml, at least about 1700 h-ng/ml, at least about 1800 h-ng/ml, at least about 1900 h-ng/ml, by men at least about 2000 h-ng/mL, at least about 2100 h-ng/mL, at least about 2200 h-ng/mL, at least about 2300 h-ng/mL, at least about 2400 h- ng/mL, at least about 2500 h-ng/mL, at least about 2600 h-ng/mL, at least about 2700 h-ng/mL, at least about 2800 h-ng/mL, at least at least about 2900 h-ng/mL, at least about 3000 h-ng/mL, at least about 3100 h-ng/mL, at least about 3200 h-ng/mL, at least about 3300 h-ng/mL /ml, at least about 3400 h-ng/ml or at least about 3500 h-ng/ml. In one embodiment, AUC ₀ _ _inf 2-PAA is measured after administration of a single dose of about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, AUC ₀ _ _inf 2-PAA in human plasma was determined following administration of a single dose of an intranasal pharmaceutical composition comprising about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, AUC0-inf 2-PAA was determined after a single intranasal dose of about 5 to about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the implementation of AUC ₀ _ _inf 2PAA was determined after intranasal administration of a single dose of about 20 or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, AUC ₀ _ _inf 2-PAA was determined after intranasal administration of a single dose of about 5 mg, about 10 mg, example

- 21 041383 but 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg betahistine or a pharmaceutically acceptable salt.

In various embodiments, the AUC ₀ _ _inf 2-PAA is about 80-125% of about 430 ng-h/ml for a dose of betahistine 5 mg administered intranasally; about 80-125% of about 760 ng-h/ml for a dose of betahistine 10 mg administered intranasally; about 80-125% of about 2000 ng-h/ml for a dose of betahistine 20 mg administered intranasally; and about 80-125% of about 2900 ng-h/ml for the intranasal dose of betahistine 40 mg.

In one embodiment, the t _1/2 (apparent half-life) of 2-PAA, as determined from administration of a single dose of a pharmaceutical composition of the present invention, is about 2.5 hours or more, about 2.6 hours or more, about 2. 7 hours or more, about 2.8 hours or more, about 2.9 hours or more, about 3.0 hours or more, about 3.1 hours or more, about 3.2 hours or more, about 3.3 hours or more, about 3.4 hours or more, about 3.5 hours or more, about 3.6 hours or more, about 3.7 hours or more, about 3.8 hours or more, about 3.9 hours or more, about 4.0 hours or more, about 4.1 hours or more, about 4.2 hours or more, about 4.3 hours or more, about 4.4 hours or more, or about 4.5 hours or more. In one embodiment, the t _1/2 of 2-PAA was determined based on the administration of a single dose of about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t _1/2 2-PAA was determined based on the administration of a single dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 or about 200 mg of betahistine or a pharmaceutically acceptable salt.

In one embodiment, the pharmaceutical composition of the present invention may be useful in methods for use in the treatment or prevention of vestibular disorders. In another embodiment, the pharmaceutical composition of the present invention may be useful in methods for use in the treatment or prevention of neurotological disorders. In some embodiments, the implementation of the pharmaceutical composition of the present invention may be useful in methods for use in the treatment or prevention of otological and/or neurological disorders.

In one embodiment, the pharmaceutical composition of the present invention may be useful in methods for use in the treatment or prevention of inner ear dysfunction or inner ear disorder. In one embodiment, the inner ear disorders include tinnitus, vertigo, Meniere's disease, inner ear inflammation or infection, autoimmune inner ear disease, or hearing loss. In one embodiment, the pharmaceutical composition of the present invention may be useful in methods for use in the treatment or prevention of tinnitus, vertigo, Meniere's disease, and hearing loss. In one embodiment, the pharmaceutical composition of the present invention may be useful in the treatment of vertigo. In another embodiment, the pharmaceutical composition of the present invention may be useful for the treatment of Meniere's disease. In one embodiment, vestibular vertigo may include benign paroxysmal positional vertigo, vestibular neuritis, and other peripheral vestibular vertigo.

In one embodiment, the pharmaceutical composition of the present invention may be useful in methods for use in the treatment or prevention or prevention of vertigo, vestibular vertigo and/or vertigo attacks. In another embodiment, the pharmaceutical composition of the present invention may be useful for reducing or reducing the symptoms of dizziness, vestibular dizziness and/or vertigo attacks.

In one embodiment, the pharmaceutical composition of the present invention may be useful in methods of use in the treatment or prevention of Eustachian tube dysfunction.

In one embodiment, the pharmaceutical composition of the present invention may be useful for treating or alleviating the symptoms of an inner ear disorder. In one embodiment, the inner ear dysfunction and/or symptoms of the inner ear disorder include hearing loss (including acute hearing loss), tinnitus, nausea, and dizziness. In one embodiment, the pharmaceutical composition of the present invention may be useful in the treatment of hearing loss. In another embodiment, the pharmaceutical composition of the present invention may be useful in the treatment of acute hearing loss.

In one embodiment, the pharmaceutical composition of the present invention may be useful as part of a vestibular therapy. In some embodiments, the vestibular therapy is vestibular rehabilitation.

In one embodiment, the pharmaceutical composition of the present invention

- 22 041383 may be useful for vestibular rehabilitation. In one embodiment, the pharmaceutical composition of the present invention may be useful in the treatment of an inner ear disorder or symptoms thereof, with or in addition to vestibular rehabilitation. In one embodiment, the pharmaceutical composition of the present invention may be useful in the treatment of an inner ear disorder or symptoms thereof to facilitate vestibular rehabilitation.

Without wishing to be bound by any theory, betahistine or a pharmaceutically acceptable salt thereof is believed to act as a partial H1 receptor (H1R) agonist and/or an H3 inverse receptor (H3R) antagonist. H1R and H3R, together with the H2 receptor (H2R) and the H4 receptor (H4R), are subtypes of the G protein-coupled receptors, histamine receptors, that is, histamine-binding receptors.

Without wishing to be bound by any theory, the pharmaceutical composition of the present invention may increase blood flow in the inner ear, such as cochlear and vestibular blood flow, and/or cerebral blood flow. In another embodiment, the pharmaceutical composition of the present invention can increase histamine turnover and increase histamine release in the central nervous system (CNS), which can balance the neuronal activity of the vestibular nuclei complexes on both sides of the vestibular system. In one embodiment, the pharmaceutical compositions of the present invention can inhibit neuronal firing in the vestibular nuclei. In another embodiment, the pharmaceutical composition of the present invention may contribute to the upregulation of histamine, which causes a general activation of the brain, promoting sensorimotor activity. In one embodiment, the pharmaceutical compositions of the present invention may facilitate vestibular compensation and/or CNS-related vestibular compensation.

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of diseases or conditions modulated by histamine. In another embodiment, the pharmaceutical composition of the present invention may be useful in the treatment of H1R modulated diseases or conditions. In some embodiments, the pharmaceutical compositions of the present invention may be useful in the treatment of H3R modulated diseases or conditions.

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of obesity, eating disorders, cognitive disorders, attention deficit disorders, memory processes, dementia, and cognition disorders such as Alzheimer's disease and attention deficit hyperactivity disorder, bipolar disorder, cognitive enhancement, cognitive impairment in psychiatric disorders, memory impairment, learning impairment, dementia, mild cognitive impairment, migraine, mood and attention changes, motion sickness, narcolepsy, neurogenic inflammation, obsessive-compulsive disorder, Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; sleep disorders such as narcolepsy, vestibular dysfunction such as Meniere's disease, migraine, motion sickness, pain, drug addiction, depression, epilepsy, jet lag, insomnia, Tourette's syndrome, dizziness and the like, as well as cardiovascular disorders, such as acute myocardial infarction, cancers such as skin cancer, medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma, gastrointestinal disorders, inflammation and septic shock, diabetes, type II diabetes, insulin resistance syndrome, metabolic syndrome, polycystic ovary syndrome, X syndrome, and the like.

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of obesity, attention deficit hyperactivity disorder, cerebrovascular disease, dementia, narcolepsy, sleep disorders, parkinsonism, drug addiction, schizophrenia, Gilles de la Tourette syndrome, and/or Alzheimer's disease.

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment or reduction of weight gain. In some embodiments, the unwanted weight gain may be caused by the administration of certain drugs. For example, antipsychotic drugs that act on histamine receptors, such as olanzapine, can cause weight gain (Barak et al. Journal of Psychopharmacology, 2016, Vol. 30(3)237-241; which is incorporated herein by reference in its entirety) . Accordingly, in one embodiment, the present invention provides a method for reducing weight gain caused by antipsychotic drugs that act on histamine receptors, comprising intranasal administration of a pharmaceutical composition of the present invention.

In one embodiment of the present invention, betahistine or a pharmaceutically acceptable salt thereof may be administered to a subject in need thereof by routes including nasal (e.g. solution, spray, drops, aerosol, gels), oral (e.g. tablets, capsules, granules, syrups , elixirs or powders) by sublingual, buccal, parenteral (eg subcutaneous, intravenous, intramuscular, intrathecal or intracisternal injections) or infusion methods (eg as sterile injectable aqueous or non-aqueous solutions or suspensions),

- 23 041383 topical (for example, drug-releasing skin patch, cream or ointment), intravaginal, by wetting, transdermal, intradermal, pulmonary, intrauterine, using an aerosol, or rectal (for example, suppositories, in a dosage unit preparations containing non-toxic, pharmaceutically acceptable carriers or diluents). In one embodiment, betahistine or a pharmaceutically acceptable salt thereof is administered nasally. In one embodiment, betahistine or a pharmaceutically acceptable salt thereof is administered via intranasal delivery.

In one embodiment, intranasal delivery of a pharmaceutical composition of the present invention is effective in providing non-invasive systemic delivery. In another embodiment, intranasal delivery of the pharmaceutical composition of the present invention prevents or reduces the first pass metabolism of betahistine (compared to oral betahistine). In one embodiment, intranasal delivery of the pharmaceutical composition of the present invention prevents or reduces gastric side effects (compared to oral betahistine). In another embodiment, intranasal delivery of the pharmaceutical composition of the present invention is beneficial in achieving a rapid onset of action of betahistine.

In one embodiment, the pharmaceutical composition of the present invention is administered nasally as drops, spray, gel, ointment, cream, powder or suspension. In one embodiment, the pharmaceutical composition of the present invention is administered nasally using a dispenser or device (e.g., single dose ampoule, metered dose dispenser, aerosol inhaler, nebulizer, pump, nasal patch, nasal sponge, or hard gelatin capsule) or any other nasal route. administration, which is known in the pharmaceutical literature.

In one embodiment, the devices for nasal administration of liquid pharmaceutical compositions of the present invention include a pipette (eg, a disposable tube); dropper, including multi-dose droppers; rhinyle catheter; steam inhaler; mechanical spray pumps, including plastic spray bottle, multi-dose dosing spray pumps, single-dose or two-dose spray pumps, bi-directional multi-dose spray pumps; gas nebulization systems/aerosol inhalers and electrically powered nebulizers/aerosol inhalers. In one embodiment, the devices for nasal administration of powdered pharmaceutical compositions of the present invention include mechanical powder blowers, breath-actuated inhalers, and insufflators, including breath-actuated bi-directional delivery devices. These devices are briefly summarized in Djupesland's review (Drug Deliv. and Transl. Res. (2013) 3:42-62), which is incorporated herein by reference in its entirety.

In one embodiment, the pharmaceutical composition of the present invention is administered to the nasal cavity in metered doses. In one embodiment, a metered-dose nasal spray may be used to administer a pharmaceutical composition of the present invention. In another embodiment, a metered dose nasal spray may be used to administer the pharmaceutical composition of the present invention in metered doses. In one embodiment, a metered irrigation spray pump may be used to administer the pharmaceutical composition of the present invention in metered doses.

In one embodiment, a nasal metered dose inhaler (pMDI) may be used to administer the pharmaceutical composition of the present invention in metered doses. In one embodiment, the pressurized nasal formulation of the present invention may be an aerosol formulation. Such an aerosol formulation in one embodiment comprises betahistine or a pharmaceutically acceptable salt thereof in a sealed package with a suitable propellant such as hydrofluoroalkanes (HFA), carbon dioxide, or other suitable propellant known in the art. The aerosol can, in one embodiment, may also include a surfactant such as lecithin. The dose of betahistine or a pharmaceutically acceptable salt thereof can be controlled using a metering valve.

In another embodiment, the pharmaceutical composition of the present invention is introduced into the nasal cavity in the usual way, for example, using a dropper, pipette or spray.

In one embodiment, the topical pharmaceutical composition of the present invention may be in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). In one embodiment, the powder carrier forms a gel in the nasal cavity. The powder composition may be presented in unit dosage form, eg in capsules or cartridges, eg gelatin or blister packs, from which the powder may be administered by inhaler.

In formulations intended for administration into the respiratory tract, including formulations for intranasal

- 24 041383 the particle size of the pharmaceutical composition, when used, must be less than 100 microns, less than 50 microns, less than 25 microns, less than 20 microns, less than 15 or less than 10 microns. In one embodiment, the particle size of the nasal pharmaceutical composition is less than 10 microns when applied. In one embodiment, the D ₅₀ particle size of the nasal pharmaceutical composition is less than 10 microns when applied. In one embodiment, the D ₉₀ particle size of the nasal pharmaceutical composition is less than 10 microns when applied.

In one embodiment, the intranasal pharmaceutical compositions of the present invention in the form of a spray provide a droplet size distribution of Dv(50) from about 150 to about 300 microns, including about 160 microns, about 170 microns, about 180 microns, about 190 microns, about 200 µm, about 210 µm, about 220 µm, about 230 µm, about 240 µm, about 250 µm, about 260 µm, about 270 µm, about 280 µm, about 290 µm, or about 300 µm, including all ranges between any of these values , when tested at a firing distance of about 20 to about 50 mm with a firing force of about 5 kg, about 6 or about 7 kg.

In one embodiment, the intranasal pharmaceutical compositions of the present invention in the form of a spray provide droplet size distribution Dv(90) from about 380 to about 650 microns, including about 380 microns, about 390 microns, about 400 microns, about 410 microns, about 420 µm, approx. 430 µm, approx. 440 µm, approx. 450 µm, approx. 460 µm, approx. 470 µm, approx. 480 µm, approx. about 550 µm, about 560 µm, about 570 µm, about 580 µm, about 590 µm, about 600 µm, about 610 µm, about 620 µm, about 630 µm, about 640 µm, about 650 µm, including all ranges between any of these values, when tested at a firing distance of about 20 to about 50 mm with a firing force of about 5 kg, about 6 or about 7 kg.

In one embodiment, the pharmaceutical compositions of the present invention are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. In one embodiment, the pharmaceutical compositions of the present invention are administered one or more times per day, where each dose introduces a controlled, metered, or fixed amount of betahistine or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutical compositions of the present invention are administered to the nasal cavity at a unit dose comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg of betahistine or a pharmaceutically acceptable salt thereof. For example, if a metered-dose nasal spray is used, one dose of spray contains approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 40, 41, 42, 43, 44 , 45, 46, 47, 48, 49, or 50 mg of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is administered to the nasal cavity in a unit dose comprising about 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg of betahistine, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention is administered to the nasal cavity at a unit dose comprising about 20 mg of betahistine or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutical compositions of the present invention are administered to the nasal cavity at a unit dose comprising about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 mg of betahistine or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutical compositions of the present invention are administered to the nasal cavity as a unit dose or metered dose that provides dose content uniformity with a relative standard deviation of less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5% less than 2.0%, less than 1.5%, less than 1.0 or less than 0.5%.

In one embodiment, the intranasal pharmaceutical compositions of the present invention are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. In one embodiment, the intranasal pharmaceutical compositions of the present invention are administered once a day, twice a day, three times a day, four times a day, five times a day, or six times a day, with each dose delivering a controlled, metered or prescribed amount of betahistine or a pharmaceutically acceptable salt thereof. In some embodiments, the implementation of the intranasal pharmaceutical composition of the present invention is administered three times a day. In some embodiments, the intranasal pharmaceutical compositions of the present invention are administered up to six times per day.

In one embodiment, the intranasal pharmaceutical composition of the present invention is administered to provide a daily dose of betahistine or a pharmaceutically acceptable salt thereof in an amount of from about 0.01 to about 20 mg/kg of body weight of a human patient, including about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0 .08 mg/kg, about 0.0 9 mg/kg, about 0.1 mg/kg, about 0.12 mg/kg, about 0.14 mg/kg, about 0.16 mg/kg, about 0, 18 mg/kg, approximately 0.2

- 25 041383 mg/kg, about 0.22 mg/kg, about 0.24 mg/kg, about 0.26 mg/kg, about 0.28 mg/kg, about 0.3 mg/kg, about 0, 32 mg/kg, about 0.34 mg/kg, about 0.36 mg/kg, about 0.38 mg/kg, about 0.4 mg/kg, about 0.42 mg/kg, about 0.44 mg /kg, about 0.46 mg/kg, about 0.48 mg/kg, about 0.5 mg/kg, about 0.52 mg/kg, about 0.54 mg/kg, about 0.56 mg/kg , about 0.58 mg/kg, about 0.6 mg/kg, about 0.62 mg/kg, about 0.64 mg/kg, about 0.66 mg/kg, about 0.68 mg/kg, about 0.7 mg/kg, about 0.72 mg/kg, about 0.74 mg/kg, about 0.76 mg/kg, about 0.78 mg/kg, about 0.8 mg/kg, about 0, 82 mg/kg, about 0.84 mg/kg, about 0.86 mg/kg, about 0.88 mg/kg, about 0.9 mg/kg, about 0.92 mg/kg, about 0.94 mg /kg, about 0.96 mg/kg, about 0.98 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg , about 1.4, mg/kg about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg /kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about 3.1 mg/kg, about 3.2 mg/kg, about 3.3 mg/kg, about 3.4 mg/kg, about 3.5 mg/kg, about 3.6 mg/kg, about 3, 7 mg/kg, about 3.8 mg/kg, about 3.9 mg/kg, about 4 mg/kg, about 4.1 mg/kg, about 4.2 mg/kg, about 4.3 mg/kg , about 4.4 mg/kg, about 4.5 mg/kg, about 4.6 mg/kg, about 4.7 mg/kg, about 4.8 mg/kg, about 4.9 mg/kg, about 5 mg/kg, about 5.1 mg/kg, about 5.2 mg/kg, about 5.3 mg/kg, about 5.4 mg/kg, about 5.5 mg/kg, about 5.6 mg /kg, about 5.7 mg/kg, about 5.8 mg/kg, about 5.9 mg/kg, about 6 mg/kg, about 6.1 mg/kg, about 6.2 mg/kg, about 6.3 mg/kg, about 6.4 mg/kg, about 6.5 mg/kg, about 6.6 mg/kg, about 6.7 mg/kg, about 6.8 mg/kg , about 6.9 mg/kg, about 7 mg/kg, about 7.1 mg/kg, about 7.2 mg/kg, about 7.3 mg/kg, about 7.4 mg/kg, about 7, 5 mg/kg, about 7.6 mg/kg, about 7.7 mg/kg, about 7.8 mg/kg, about 7.9 mg/kg, about 8 mg/kg, about 8.1 mg/kg , about 8.2 mg/kg, about 8.3 mg/kg, about 8.4 mg/kg, about 8.5 mg/kg, about 8.6 mg/kg, about 8.7 mg/kg, about 8.8 mg/kg, about 8.9 mg/kg, about 9 mg/kg, about 9.1 mg/kg, about 9.2 mg/kg, about 9.3 mg/kg, about 9.4 mg /kg, about 9.5 mg/kg, about 9.6 mg/kg, about 9.7 mg/kg, about 9.8 mg/kg, about 9.9 mg/kg, about 10 mg/kg, about 11.1 mg/kg, about 11.2 mg/kg, about 11.3 mg/kg, about 11.4 mg/kg about 11.5 mg/kg, about 11.6 mg/kg, about 11, 7 mg/kg, about 11.8 mg/kg, about 11.9 mg/kg, about 12 mg/kg, about 12.1 mg/kg, about 12.2 mg/kg, about 12.3 mg/kg , about 12.4 mg/kg, about 12.5 mg/kg, about 12.6 mg/kg, about 12.7 mg/kg, about 1 2.8 mg/kg, about 12.9 mg/kg, about 13 mg/kg, about 13.1 mg/kg, about 13.2 mg/kg, about 13.3 mg/kg, about 13.4 mg /kg, about 13.5 mg/kg, about 13.6 mg/kg, about 13.7 mg/kg, about 13.8 mg/kg, about 13.9 mg/kg, about 14 mg/kg, about 14.1 mg/kg, about 14.2 mg/kg, about 14.3 mg/kg, about 14.4 mg/kg, about 14.5 mg/kg, about 14.6 mg/kg, about 14, 7 mg/kg, about 14.8 mg/kg, about 14.9 mg/kg, about 15 mg/kg, about 15.1 mg/kg, about 15.2 mg/kg, about 15.3 mg/kg , about 15.4 mg/kg, about 15.5 mg/kg, about 15.6 mg/kg, about 15.7 mg/kg, about 15.8 mg/kg, about 15.9 mg/kg, about 16 mg/kg, about 16.1 mg/kg, about 16.2 mg/kg, about 16.3 mg/kg, about 16.4 mg/kg, about 16.5 mg/kg, about 16.6 mg /kg, about 16.7 mg/kg, about 16.8 mg/kg, about 16.9 mg/kg, about 17 mg/kg, about 17.1 mg/kg, about 17.2 mg/kg, about 17.3 mg/kg, about 17.4 mg/kg, about 17.5 mg/kg, about 17, 6 mg/kg, about 17.7 mg/kg, about 17.8 mg/kg, about 17.9 mg/kg, about 18 mg/kg, about 18.1 mg/kg, about 18.2 mg/kg , about 18.3 mg/kg, about 18.4 mg/kg, about 18.5 mg/kg, about 18.6 mg/kg, about 18.7 mg/kg, about 18.8 mg/kg, about 18.9 mg/kg, about 19 mg/kg, about 19.1 mg/kg, about 19.2 mg/kg, about 19.3 mg/kg, about 19.4 mg/kg, about 19.5 mg /kg, about 19.6 mg/kg, about 19.7 mg/kg, about 19.8 mg/kg, about 19.9 mg/kg, or about 20 mg/kg, including all ranges between any of these values.

In one embodiment, the intranasal pharmaceutical composition of the present invention is administered to provide a daily dose of about 1 to about 200 mg of betahistine or a pharmaceutically acceptable salt thereof per patient. In another embodiment, the intranasal pharmaceutical composition of the present invention is administered to provide a daily dose of about 5 mg to about 100 mg of betahistine or a pharmaceutically acceptable salt thereof.

In one embodiment, the intranasal pharmaceutical compositions of the present invention comprise betahistine or a pharmaceutically acceptable salt thereof at a concentration of about 1 to about 1000 mg/mL. In another embodiment, the intranasal pharmaceutical composition of the present invention comprises betahistine or a pharmaceutically acceptable salt thereof in an amount of from about 10 to about 400 mg/ml, including about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 105 mg/ml, about 110 mg /ml, about 115 mg/ml, about 120 mg/ml, about 125 mg/ml, about 130 mg/ml, about 135 mg/ml, about 140 mg/ml, about 145 mg/ml, about 150 mg/ml , about 155 mg/ml, about 160 mg/ml, about 165 mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, about 185 mg/ml, at

- 26 041383 190 mg/ml, about 195 mg/ml, about 200 mg/ml, about 205 mg/ml, about 210 mg/ml, about 215 mg/ml, about 220 mg/ml, about 225 mg/ml , about 230 mg/ml, about 235 mg/ml, about 240 mg/ml, about 245 mg/ml, about 250 mg/ml, about 255 mg/ml, about 260 mg/ml, about 265 mg/ml, about 270 mg/ml, about 275 mg/ml, about 280 mg/ml, about 285 mg/ml, about 290 mg/ml, about 295 mg/ml, about 300 mg/ml, about 305 mg/ml, about 310 mg /ml, about 315 mg/ml, about 320 mg/ml, about 325 mg/ml, about 330 mg/ml, about 335 mg/ml, about 340 mg/ml, about 345 mg/ml, about 350 mg/ml , about 355 mg/ml, about 360 mg/ml, about 365 mg/ml, about 370 mg/ml, about 375 mg/ml, about 380 mg/ml, about 385 mg/ml, about 390 mg/ml, about 395 mg/ml or about 400 mg/ml, including all ranges between any of these values.

In one embodiment, the intranasal pharmaceutical compositions of the present invention comprise betahistine, or a pharmaceutically acceptable salt thereof, when administered at a unit dose or metered dose of about 1 to about 1000 µl, including about 1 µl, about 10 µl, about 20 µl, about 30 µl, approx. 40 µl, approx. 50 µl, approx. 60 µl, approx. 70 µl, approx. 80 µl, approx. 90 µl, approx. 100 µl, approx. 110 µl, approx. 120 µl, approx. approx. 160 µl, approx. 170 µl, approx. 180 µl, approx. 190 µl, approx. 200 µl, approx. 210 µl, approx. 220 µl, approx. µl, approx. 290 µl, approx. 300 µl, approx. 310 µl, approx. 320 µl, approx. 330 µl, approx. 340 µl, approx. 350 µl, approx. about 41 0 µl, approx. 420 µl, approx. 430 µl, approx. 440 µl, approx. 450 µl, approx. 460 µl, approx. 470 µl, approx. , approx. 545 µl, approx. 550 µl, approx. 560 µl, approx. 570 µl, approx. 580 µl, approx. 590 µl, approx. 600 µl, approx. 660 µl, approx. 670 µl, approx. 680 µl, approx. 690 µl, approx. 700 µl, approx. 710 µl, approx. 720 µl, approx. , about 7 90 µl, about 800 µl, about 810 µl, about 820 µl, about 830 µl, about 840 µl, about 850 µl, about 860 µl, about 870 µl, about 880 µl, approx. approx. 910 µl, approx. 920 µl, approx. 930 µl, approx. 940 µl, approx. 950 µl, approx. about 970 µl, about 980 µl, about 990 µl, or about 1000 µl, including all ranges between any of these values. In some embodiments, the intranasal pharmaceutical compositions of the present invention comprise betahistine, or a pharmaceutically acceptable salt thereof, when administered as a unit dose or metered dose of about 10 to about 200 microliters. In another embodiment, the intranasal pharmaceutical composition of the present invention comprises betahistine, or a pharmaceutically acceptable salt thereof, when administered as a unit dose or metered dose of about 10 to about 100 μl.

In one embodiment, a unit dose or metered dose of an intranasal pharmaceutical composition of the present invention comprising betahistine or a pharmaceutically acceptable salt may be administered as one unit or metered dose per serving, two unit or metered doses per serving, three unit or metered doses per serving, reception, or four standard or measured doses per reception.

In one embodiment, a course of treatment with a pharmaceutical composition of the present invention may be from about 1 day to about 7 days, from about 1 week to about 5 weeks, or from about 1 month to about 12 months. In one embodiment, the course of treatment with the intranasal pharmaceutical composition may be from about 1 day to about 7 days, about 1 week to about 5 weeks, or about 1 month to about 12 months. In one embodiment, the course of treatment with the intranasal pharmaceutical composition may be about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months or about 12 months. In one embodiment, the course of treatment with the intranasal pharmaceutical composition may be about 3 months or about 6 months. In one embodiment, the course of treatment with the intranasal pharmaceutical composition of the present invention may be for more than one year. In another embodiment, the course of treatment may be greater than one year, greater than 1.5 years, greater than 2 years, greater than 2.5 years, greater than 3 years, greater than 4 years, or greater than 5 years. The appropriate duration of treatment with the pharmaceutical composition of the present invention may be determined by the patient's physician and used as directed.

In one embodiment, the pharmaceutical composition of the present invention is a solution, suspension, powder, or aerosol. In one embodiment, the pharmaceutical composition of the present invention is an aqueous solution.

- 27 041383

In one embodiment, the pharmaceutical compositions of the present invention may be administered in combination with at least one of the enzyme inhibitors or absorption promoters. In one embodiment, at least one enzyme inhibitor is selected from betastatin, amastatin, boroleucine, borvovalin, aprotinin, trypsin inhibitors, fusidic acids, and bile salts. In another embodiment, at least one absorption promoter is selected from β-cyclodextrin, fusidic acid derivatives (sodium taurodihydrofusidate), microspheres, liposomes, bile salts, lauaret-9, saponins, BL-9, glycolate, chitosan, dideanoil-b- phosphatidylcholine and lysophosphatidylcholine.

In one embodiment, the pharmaceutical compositions of the present invention may further comprise at least one additional pharmaceutically active agent. In some embodiments, at least one additional pharmaceutically active agent is a drug that treats vestibular disorders, neurotological disorders, otological and/or neurological disorders. In some embodiments, the at least one additional pharmaceutically active agent is a drug that treats inner ear disorders or inner ear disorders and/or a drug that treats or alleviates symptoms of inner ear disorders and dysfunctions.

In one embodiment, at least one additional pharmaceutically active agent is selected from the group of glutamate receptor modulators. Non-limiting examples of glutamate receptor modulators include glutamate receptor antagonists, AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methylD-aspartate) receptor antagonists. In one embodiment, the AMPA receptor antagonist is selected from 6-cyano-7-nitroquinoxaline-2,3-dione, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3dione), 6,7- dinitroquinoxaline-2,3-dione, kynurenic acid, 2,3-dihydroxy-6-nitro-7sulfamoylbenzo-quinoxaline, or combinations thereof.

In one embodiment, the glutamate receptor antagonist, including the NMDA receptor antagonist, is selected from 1-aminoadamantane; dextromethorphan; dextrorphan; ibogaine; ifenprodil; (S) ketamine; (R)-ketamine; memantine; dizocilpine; hacyclidine; traxoprodil; D-2-amino-5phosphonopentanoic acid; 3-((±)2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; conantokine; 7-chlorokynurenate; lycostinel; nitrogen oxide; phencyclidine; riluzole; tiletamine; aptiganela; remacimide; 5,7-dichlorokynurenic acid; kynurenic acid; 1-aminocyclopropanecarboxylic acid; 2-amino-7-phosphonoheptanoic acid; R-2-amino-5-phosphonopentanoate; 3-[(R)-2-carboxypiperazin-4-yl]prop-2-enyl-1-phosphonic acid; (+)-(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy4-phenylpiperidino)-1-propanol; (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl-)-chroman-4,7-diol; (1 R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)propan-1-ol mesylate; or their combinations.

Examples

Example 1 Composition Example

The intranasal delivery formulations of the present invention containing betahistine dihydrochloride were supplied by Otifex Therapeutics and stored in a desiccator at ambient conditions until needed.

Formulations with 10, 50 or 200 mg/ml betahistine were prepared as follows:

Composition 10 mg/ml betahistine. 20 mg of benzalkonium chloride (warmed to about 65° C. to facilitate transfer) and 20 mg of disodium edetate were added to the same beaker and dissolved in about 10 ml of water for injection using a stirrer. 1 g of betahistine dihydrochloride was placed in a sterile plastic vial and 97.5 mg of dibasic sodium phosphate and 552.5 mg of monobasic sodium phosphate were added. Approximately 25 ml of water for injection was added to the vial and the resulting solution was thoroughly mixed. Then 100 mg of glycerol, 1.25 g of polyvinylpyrrolidone, 3.75 g of polyethylene glycol 400 and 2 g of propylene glycol were added (using a small amount of water for transfer). To the resulting mixture was added the prepared solution of benzalkonium chloride and disodium edetate using approximately 10 ml of water for injection.

The pH value of the resulting solution was adjusted to 5.0 by adding 3.88 ml of 1 M sodium hydroxide. The pH value of the solution was checked before quantitatively transferring it to a 100 ml volumetric vial using a small amount of water for injection.

Water for injection was added to obtain 100 ml of the composition. The pH was rechecked/adjusted to 5.0 and the formulation was stored at 2-8° C. until required.

The intranasal formulation of betahistine 10 mg/ml thus obtained included the following constituents (all concentrations are expressed as w/w unless otherwise indicated): 1.0% betahistine dihydrochloride as active substance, 0.1% glycerol, 3. 75% polyethylene glycol 400 and 2% propylene glycol as wetting agents, 1.25% polyvinylpyrrolidone for viscosity and for

- 28 041383 increasing mucociliary clearance, 0.02% disodium edetate as preservative/stabilizer, 0.02% benzalkonium chloride as preservative, 0.0975% sodium phosphate dibasic and 0.5525% sodium phosphate monobasic as buffer, 1 M sodium hydroxide 3.88 ml to adjust the pH to 5.0 and water for injection q.s. (in sufficient quantity) up to 100 ml as a solvent.

Composition of 50 and 200 mg/ml betahistine. The required concentration of betahistine dihydrochloride was 5.0 and 20.0%, respectively, and the amount of 5 M sodium hydroxide 4.38 ml and 10 M sodium hydroxide 9.3 ml, respectively.

Table 2. A sample of the composition obtained according to example 1

Component Quantity in Concentration (mg/ml) Function betahistine dihydrochloride 1 g 5 g 100 50.0 Active substance 20 g 200.0 benzalkonium chloride 2 0 mg 0.2 preservative glycerol 100 mg 1.0 moisturizing agent edetate disodium 2 0 mg 0.2 preservative / stabilizer polyvinylpyrrolidone 1.25 g 12.5 Viscosity / mucociliary clearance polyethylene glycol 400 3.75 g 37.5 moisturizing agent propylene glycol 2 g 20 moisturizing agent dibasic phosphate sodium 97.5 mg 0.975 Buffer monobasic phosphate sodium 552.5 mg 5,525 Buffer 1M sodium hydroxide 3.88 ml 4.38 ml 9.3 ml pH adjustment up to 50 Water up to 100 ml Solvent

Example 2 Evaluation of safety and pharmacokinetic profile in dogs

The safety and pharmacokinetic profile of intranasal betahistine were first evaluated in a single dose toxicology study in male and female Beagle dogs (age 14-21 months, weight 8.2-11.8 kg). Both vehicle and test drug were delivered in a single dose using a nasal spray pump (Aptar Classic Line) with a delivery volume of 100 µl in both nostrils at total dose levels of 0 (vehicle), 4, 20 or 80 mg betahistine dihydrochloride. Each treatment group consisted of 1 dog/sex. Animals were observed for 7 days, then given a 3 day washout period before being used for a repeat dose study where they received for 14 consecutive days daily at three doses separated by approximately 4 hours 0 (vehicle), 12, 60, or 240 mg betahistine dihydrochloride.

For toxicokinetic studies, blood samples were collected as follows: pre-dose and approximately 5, 15, and 30 min, 1, 2, 6, 24, and 168 h post-dose in the single-dose phase and prior to the first dose on study days 1. 8 and 14, and 2 hours after the third dose on study days 1 and 14, and on study day 15 before necropsy. Plasma concentrations were measured by liquid chromatographic tandem mass spectrometry (LC-MS/MS; SCIEX API 5000 for betahistine and SCIEX API 4000 for 2-pyridylacetic acid (2-PAA)) using a validated method. Betahistine- ¹³ CD ₃ dihydrochloride and 2-PAA-D4 hydrochloride served as internal standards. The standard calibration range - using a plasma sample volume of 0.05 ml - for betahistine was from 0.05 to 50 ng/ml and for 2-PAA it was from 1 to 1000 ng/ml. The limit of quantitation was 0.05 ng/ml for betahistine and 1.0 ng/ml for 2-PAA.

In the case of betahistine, the method included liquid-liquid extraction; in the case of 2-PAA, it involves protein precipitation. For betahistine, plasma samples were extracted under basic conditions with an organic solvent; the organic phase was dried and recovered in a recovery solvent.

Approximately 0.1 ml of the aqueous layer was transferred to polypropylene vials for LC-MS/MS analysis. For 2-PAA, plasma samples were precipitated with a mixture of organic solvents, the supernatant was diluted and 0.12 ml was transferred into polypropylene vials for LC-MS/MS analysis. Sample analysis was performed using reverse phase chromatography.

Intranasal betahistine was well tolerated. Clinical signs associated with the test product, consisting of mild to moderate salivation, were noted after

- 29 041383 intranasal delivery of 80 mg of the test drug both in a single dose and in a repeated dose (240 mg/day) of the study phase. Salivation after betahistine treatment was previously reported to occur in dogs, was transient in nature in the present study, and resolved rapidly. Body weight, clinical pathology, and general autopsy were unremarkable. There were no treatment-related adverse outcomes in the study.

Betahistine was rapidly absorbed after intranasal administration of a single dose, with the maximum concentration observed at the 5-minute control time point (T _max ) (Fig. 1). Without being bound by any theory, T _max 5 minutes after dosing suggests a rapid onset of betahistine pharmacological activity. The increase in C _max was linear with respect to the administered dose, but not proportional - C _max was 26, 81 and 248 ng / ml for groups 4, 20 and 80 mg (average for male and female animals). Concentrations rapidly declined by more than 90% at the 1 hour time point. Quantifiable plasma concentrations were no longer observed after the 2 or 6 hour time points in the 4 and 20 mg dose groups, but were observed up to the 24 hour time period in the 80 mg dose group. The 2-PAA metabolite, like its parent, appeared rapidly by the 5 minute time point, indicating rapid formation at similar rates at different dose levels (FIG. 2). 2-PAA reached maximum concentrations of 606, 2195 and 4615 ng/ml for the 4, 20 and 80 mg groups (average for male and female animals) in the time interval from 15 minutes to 1 hour. The increase in C _max was approximately proportional to the dose 4 to 20 mg in dose groups and less in proportion to 20 to 80 mg in dose groups, indicating saturation of the elimination process above the 20 mg dose level. After peak levels, 2-PAA declined rapidly and approximately linearly, generally with last measured values 24 hours post-dose.

In repeat dose evaluation, betahistine and 2-PAA levels were measured in all collected samples in the 20 and 80 mg dose groups and in most samples in the 4 mg dose group. The increase in betahistine concentration across dose levels was less than proportional at comparable plasma sampling times. Although total betahistine was rapidly eliminated, small plasma concentrations could still be observed in samples at days 8 and 14 of the study, indicating that some, albeit low, basal levels were maintained. Results from single and multiple dose toxicology studies indicate that intranasal betahistine is effective and results in rapid and significant systemic exposure. The dogs tolerated the treatment well.

Example 3 Evaluation of safety and pharmacokinetic profile in humans

The safety and pharmacokinetic profile of intranasal betahistine were further evaluated in a double-blind, randomized, placebo-controlled, single dose incremental clinical trial in a total of 32 healthy male and female volunteers. The main inclusion criteria were that subjects must be aged 18-45 years and show a body mass index in the range of 18-30 kg/m ² . Subjects were required to fast for 8 hours prior to test drug administration and for 2 hours post-dose. Water was not given for 1 hour before test drug administration and for 1 hour after dosing.

Betahistine dihydrochloride was tested in four dose cohorts of 5, 10, 20, and 40 mg; in each cohort, 6 subjects received the active drug and 2 subjects received the corresponding placebo. Betahistine was supplied as a 50 and 200 mg/mL solution in an HDPE vial and a spray pump bag (Aptar Classic Line) that delivers an accurate 100 µL per pump. The study drug was injected into the right nostril of the subjects while they were in the supine position. The 5 and 20 mg doses required one application of 50 and 200 mg/mL, respectively, while the 10 and 40 mg doses required two applications of 50 and 200 mg/mL.

Serial blood samples were collected 24 hours post-dose on day 1, day 4 and day 7 to determine plasma concentrations of betahistine and its major metabolite, 2-PAA. Plasma samples were analyzed for VL content using approved procedures and methods. Blood samples (6 ml) were collected in tubes containing K ₂ EDTA and centrifuged at approximately 2000 g for 10 minutes at +4°C, and the resulting plasma was transferred into 2 clean, labeled 2 ml cryovials. All plasma samples were stored at -70° C. or below until all samples were collected and sent as a single batch for analysis. Aliquots 1 and 2 were sent in separate lots. Concentrations were determined using liquid chromatographic tandem mass spectrometry (LC-MS/MS; SCIEX API 5000 for betahistine and SCIEX API 4000 for 2-PAA) using a validated method. Betahistine- ¹³ CD ₃ dihydrochloride and 2-PAA-D4 hydrochloride served as internal standards. The standard calibration range - using plasma sample volumes of 0.2 and 0.1 ml, respectively - for betahistine was 10 to 800 pg/ml and for 2-PAA it was 2 to 2000 ng/ml. The limit of quantitation was 10 pg/ml for betahistine and 2.0 ng/ml for 2-PAA.

In the case of betahistine, the method included liquid-liquid extraction; in the case of 2-PAA, it involves protein precipitation. For betahistine, plasma samples were extracted under basic conditions with an organic solvent; the organic phase was dried and reconstituted in a solvent to restore

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Approximately 0.120 ml of the aqueous layer was transferred to polypropylene vials for LC-MS/MS analysis. For 2-PAA, plasma samples were precipitated with a mixture of organic solvents, the supernatant was diluted and 0.120 ml was transferred into polypropylene vials for LC-MS/MS analysis. Sample analysis was performed using reverse phase chromatography.

Treatment with betahistine at the tested doses of 5, 10, 20 and 40 mg was well tolerated. There were no differences in assessment of hematology, biochemistry, urinalysis, vital signs, and electrocardiogram between active drug and placebo treated subjects. The frequency of adverse events occurring during treatment was also similar for both groups of subjects, and there was no clear dose-dependent trend in the frequency of adverse events for subjects treated with the active drug. The pharmacokinetic parameters of systemic exposure to betahistine and 2-PAA increased with increasing dose levels. For betahistine, peak plasma concentrations were 4.1 and 10.5 ng/mL for the two highest doses (FIG. 3), which are notably higher than C _max <0.5 ng/mL according to Chen et al. (Xenobiotica, 2003, 3 (12) 3, 1261) after oral administration of betahistine 24 mg. The maximum was reached approximately 10 minutes after dosing. For 2-PAA metabolites, the maximum concentrations were 370 and 519 ng/mL for the two highest doses (FIG. 4), which is similar to the level reported by Val et al. (Arzneimittelforschung, 2010, 60(7), 440) after oral administration of betahistine 16 mg (522 ng/ml). T _max was reached after 1.2 hours, which is also similar to the results of studies with oral administration of betahistine 16 or 50 mg, according to Chen et al. (2003) after 1 h and Moorthy et al. (Biopharm. Drug Dispos., 2015, 36(12), 429) after 1.5 hours.

For each subject who completed the study, plasma concentration-time data for betahistine and 2-PAA were used to calculate the following pharmacokinetic parameters:

C _max - Observed maximum plasma concentration obtained directly from the data.

t _max - Time to reach the observed maximum concentration, taken directly from the data. If the maximum plasma concentration occurs at more than one time point, then the first one is selected.

AUC ₀ . _last - Area under the plasma concentration-time curve calculated using the linear trapezoid rule from time 0 to time t, where t is the time of the last measured concentration.

λ _ζ - Terminal elimination rate constant obtained from the slope of a line fitted by least squares linear regression through the endpoints in logarithmic concentration-time profiles (sometimes also referred to as k _el ).

AUC-inf - Area under the plasma concentration-time curve from zero to infinity, calculated as (AUC ₀ . _t + C _t /λ _Z ), where C _t is the last concentration measured.

t1/ ₂ - Apparent terminal half-life, calculated as t _1/2 =In(2)/λ _Z .

Dose-normalized parameters Cmax/Dose and AUC/Dose were also calculated.

Summary data of certain pharmacokinetic parameters of betahistine during treatment are given in table. 3-4.

Table 3 Summary of betahistine pharmacokinetic parameters

Average (CV%) Median (interval) Cohort * Dose (mg) N (pg/ml) AUC ₀ , _Mt (h * pg / ml) AUC^m (h*pg/ml) (H) ....... (H) Cohort 1 Linear 5 mg 6 638 (67%) 209 (75%) 277 ⁴ (60%) 0.208 ⁴ (83%) 0.208 (0.08-0 33) Cohort 2 Linear 10 mg 6 2112 (46%) 533 (45%) 697' (39%) 0 883' (140%) 0.167 ........(0.08-0 17)...... Cohort 3 Linear 20 mg 6 4105 (53%) 1608 (65%) 1626 (65%) 0.519 (116%) 0.167 (0 08-0 33) Cohort 4 Linear 40 mg 6 10490 (26%) 3531 (31%) 2941 ¹ (2.3%) 0 926 ^th 008%) 0 125 (0.08-0 27)

Notation: ^a n=3; ^bn =2; NA - not determined (n=0) *Linear - carried out in linear clinical trials.

Table 4 Additional pharmacokinetic parameters for betahistine

Dose

Pharmacokinetic parameter Cohort (mg) N Mean CV (%)

Kel (14 ) 1 l 5 3 5.09 68% Kel (14 ) 2L 10 3 2.83 78% Kel (1/h) 3 L 20 6 2.27 48% Kel (1/h) 4L 40 2 1.79 1083

Summary data of certain pharmacokinetic parameters of 2-PAA are given in table. 5, 6.

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Table 5 Summary of 2-PAA pharmacokinetic parameters

Average fCV%) Median (interval) | Cohort Dose (mg) N (ng/ml) AUC _04ast (h * ng / ml) AUC®_, _n f (h * ng / ml) (h) keels i (h); Cohort 1 Linear 5 MG 6 67.8 (61¾) 397 (57%) 427 (54%) 4 36 (41%) 1008 | .........0 00-1 50 )....j Cohort 2 Linear 10 mg 6 148 (19%) 736 (13%) 7β8 (13") 3.76 (29%) 1 250 1 ........ (0.55-2.00) ....... | Cohort 3 Linear 20 mg 6 370 (18%) 2000 (20%) 2029 (19%) 3.49 P5%) 1.250 | (0.50-1.50) \ Cohort 4 Linear 40 mg 6 519 (29%) 2828 (24%) 2901 (24%) With (23%) 1000 (5 00-1 50) ί

Notation: ^a n=3; ^bn =2; NA = not determined (n=0) *Linear - carried out in linear clinical trials. Table 6. Additional pharmacokinetic parameters of 2-PAA

Dose

Pharmacokinetic parameter Cohort (mg) N Mean CV (%)

Kei ¢1/4 ) 1L 5 6 0.180 36% Kei 11 /h ) 2 L 10 6 0.199 thirty% Kei I/h 1 EL 20 6 0.203 182 Kei (1/h) 4L 40 6 0.187 325

The above data in table. 3-6 indicate that the pharmacokinetic parameters of systemic exposure to betahistine and 2-PAA increase with dose level. The dose response graphic suggests that betahistine exposure is dose proportional over the betahistine dose range in this study from 5 to 40 mg. For betahistine, peak concentrations are reached in 5-20 minutes and the apparent half-life is less than 1 hour. the half-life is approximately 4 hours.

Thus, the results of this study showed that intranasal betahistine is well tolerated and, unlike oral administration, provides quantitative and significant plasma concentrations of the active parent compound. The maximum concentration is reached approximately 10 minutes after dosing and, without being bound to any theory, suggests a rapid onset of action, which may be of particular therapeutic importance, for example, in case of acute medical need. The experiment shows for the first time that betahistine can be effectively and safely administered systemically in a non-invasive way by the intranasal route.

Example 4 Dose Formulation Uniformity

Compositions with 10 and 200 mg/ml betahistine were prepared in accordance with example 1 and table. 2 except for adjusting the pH to 5.5.

The formulations were placed in a 100 μl Aptar Classic Line spray pump and then placed in an appropriate volumetric flask made up to volume with diluent. In table. 7 and 8 show the uniformity of the dose composition.

Table 7. Dosing uniformity of the 10 mg/mL formulation

Received

V"

Analysis, mcg

1.02443

- .00 Ό0 0.97018 0.99444 0.96749 1.02131 SAZh'41 0.94260 1.01197 0.99125' 0.99

2.G0 %Average ' 103.2

N 97.8 100.2 97 5 '92 9

95.0 102.0 99.9 ^Mean %RSD

Table 8. Dosing uniformity of the 200 mg/mL formulation

I Received Analysis, mcg %Average I ₁ 2G.51925 09 3 । 2 20.45679 99.0 3 2С 06933 100.0 ' 4 20 8742: W1.0 5 20.83816 YuO.Z 6 20 32872 98 4 ‘7 20 54321 99 4 I 8 20.43037 98.9 5 2CS1349; *01 2 i 10 21.05841 1C1.9 i Mean value 20.66 1%RSD 1J8

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Example 5 Pharmacokinetic Profile Evaluation in Dogs

In this study, the pharmacokinetic profile of betahistine was assessed following a single dose of betahistine to male and female beagle dogs (age 5-7 months; weight 5-11 kg, within 3 kg for each sex) for three routes of administration: oral, intranasal, and intravenous.

On the first day of the study, betahistine (VH) was administered orally at a dose of 12, 24, or 48 mg/kg. Each treatment group consisted of 8 animals (4 males and 4 females). For pharmacokinetic evaluation, plasma samples were collected pre-dose and then 5, 10, 20 and 30 min, 1, 2, 3, 6, 24 hours post-dose.

On the 8th day of the study, animals receiving oral VN at a dose of 12 mg/kg were injected intranasally with the test composition of betahistine at a dose of 40 mg betahistine dihydrochloride; animals receiving oral VN at a dose of 24 mg/kg were intranasally injected with the test composition of betahistine at a dose of 80 mg betahistine dihydrochloride; and animals that received oral VN at a dose of 48 mg/kg were injected intranasally with the test composition of betahistine at a dose of 120 mg of betahistine dihydrochloride. The betahistine test formulation was delivered intranasally in a single dose via the Aptar nasal spray pump at a total dose level of 40, 80 and 120 mg betahistine dihydrochloride.

Plasma samples were collected before dosing and then at 5, 10, 20 and 30 minutes, 1, 2, 3, 6, 24 hours after administration.

On study day 15, animals receiving 12 mg/kg oral VL and 40 mg betahistine dihydrochloride test composition intranasally were given an intravenous bolus injection of 0.44 mg/kg betahistine. Plasma samples were collected before dosing and then at 5, 10, 20 and 30 minutes, 1, 2, 3, 6, 24 hours after administration. Plasma concentrations were measured by liquid chromatographic tandem mass spectrometry (LC-MS/MS; SCIEX API 5000 for betahistine, SCIEX API 4000 for 2-pyridylacetic acid (2-PAA)) using validated methods. Betahistine-13CD3 dihydrochloride and 2-pyridylacetic acid-D4 hydrochloride were used as the respective internal standards. The calibration range for betahistine was 0.05-250 ng/ml and for 2-PAA 2.00-3000 ng/ml using a plasma sample volume of 0.50 ml.

For the determination of betahistine, the method included liquid-liquid extraction; for 2-PAA, the method included protein precipitation. For betahistine, plasma samples were obtained by extraction under basic conditions with an organic solvent, then the organic phase was dried, recovered and transferred for LC-MS/MS analysis. For 2-PAA, plasma samples were precipitated with a mixture of organic solvents, the supernatant was dried, reconstituted and transferred for LC-MS/MS analysis. Sample analysis was performed using reverse phase chromatography.

Intranasal administration of betahistine was well tolerated by dogs. At the highest concentration in the betahistine group, salivation was observed in most animals, and sneezing was observed in 2/8 of the animals at this dose level.

Plasma levels of betahistine and 2-PAA in the studied animals were as shown in Table 1. 9-17.

Table 9 Plasma levels of betahistine following intranasal administration of the test composition of betahistine at a total dose of 40, 80 and 120 mg betahistine dihydrochloride (values for male and female animals are shown separately)

Plasma concentration of betahistine (pg/ml) Time (h) Male 4 0 mg Women's specimen 40 mg Male 80 mg Female 8 0 mg Male 12 0 mg Female 12 0 mg 0 0 54.25 29.25 0 90 25.5 0.08333333 469250 733750 606500 1639750 661750 1144000 0.167 440300 457750 619750 1178000 515250 825250 0.333 333883 295950 179300 605000 295000 244750 0.5 52123 15475 14540 50450 27175 31200 1 9045 5088 12143 20975 13060 16510 2 2319 879 546 8680 3718 5010 3 453 850 252 2078 945 1894 6 244 361 340 712 266 1118 24 221 96 67 189 288 314

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Table 10. Plasma betahistine levels following intranasal administration of the betahistine test composition at a total dose of 40, 80 and 120 mg betahistine dihydrochloride (values for male and female animals combined)

Plasma concentration of betahistine (pg/ml) Time (h) 40 mg 80 mg 120 mg 0 27 15 58 0.08333333 601500 1123125 902875 0.167 449025 898875 670250 0.333 314916 392150 269875 0.5 33799 32495 29188 1 7066 16559 14785 2 1599 4613 4364 3 652 1165 1419 6 303 526 692 24 158 128 301

Table 11 Plasma levels of betahistine after oral administration of betahistine at 12, 24 g, and 48 mg/kg (values for male and female animals are shown separately)

Plasma concentration of betahistine (pg/ml)

Time (h) Male 12 mg/kg Women's individual 12 mg/kg Male 24 mg/kg Women's individual 24 mg/kg Men's specimen 48 mg/kg Women's specimen 48 mg/kg 0 0 0 0 0 0 0 0.08333333 1.35 2588 4690 5316 14328 9873 0.167 2728 6465 5055 5238 35703 9243 0.333 5800 10113 23903 7133 14330 11483 0.5 18915 7798 17840 11983 33700 19350 1 5653 14058 26880 36825 80150 32825 2 457 263 2079 3578 21680 21325 3 36 0 611 1710 2997 10138 6 16 0 78 342 238 640 24 21 0 0 0 0 0

Table 12: Plasma levels of betahistine after oral administration of betahistine at 12 mg/kg, 24 mg/kg and 48 mg/kg (male and female values combined)

Plasma concentration of betahistine (pg/ml) Time (h) 12 mg/kg 24 mg/kg 48 mg/kg 0 0 0 0 0.08333333 1969 5002.875 12100 0.167 4596.25 5146.25 22472.5 0.333 7956.25 15517.5 12906.25 0.5 13356.25 14911.25 26525 1 9855 31852.5 56487.5 2 359.88 2828 21503 3 18.1 1160.6 6567.1 6 7.975 210.1 438.99 24 10.4625 0 0

Table 13. Plasma betahistine levels following intravenous betahistine 0.44 mg/kg (values for male and female animals are shown separately)

Plasma concentration of betahistine (pg/ml) Time (h) Male 0.44 mg/kg Female 0.44 mg/kg

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0 110 55, 05 0.08333333 58175 43700 0.167 29100 14825 0.333 8063 5995 0.5 5568 4063 1 349 268 2 993 274 3 81 95 6 1051 648 24 0 405

Table 14 Plasma Betahistine Levels Following Intravenous Dose of Betahistine

0.44 mg/kg (values for male and female animals combined)

Plasma concentration of betahistine (pg/ml) Time (h) 0.44 mg/kg 0 82.525 0.08333333 50937.5 0.167 21962.5 0.333 7028.75 0.5 4815 1 308.375 2 633.34 3 87.75 6 849.25 24 202.25

Table 15. Plasma levels of 2-PAA following intranasal administration of the test composition of betahistine at a total dose of 40, 80 and 120 mg of betahistine dihydrochloride (values for male and female animals combined)

Plasma 2-PAA concentration (ng/ml) Time (h) 40 mg 80 mg 120 mg 0 1 3 3 0.08333333 350 422 482 0.167 1436 1414 1356 0.333 3242 2996 2424 0.5 4231 3531 2715 1 4101 5163 3835 2 2937 3345 2494 3 1676 2073 1499 6 382 424 318 24 8 13 15

Table 16. Plasma levels of 2-PAA following oral administration of betahistine at 12, 24, and 48 mg/kg (male and female values combined)

Plasma 2-PAA concentration (ng/ml) Time (h) 12 mg/kg 24 mg/kg 48 mg/kg 0 0 0 0 0.08333333 186.31625 266.46 233.64875 0.167 720.45 528.7875 694.2125 0.333 2492.75 2619.25 2298.75 0.5 5722.5 5121.25 5175 1 13236.3 17751.3 25963.8 2 11664 21963 39113 3 6443.8 14701 33845 6 1611.5 3966.3 10266 24 7.73125 13.7863 35.675

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Table 17. Plasma levels of 2-PAA after intravenous administration at a dose of 0.44 mg/kg (values for male and female animals are combined)

Plasma 2-PAA concentration (ng/ml) Time (h) 0.44 mg/kg 0 0.6088 0.08333333 652.875 0.167 709.875 0.333 633.375 0.5 583.75 1 513 2 286.13 3 164.75 6 36.475 24 2.1475

In FIG. 5 and 6 are graphs showing median (FIG. 5) and mean (FIG. 6) plasma concentrations of betahistine following intranasal administration of total dose of betahistine dihydrochloride.

40, 80 and 120 mg over time, with combined values for male and female animals. Plot based on median values, FIG. 5 shows the dose-dependent increase in betahistine plasma concentration. In a graph based on averages (FIG. 6), the average C _max for the 80 mg dose appears to be higher than the average C _max for the 120 mg dose. This discrepancy is due to certain outliers.

Fig. 7 and 8 are graphs showing median (FIG. 7) and mean (FIG. 8) plasma concentrations of betahistine, with pooled values for male and female animals following oral administration of betahistine over time.

Fig. 9 and 10 are graphs showing median (FIG. 9) and mean (FIG. 10) betahistine plasma concentrations, with pooled values for male and female animals following intravenous betahistine over time.

In table. 18-20 summarize the pharmacokinetic parameters for betahistine (VH) after oral, intranasal and intravenous administration. Tab. 21-23 show a summary of the pharmacokinetic parameters for 2-PAA after oral, intranasal and intravenous administration of betahistine.

Table 18 Summary data (mean ± SD) of plasma VL pharmacokinetic parameters in beagle dogs following oral VL administration on Day 1

Day analyte Path Floor Dose (mg/kg) f a ^x max (H) ^max (ng/ml) Stach / D (ng / ml / (mg / kg)) AUC ₍₀ . ₆₎ (h * ng / ml) AUC ₍₀ _ _t) (h * ng / ml) AUC ₍₀ - _t) /fl (h * ng / ml / (mg / kg) ) AUC ₍₀ . _inf) (h * ng / ml) Tl/2 (4) 1 VN oral male 12 0.5 (0.5- 0.5) 18.9+9.9 9 1.58+0.833 13.0+2.23 12.5+2.02 1.04+0.16 8 13.3+ID 0.313+ID 24 1 (0.33-1) 38.3+28.1 1.60+1.17 34.5+17.2 34.5+17.1 1.44+0.71 4 34.6+17.1 0.785+0.388 48 1d-D 102+30.2 2.13+0.628 131+28.3 131+28.3 2.73+0.59 0 133+ID 0.522+ID Women's individual 12 1 (0.5-1) 14.7+4.5 6 1.22+0.380 NC 15.9+5.80 1.33+0.48 3 NC NC 24 1 (0.33-1) 38.0+26.1 1.58+1.09 26.2+ID 41.0+17.9 1.71+0.74 8 27.7+ID 1.41+ID 48 1 (0.08-1) 33.5+9.1 1 0.697+0.19 0 77.5+25.4 77.5+25.4 1.61+0.52 8 69.2+23.3 0.599+0.035 1 For both sexes 12 0.5 (0.5-1) 16.8+7.5 4 1.40+0.628 13.0+2.23 14.2+4.41 1.18+0.36 8 13.3+ID 0.313+ID 24 1 (0.33-1) 38.2+25, 1 1.59+1.05 31.7+14.0 37.8+16.6 1.57+0.69 2 32.3+13.8 0.995+0.458 48 1 (0.08-1) 62.9+41, 1.31+0.857 100+37.6 100+37.6 2.09+0.78 94.6+43.4 0.568+0.056 L 1 2 3 5

^a Median T _max (Min - Max);

NC=He calculated;

ID=Insufficient data.

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NM=He is significant;

NC=He calculated;

ID=Insufficient data.

Table 20. Summary data (mean ± SD) of plasma VL pharmacokinetic parameters in beagle dogs after intravenous bolus administration of VL on day 15

Day Anal t Path Floor Dose (mg/kg) m a --max (h) Stakh (ng/ml) C _max /d (ng / ml / (mg / kg)) AUG (0-6) (h*ng/ml) AUG ₍₀ _ _t) (h * ng / ml) AUC ₍₀ - ₇₎ /d (h * ng / ml / (mg / kg)) AUC(o - inf) (h * ng / ml ) T _1/2 (h) CL (ml/h/kg) Vd (ml/kg) VV Men's 15 VN 0.44 bolus individual Women's 0.44 individual For both 0.44 sexes 0.08 58.2 ±132 ±19.5 ±19.5 ±44.3 ± 0.930 23900 32100 (0.08-18.4±ID 7.93 18.0 5.05 5.06 11.5 ±ID ±ID ±ID 0.08) 0.09 43.7 ±99.3 ±16.3 ±26.5 ±60.3 ± 0.238 30800 10600 (0.08-14.3±ID 8.84 20.1 6.54 17.6 40.0 ±ID ±ID ±ID 0.11) 0.08 50.9 ±116 ±17.9 ±23.0 ±52.3 ± 0.584 27400 21300 (0.08-16.3±ID 11, 0 24.9 5.67 12.6 28.5 ±ID ±ID ±ID 0.11)

^a Median T _max (Min-Max);

ID=Insufficient data.

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Table 21. Summary data (mean ± SD) of plasma pharmacokinetic parameters of 2-PAA in beagle dogs after oral administration of VN on Day 1_______________________________

Day analyte Path Floor Dose (mg/kg) (h) C check (ng/ml) C^x/D (ng/ml/(mg/kg)) AUC ₍₀ . ₆₎ (h * ng / ml) AUC ₍₀ . _t) (h * ng / ml) AUC( ₀ t)/fl (h*ng/mL/(mg/kg)) AUC ₍₀ . _{in £)} (h * ng / ml) Tl/2 (h) 1 2-PAA orally male 12 1.5 (1-2) 12700+2420 1060 12 02 37300110500 50500121100 421011760 50500121100 2.2110.16 0 24 1.5 2640017520 1100 76400121100 107000128200 446011180 107000128200 2.0410.10 (1-2) 1313 7 48 2 (2-2) 5090018840 1060 1184 178000124900 286000139200 59501817 286000139300 2.1010.18 1 Women's individual 12 1 (1-2) 1450011370 1210 1114 4130015020 57200111300 47601940 57200111300 2.1210,I 0 24 2 (1-2) 2130013530 885 1147 6930017850 110000114300 45901594 110000114300 2.1410.17 6 48 2 (2-3) 3750018560 781 1178 144000135400 237000163500 493011320 208000135000 2.2410.17 0 For both sexes 12 1 (1-2) 1360012060 ISO 1172 3930017930 53800116000 449011340 53900116100 2.1710.13 5 24 2 (1-2) 2380016090 992 1254 72900115200 109000120800 45301866 109000120800 2.0910.14 5 48 2 (2-3) 4320011070 0 901 1222 158000134200 258000156700 537011180 247000153900 2.1710.17 6

^a Mean T _max (Min-Max).

Table 22. Pooled data (mean ± SD) of 2-PAA plasma pharmacokinetic parameters in beagle dogs after intranasal VN administration on Day 8

Den An or whether T Path Floor nominal th dose (mg) dose (mg/kg ) m a (h) (ng/ml) s _max /d (ng/ml/ (mg/kg)) AUG ( ₀ _ ₆ ) (h*ng/ml) AUC ₍₀ _ _t) (h * ng / ml) AUC,o- t)/d (h*ng/ml / (mg/kg)) AUC ₍₀ _ _inf) (h * ng / ml) Т1/2 (h) intranasal 8 2-PAA but Men's 40 5 individual 80 9, 8 120 15.8 0.5 3480122 122001108 24401216122001108 2.9610.5 (0.5- 6951454 944017580 70 00 0 00 36 1) 1 3320110 104001360 104001361 2.8610.1 (0.5- 3391109 845012870 10601368 70 0 0 86 1) 1 3930198 249162, 102001264127001311 128001309 2.8710.4 (0.33-8061197 7 5 0 0 0 34 1) Women's 40 6 individual 80 13 120 17.7 0.75 5570112 148001371190001487 1900014862.6610.2 (0.5- 9281215 31701812 90 0 0 0 75 1) 1 7030+30 193001776252001109 253001109 2.9710.3 5411232 19401838 (1-1) 20 0 00 00 48 1 3810+76 215143, 106001347140001544 141001547 3.4610.2 7901307 (1-2) 5200 0 39

^a Median T _max (Min-Max).

Table 23 Pooled Data (Mean ± SD) of 2-PAA Plasma Pharmacokinetic Parameters in Beagle Dogs after IV Bolus VN on Day 15

Den analyte Path Floor Dose (mg/kg (h) s _max (ng/ml) s _max /d (ng / ml / (mg / kg)) AUC ₍₀ _ ₆₎ (h*ng/ml) AUC(o - _t) (h * ng / ml) AUC( ₀ - _t) /fl (h^ng/ml/ (mg/kg)) AUC(o-mt) (h*ng/ml) Tl/2 (h) VV Men's 15 2-PAA 0.44 bolus individual Women's 0.44 individual For 0.44 both sexes 0.13 736 +1670 ± 3960 1 2.59 1 (0.08- 1450 ± 388 1740 ± 641 1760 1642 53.5 121 1460 1.07 0.33) 0.18 722 +1640 ± 2.78 1 1540 ± 101 1830 ± 209 4160 ± 475 1860 1 188 (0.11-0.2) 75.3 171 1.01 0.17 729±1660±4060±2.69± (0.08- 1500 ± 267 1790 ± 444 1810 ± 441 60.9 138 1010 0.968 0.33)

^a Median T _max (Min-Max).

In table. 24 and 25 show the absolute bioavailability (%F) of betahistine (BH) in dogs after oral and intranasal administration.

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Table 24 Absolute Bioavailability (%F) of BH in Beagle Dog Plasma Following Oral VN Administration

Comparison of routes of administration Anali Floor Dose (mg/kg) %F t)/D AUC _{(0_} oral/IV bolus VN Men's individual 12/0.44 2.35 24/0.44 3.24 48/0.44 6, 17 Women's individual 12/0.44 2.20 24/0.44 2.84 48/0.44 2.68 For sexes both 12/0.44 2.26 24/0.44 3.01 48/0.44 4.01

Table 25 Absolute Bioavailability (%) of VL in Plasma Beagle Dogs Following Intranasal Administration of VL

Comparison of routes of administration Anali Floor Dose (mg/kg) %F AUC _{(0 t)} /D intranasal/IV bolus VN male 5/0.44 82.1 9.8/0.4 4 39.5 15.8/0.44 28.4 Women's individual 6/0.44 50.2 13/0.44 56.1 17.7/0, 44 27.1

In table. 26 shows the relative bioavailability (Frel) of betahistine (BH) administered intranasally relative to oral administration.

Table 26 Bioavailability of intranasal versus oral betahistine in dogs

intranasal Oral Relative bioaccess. Dose (mg) Dose (mg/kg) AUC / dose (h.ng / ml) / (mg / kg) mg/kg AUC / dose (h.ng / ml) / (mg / kg) Dogs, male 40 5 36, 4 12 1.04 35.0 80 9, 8 17.5 24 1.44 12.2 120 15, 8 12.6 48 2.73 4, 6 Dogs, female 40 6 30.2 12 1.33 22.7 80 13 33, 8 24 1.71 19, 8 120 17.7 16, 4 48 1, 61 10.2

Example 6 Relative Bioavailability of Intranasal Versus Oral Betahistine in Humans

To calculate the relative bioavailability of intranasal betahistine compared to oral betahistine, the area under the concentration-time curve (AUC) determined in Example 3 was compared with the AUC determined in the study of oral betahistine in healthy volunteers described by Barak et al. (Journal of Psychopharmacology, 2016, Vol. 30(3) 237-241). Briefly, in this study, forty-eight healthy women were selected and randomized to receive oral (i.e., oral) either betahistine 144 mg/day (48 mg three times a day), or matched placebo, for 4 weeks. Their mean weight was 60.2 kg in the active treatment group (n=24) and 59.8 kg in the placebo group (n=24). Investigational drug (betahistine or

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Claims (24)

the corresponding placebo) was administered at least 30 minutes before meals. On the 8th day, 6 ml blood samples were collected at 8 o'clock in the morning, and then after 30, 60, 150 and 300 minutes. Plasma concentrations of betahistine and its metabolite 2-PAA were determined by high performance liquid chromatography. AuS( _0.5h ) was 121 pg-h/mL at a dose _of approximately 0.8 mg/kg. At the intranasal dose of 40 mg (or 0.57 mg/kg) in Example 3, the AUC was 3531 pg-h/ml (see Table 3). Based on oral AUC values in a study by Barak et al. and AUC values for intranasal administration from example 3 relative oral bioavailability vs. intranasal (i.e., oral versus intranasal bioavailability) was approximately 2.4%, while the relative intranasal versus oral bioavailability (nasal versus oral bioavailability) is summarized in the following table. Table 27 Bioavailability of intranasal versus oral betahistine Data from Barak et al. (orally) Dose (mg) Weight (kg) Dose (mg/kg) AUC (h*ng/ml) AUC / Dose (h.ng / ml) / (mg / kg) Relative bioaccess. 48 60.2 0.8 0.121 0.15 Example 3 data (intranasal) 5 71.9 0.07 0.209 3, 01 19, 9 10 68.8 0.15 0.533 3, 67 24.2 20 69.6 0.29 1,608 5, 60 37.0 40 70.4 0.57 3.531 6.21 41.1 Tab. 27 shows that the bioavailability with intranasal administration is 20-40 times higher than with oral administration. When using relative bioavailability at comparable absolute doses - 40 mg intranasally versus 48 mg orally - the fold factor is 41.1x0.8 mg/kg in the study by Barak et al. represents the currently approved daily dose of 48 mg per administration; although patients received 3x48 mg per day, each dose is considered separate due to rapid elimination. Inclusion in the description of the invention of information by reference All references, articles, publications, patents, patent publications and patent applications cited herein are incorporated by reference in their entirety in all respects. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein does not constitute and should not be taken as an endorsement or any form of suggestion that they constitute current prior art or are part of general knowledge in any country in the world. CLAIM 1. Pharmaceutical composition for intranasal delivery to a human patient, containing a solution or suspension of a therapeutically effective amount of betahistine dihydrochloride, a viscosity increasing agent, and a buffering agent, where the pH of the pharmaceutical composition is from 4.4 to 6.4. 2. The pharmaceutical composition according to claim 1, where the pH value of the pharmaceutical composition is 4.4, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2 or 6.4 or where the pH value is between any of the specified values. 3. Pharmaceutical composition according to claim 1, where in human plasma after a single intranasal administration of the composition: (i) C _max betahistine is in the range of 80-125%: 640 pg/ml for a 5 mg dose of betahistine; 2000 pg/ml for a 10 mg dose of betahistine; 4000 pg/ml for a 20 mg dose of betahistine; 10500 pg/ml for a 40 mg betahistine dose or (ii) betahistine AUC0.last is between 80-125%: 210 pg-h/ml for a dose of betahistine 5 mg; 500 pg-h/ml for a dose of betahistine 10 mg; 1600 pg-h / ml for a dose of betahistine 20 mg; 3500 pg-h / ml for a dose of betahistine 40 mg; or (iii) AUC ₀ _ _mf betahistine is between 80-125%: - 40 041383 275 pg-h/ml for a dose of betahistine 5 mg; 700 pg-h/ml for a dose of betahistine 10 mg; 1630 pg-h / ml for a dose of betahistine 20 mg; 3840 pg-h / ml for a dose of betahistine 40 mg; or (iv) t _max betahistine is 0.08-0.5 hours. 4. Pharmaceutical composition according to any one of claims 1 to 3, wherein the viscosity increasing agent is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, carboxymethylcellulose-Na, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, carbopol, polyethylene glycol, propylene glycol, glycerin, alginates, carrageenan, pectins, maltodextrin, sodium starch glycolate, gum tragacanth, gum arabic, microcrystalline cellulose, and combinations thereof. 5. The pharmaceutical composition of claim 4, wherein the viscosity increasing agent is hydroxypropyl methylcellulose. 6. Pharmaceutical composition according to any one of paragraphs.1-5, additionally containing one or more wetting agents; optionally, where one or more moisturizing agents are selected from the group consisting of glycerol, ethylene glycol, propylene glycol, propylene glycol 400, hexalene glycol, butylene glycol, dextrose, glyceryl triacetate, polydextrose, glycerol, glyceryl triacetate, sorbitol, mannitol, and combinations thereof. 7. Pharmaceutical composition according to any one of claims 1 to 6, wherein the composition contains betahistine dihydrochloride at a concentration of 1 to 1000 mg/ml, preferably 10 to 400 mg/ml. 8. Pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is in the form of a spray or aerosol. 9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the _Cmax of betahistine in human plasma after a single intranasal dose of the composition is at least 0.5 ng/ml or at least 4 ng/ml. 10. Pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is in the form of a dose containing betahistine dihydrochloride in an amount of 5 to 100 mg, 5, 10, 20, 40 or 80 mg. 11. Pharmaceutical composition according to any one of paragraphs. 1-6, where the composition is in the form of a dose containing from 1 to 1000 μl of the composition. 12. Pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is an aqueous solution. 13. A pharmaceutical composition according to any one of claims 1 to 7, wherein the composition further comprises a lipid. 14. A pharmaceutical composition according to any one of claims 1 to 7, wherein the composition further comprises at least one additional pharmaceutically active agent. 15. The pharmaceutical composition of claim 14 wherein at least one additional pharmaceutically active agent is a glutamate receptor antagonist. 16. A pharmaceutical composition according to any one of claims 1 to 7, wherein the composition further comprises at least one enzyme inhibitor or absorption promoter. 17. A pharmaceutical composition according to any one of claims 1 to 8, wherein a single dose of the composition contains 20 or 40 mg of betahistine dihydrochloride. 18. The pharmaceutical composition according to any one of claims 1 to 8, wherein the t _max of betahistine in human plasma after a single intranasal dose of the composition is 0.08 h or more, or is 0.12 h or more. 19. A pharmaceutical composition according to any one of claims 1 to 8, wherein the AUC ₀ _ _last of betahistine in human plasma after a single intranasal dose of the composition is at least 0.2 h-ng/ml, at least 1.5 h-ng/ ml or at least 3.0 h-ng/ml. 20. The use of a pharmaceutical composition according to any one of claims 1 to 19 as a medicament for the treatment, symptom relief or prevention of a vestibular disorder, an inner ear disorder, a neurotological disorder, an otologic disorder, or a neurological disorder. 21. The use of a pharmaceutical composition according to any one of claims 1 to 19 for intranasal administration for the treatment, for the relief of symptoms, or for the prevention of an inner ear disorder, vestibular disorder, neurotological disorder, otological disorder, or neurological disorder. 22. Use according to claim 21, wherein the vestibular disorder is vestibular vertigo or Meniere's disease. 23. The use of a pharmaceutical composition according to any one of claims 1 to 19 to facilitate vestibular rehabilitation. 24. The use of a pharmaceutical composition according to any one of claims 1 to 19 for intranasal administration for the treatment of obesity, the reduction of weight gain, the treatment of weight gain and/or the treatment -