KR20240065134A - Compositions and methods for preventing and treating skin radiation damage - Google Patents

Abstract

Compositions and methods for treating cutaneous radiation injury (CRI), including radiation dermatitis, radiation proctopathy, or oral mucositis, using one or more functional inhibitors of acid sphingomyelinase (FIASMA).

Description

Compositions and methods for preventing and treating skin radiation damage

The present invention relates to compounds, compositions and methods for treating skin diseases or disorders induced by radiation exposure.

Cutaneous radiation injury (CRI) is a condition in animals, including mammals and humans, that is induced by or results from exposure to radiation from industrial or military-related sources, such as radioactive materials used in nuclear power plants or nuclear weapons. Damage to the skin or underlying tissue. Mild skin injuries, such as sunburns from overexposure to sunlight, are generally not considered to fall within the definition of CRI; The term CRI may include skin conditions, such as radiation dermatitis, or other conditions, such as radiation proctopathy, oral mucositis, or severe oral mucositis, each of which can be used to treat cancer or other conditions treatable using radiation. It can be observed after medical radiation therapy administered to certain areas of the body.

In medicine, radiotherapy has been used successfully in the treatment of local or regionally advanced cancer and can be used as a stand-alone treatment or as an adjunct to chemotherapy or surgery. However, radiation exposure in these treatments can cause permanent changes in pigmentation as well as severe burns of the skin and surrounding tissues. 95% of patients treated with radiation therapy for cancer will experience a skin reaction. Certain skin reactions resulting from radiation therapy administered to breast cancer patients are, for example, referred to as “radiation dermatitis.”

Patients with head and neck cancer may experience an inflammatory response in the mouth due to damage caused to the epithelial cells of the lining of the mouth following radiation therapy to treat head and neck cancer, resulting in conditions such as oral mucositis. When radiation therapy causes ulcerative lesions to form in the mouth, or when the patient becomes unable to swallow solid food, the condition is considered "severe oral mucositis" or "SOM."

Radiation therapy administered to the pelvic area can cause damage to rectal tissue. A variety of disorders resulting from targeted radiation therapy to the pelvic region may affect the anorectal region and may include one or more of the following: inflammatory, ischemic, infectious, traumatic, or neoplastic conditions. Symptoms of anorectal disease include anal or rectal pain, urgency to defecate, fecal incontinence, diarrhea, rectal bleeding, and difficulty in rectal defecation. These diseases are more recently referred to as “radiation proctitis” and more accurately as “radiation proctopathy.”

Considering the prevalence of these diseases in cancer patients receiving radiation therapy, several strategies and treatments have been proposed for patients suffering from radiation dermatitis, but have not shown much success. Aloe vera and topical vitamin C have been tried with no improvement in the outcome of irradiated breast tissue.

Other reports indicate that prophylactic and ongoing use of topical corticosteroids or dexpanthenol-containing emollients can improve, but not prevent, radiation dermatitis. Another report showed that moist skin care using 3% urea lotion delayed the onset and reduced the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors. The negative side effects of corticosteroids are widely documented, and it is advisable to avoid their use. Topical corticosteroids have little or no effect on pigmentation changes.

Biafine and Lipiderm were shown to have no radioprotective effect, but a retrospective analysis showed a significant skin-cytoprotective effect from the use of amifostine.

Misoprostol, a prostaglandin E(1) analogue, has been shown to be an effective radioprotectant in animal studies preventing tumorigenic transformation in Syrian hamster embryos exposed to radiation in utero. However, no successful results were obtained in humans.

Attempts to prevent or treat radiation proctopathy or proctitis have also been largely unsuccessful. Many topical treatments used for anorectal or lower intestinal disorders have not been shown to be effective. For example, the use of 5-aminosalicylic acid (5-ASA), an anti-inflammatory agent previously used to treat inflammatory bowel disease (IBD), has been used to treat radiation proctopathy or proctitis with or without steroids such as hydrocortisone. It wasn't successful. Sucralfate has also been recommended for radiation proctopathy, but has not proven effective.

Topical therapies such as nitroglycerin and calcium channel blockers have also been found to be ineffective in the treatment of radiation proctopathy. Short-chain fatty acid enemas have also been used in the treatment of radiation proctopathy, but are not readily available and difficult to administer.

Recently, antioxidants such as vitamin A, vitamin C and vitamin E formulated as suppositories have been described for the treatment of radiation proctopathy or proctitis. Suppositories are solid dosage forms containing medicaments for placement in the anus or vagina for the treatment of certain systemic diseases, but can also be used for topical treatment of anorectal and gynecological disorders. For example, one common use of rectal suppositories is for the treatment of constipation.

Rectal suppositories are also used as an alternative form of drug delivery in patients who cannot receive the drug orally, whereby the drug is absorbed by the mucosa and distributed throughout the body. Examples of these types of rectal suppositories include treatments for nausea and pain.

It has been suggested that damage to healthy tissue from radiotherapy may involve an endothelial response involving signaling from the plasma membrane through the acid sphingomyelinase/ceramide pathway (Corre, I., et al., Intl J. Mol. Sci (2013) 14, 22678-22696]. For example, protection against endothelial damage by inhibiting acid sphingomyelinase (ASMase) activity is proposed as a means to limit radiation toxicity in normal tissues. See Corre, at 22685, supra. Although inhibitors of ASMase are known, none have been developed for topical administration and have not been proven effective in preventing or treating CRI in general or radiation dermatitis, radiation proctopathy, or oral mucositis specifically.

A class of ASMase inhibitors known as tricyclic antidepressants are not previously known to be used to treat anorectal disorders such as radiation proctopathy or proctitis. Dosage forms containing tricyclic antidepressants, such as amitriptyline, have not been formulated for anal or rectal administration, or for orthotopic (or non-systemic) treatment of radiation proctopathy or proctitis. Amitriptyline is formulated as a suppository dosage form. However, amitriptyline suppositories are formulated only for systemic delivery and to treat depression, a known indication for amitriptyline. Another indication for amitriptyline suppositories for systemic delivery is insomnia, which takes advantage of the sleep-inducing side effects observed for amitriptyline. Amitriptyline suppositories are not previously known to be administered to patients who are receiving or have received pelvic radiation therapy, or to treat radiation proctopathy or proctitis, or for any other orthotopic treatment in the lower intestinal tract.

More specifically, amitriptyline has not previously been formulated in a dosage form, such as a suppository or other anorectal delivery device, for topical treatment of radiation proctopathy or proctitis. Tricyclic antidepressants, such as amitriptyline, can be used in a low pH environment (acidic pH below 7) such that drug release occurs primarily in the intestine, preferably in the lower intestine, for orthotopic delivery of the drug to treat radiation proctopathy or proctitis. ) has not been formulated in a controlled release dosage form, such as to bypass release in the stomach.

Another class of ASMase inhibitors, the selective serotonin reuptake inhibitors (SSRIs), are not known to be available in suppository form; SSRIs are not known to have been previously used for the treatment of radiation proctopathy or proctitis.

There are a number of anorectal diseases that may benefit from topical administration of a TCA, such as amitriptyline, or an SSRI, such as sertraline. These conditions include inflammatory bowel disease (IBD), including ulcerative proctitis and Crohn's disease, fissures, internal hemorrhoids, radiation proctopathy, anal and rectal neoplasms, anal warts, anal dysplasia, solitary rectal ulcer syndrome, anal pruritus, and anus. Includes (but is not limited to) rectal ischemia. These diseases represent a variety of significant clinical problems for which limited treatment options are currently available.

ASMase inhibitors such as TCAs such as amitriptyline or SSRIs such as sertraline are not known to be of use against CRI diseases such as radiation dermatitis or oral mucositis. Moreover, liquid oral dosage forms comprising TCAs or SSRIs, such as oral solutions suspensions or emulsions (individually or collectively referred to herein as “oral rinses” or simply “rinses”) is not known to be formulated to treat oral mucositis. Patients who have reduced saliva production due to radiation damage to the salivary glands and difficulty swallowing oral dosage forms or orally dissolving rapidly disintegrating solid oral dosage forms may use rinses or mouthwashes to deliver the active ingredients to the mouth and damaged tissues within the oral cavity. Benefits may be obtained from oral solutions, suspensions or emulsions that can be used as mouthwashes.

The continued and increasing use of radiotherapy in the treatment of cancer and the lack of available prophylactic or therapeutic agents for CRI, including radiation dermatitis or radiation proctopathy, are long-standing unmet patient needs affecting millions of patients. .

The subject invention covers skin radiation injury (CRI) resulting from environmental exposure to radiation from industrial or military radioactive sources, or radiation dermatitis, radiation proctopathy or oral mucositis (severe oral mucositis or Methods for improving or reducing the severity of, preventing, reducing the incidence or recurrence of, suppressing, treating or reversing (including SOM). The term CRI generally includes radiation damage to the outer layer of the skin, or dermis, but can also include damage to deeper skin layers, such as the subcutaneous layer or the fatty layer. Radiation dermatitis, radiation proctopathy, and oral mucositis fall within the definition of CRI, but are generally believed to be diseases associated with damage to the dermis.

The method according to the invention involves topically administering a composition comprising at least one acid sphingomyelinase (ASMase) inhibitor to the skin surface or mucosa of a patient suffering from CRI, including radiation dermatitis, radiation proctopathy, or oral mucositis, or Including the step of applying. Functional inhibitors of acid sphingomyelinase, known in the art by the acronym FIASMA, include certain selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenergic receptor blockers (ARBs), and beta. Including blockers, etc.

SSRIs useful in the methods of the invention include one or more of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or Tralin. A preferred SSRI is sertraline. According to a preferred embodiment, the dosage form of the invention is administered in a dosage range of 0.1 mg to 1000 mg; More preferably an ASMase inhibitor, such as an SSRI, in a dose of about 1 mg to 500 mg and most preferably in a dose of about 5 mg to 100 mg. It is contemplated that a preferred dose is about 10 to 100 mg of SSRI formulated at 0.5 to 10% (w/w) composition. Dosage can vary, being lower for dosage forms that deliver the drug to the site more rapidly or higher for dosage forms that release the drug more slowly.

Tricyclic antidepressants (TCAs) useful in the methods or compositions of the invention include one or more of the following: amineptine, amitriptyline, amoxapine, butriptyline, clomipra. Clomipramine, desipramine, dibenzepin, dosulepin, doxepin (in combination, not alone), imipramine, iprindole, lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, opipramol, protriptyline, Tianeptine or trimipramine. A preferred TCA is amitriptyline. According to one preferred embodiment, the dosage form of the present invention is administered in a dosage range of 0.1 to 1000 mg; More preferably, it comprises amitriptyline in a dose of about 1 mg to 100 mg, most preferably in a dose of about 5 mg to 50 mg. A preferred dose is about 10 to 50 mg of TCA formulated at 1 to 5% (w/w) composition. Dosage can vary, being lower for dosage forms that deliver the drug to the site more rapidly or higher for dosage forms that release the drug more slowly.

More specifically, the method of the present invention includes the following steps:

- providing a topical composition comprising as an active ingredient a pharmaceutically effective amount of at least one FIASMA or a combination of two or more FIASMA drugs,

- Topically administering or applying an effective amount of the composition to a patient in need thereof, either before or after radiation therapy or both.

In a method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, reducing the severity of, or reversing radiation proctopathy, the method may include the following steps:

- administering a dosage form comprising a pharmaceutically effective amount of one or more active ingredients anorectally to a patient in need thereof, such as a patient undergoing radiation therapy of the pelvic region or a patient suffering from radiation proctopathy or proctitis, wherein at least one active ingredient is FIASMA.

In a method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of, or reversing oral mucositis or severe oral mucositis, the method may include the following steps:

- providing a solid oral dosage form comprising FIASMA as active ingredient, and

- administering a solid oral dosage form comprising a pharmaceutically effective amount of one or more active ingredients to a patient in need thereof, such as a patient undergoing radiotherapy for head and neck cancer, wherein at least one active ingredient is FIASMA.

In one embodiment, the solid oral dosage form is a modified release dosage form for sublingual administration comprising FIASMA as the active ingredient.

In another method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, reducing the severity of, or reversing oral mucositis or severe oral mucositis, the method may include the following steps:

■ providing a liquid oral dosage form or “rinse” comprising at least one FIASMA as an active ingredient as a solution, suspension or emulsion, and

■ Administering a liquid oral dosage form comprising a pharmaceutically effective amount of at least one FIASMA as the active ingredient in the liquid dosage form to a patient in need thereof, such as a patient undergoing radiation therapy for head and neck cancer.

Controlled release dosage forms for sublingual administration are known in the art and are known in the art to slow the dissolution of the dosage form, thereby prolonging the release of the drug over time, thereby maintaining the presence of the active drug in the oral cavity or increasing its residence time. You can do it. Such controlled release dosage forms may be tablets, capsules, lozenges, pastilles, troches or thin strips, etc., as will be recognized by those skilled in the pharmaceutical arts. Controlled release dosage forms for sublingual administration are also known to dissolve or disintegrate rapidly in the oral cavity, providing immediate administration of the active ingredient from the dosage form. Accordingly, “controlled release” is not limited to slowing dissolution, but can be “controlled” in such a way that it disintegrates rapidly in the mouth and dissolves faster than the standard dissolution rate for “immediate-release” solid dosage forms; , wherein “immediate release” generally refers to release in the stomach without significant delivery of the active agent prior to swallowing the dosage form.

It will be understood that applying or administering a composition prior to radiation therapy may include retention of the composition in place during a radiation therapy session. The method may be repeated for each radiation therapy session and may include administering or applying the composition at least once per week, several times per week, daily, or multiple times daily before, after or between radiation therapy sessions. You can. The method according to the subject invention may be continued after radiation treatment has been completed, for example, for 1 to 5 days after radiation treatment, for 1 to 3 weeks after radiation treatment, or for at least 1 month after radiation treatment. Typically, the method includes administering the composition about 1 week to about 1 month after the radiation therapy session has ceased.

Alternatively, methods according to the subject invention may comprise orally administering an effective amount of a composition comprising at least one FIASMA. These oral compositions may be in immediate or controlled release solid dosage forms. For diseases affecting the oral cavity, such as oral mucositis or severe oral mucositis, an oral dosage form that dissolves in the mouth and is not swallowed whole may be desirable.

In certain patients who suffer from damage to the salivary glands and do not produce adequate saliva to dissolve solid dosage forms in the oral cavity, a liquid oral dosage form comprising FIASMA as the active ingredient may be a preferred dosage form. These liquid oral dosage forms are also known as “rinses,” “mouth rinses,” “washes,” “mouthwashes,” or may be used as “sprays.” The preferred term used in this disclosure for liquid oral dosage forms is “rinse.” These liquid oral dosage forms will be understood to be in the form of liquid solutions, emulsions or suspensions and may contain thickening or gelling agents to increase the viscosity of the solutions, emulsions or suspensions.

In patients undergoing radiation therapy in the pelvic region, radiation proctopathy, a preferred method includes providing a solid suppository or rectal plug dosage form comprising a composition comprising FIASMA, and delivering the active ingredient to the site using the dosage form. It may include placing it in the rectal cavity for a period of time necessary.

The subject invention also includes at least one useful for preventing, reducing the incidence or recurrence of, treating, ameliorating, reducing the severity of, or reversing cutaneous radiation injury (CRI), including radiation dermatitis or radiation proctopathy. It relates to a topical pharmaceutical composition comprising a functional inhibitor of acid sphingomyelinase (FIASMA) as an active drug or active substance.

The invention may also include suppository dosage forms for use in preventing, reducing the incidence or recurrence of, treating, ameliorating, reducing the severity of, or reversing radiation proctopathy. Suppository dosage forms may comprise a soluble base and a TCA, such as amitriptyline, an SSRI such as sertraline, or a combination of one or more TCAs or SSRIs, and other pharmaceutical agents as are commonly used in suppository dosage forms. It may additionally contain acceptable excipients.

In the method of using a suppository or rectal plug delivery device for delivery of FIASMA to the anorectal cavity and orthotopic administration of the drug, the dosage form may be a controlled release dosage form provided with or incorporated into the rectal plug delivery device, which may include: It has one or more excipients capable of retarding the release of the active drug incorporated into the dosage form or coated on the outer surface of the dosage form or particles, granules or beads within the dosage form containing the active ingredient. Controlled release dosage forms may also be provided for oral administration, wherein the oral dosage form is a delayed release dosage form that bypasses the acidic environment in the stomach and releases the active ingredient in the intestinal tract where the pH is greater than 7.0. I get angry. Such controlled release dosage forms may be formulated using an enteric coating on tablets, provided in delayed release capsules or dragees, formulated in sustained release matrix compositions, or combinations of the above.

When the dosage form is a rectal plug delivery device, the device may be an insoluble plug defining a housing having an internal chamber to receive therein a pharmaceutical composition comprising FIASMA, which may be a TCA, an SSRI, or various combinations thereof. For example, the chamber of the rectal plug can be filled with a viscous composition comprising TCA or can contain a suppository dosage form comprising the TCA active ingredient.

Alternative embodiments of rectal plug delivery devices useful for carrying out the methods of the invention are injected with or coated with a composition comprising a TCA, such as amitriptyline, an SSRI, such as sertraline, or a combination thereof. It contains a porous compressible foam material. The devices described for the methods of the present invention may comprise an effective dose of FIASMA or a combination of FIASMA from about 0.1 mg to about 1000 mg or more.

Compositions according to the invention may also comprise two or more active pharmaceutical ingredients mixed together or formulated in a single fixed-dose composition, e.g. the composition may contain two or more different TCAs, two or more different SSRIs or one or more SSRIs. and one or more TCAs in combination with, etc.

Compositions for use in the methods of the invention may include about 0.1 to 1000 milligrams (mg) of one or more FIASMA. Topical compositions useful in accordance with the methods of the present invention may be provided as topical liquids, but are preferably formulated as topical creams, gels, lotions or ointments. One preferred FIASMA useful as an active ingredient in the compositions and methods of the present invention is the SSRI, sertraline. Another FIASMA useful as an active ingredient in the compositions and methods of the present invention is TCA, amitriptyline. Other FIASMA compounds may be substituted or provided in combination with the compositions or methods of the present invention.

Topical dosage forms may comprise conventional and commercially available pharmaceutical base compositions that are pharmaceutically compatible with one or more FIASMA used as one or more active ingredients and other agents as commonly used in topical or oral dosage forms. Additional scientifically acceptable excipients may be included. These commercially available pharmaceutical bases can act as a vehicle or medium for the active drug substance and are commonly used as emollients, penetration enhancers, solvents, gelling agents, thickening or viscosity enhancing agents, preservatives or in topical preparations. It may contain one or more of other suitable excipients.

Preferably, FIASMA for topical administration is provided in an immediate release topical formulation that allows targeted administration and immediate delivery of the drug from the composition to the skin upon application or administration of the composition. Retention of the FIASMA component at the site of administration or application may be desirable. Accordingly, the compositions of the present invention enable or promote penetration of the active substances into or under the skin, thereby maintaining the composition and active substances in the skin for a longer period of time compared to compositions containing penetration enhancers that can be absorbed systemically. Penetration enhancers may be excluded in order to remain on the surface. Alternatively, in certain instances, penetration enhancers may be desirable and may be used within the composition.

Oral dosage forms of the composition may be immediate-release, may be formulated with excipients such as polymers, gels, gums, waxes, etc., may be incorporated into a matrix, or may be used to slow the release of the active ingredient from the composition after oral administration. It may include a coating to delay, delay, sustain, or prolong it. For example, solid dosage forms for sublingual administration of FIASMA in the treatment of oral mucositis can be formulated to dissolve in the oral cavity, controlling, delaying, slowing, or prolonging the release of the drug from the dosage form; May contain prolonging excipients. Alternatively, solid oral dosage forms can be formulated to dissolve or disintegrate rapidly in the oral cavity, for example, when treating oral mucositis. One preferred dosage form for treating oral mucositis is a liquid oral solution, emulsion or suspension containing FIASMA, preferably formulated as a rinse containing an SSRI such as sertraline.

According to a further aspect of the invention, the dosage form may comprise a second active agent, such as a TCA or SSRI component, or may comprise a second active agent that is not a TCA or SSRI, for example, an active ingredient of a different class of drug. can do. In a preferred embodiment, the composition comprises a first active ingredient that is a TCA, and a second active ingredient that is a different TCA, an SSRI, or a class of compound other than a TCA. For example, the second active ingredient may be an antioxidant such as vitamin A, vitamin C, vitamin D or vitamin E. Preferably, the second active agent in the composition is not an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic, such as a local anesthetic, eg, lidocaine.

In another preferred embodiment, the compositions of the invention comprise a first active ingredient that is an SSRI, and a second active ingredient that is a different SSRI, a TCA, or a class of compound other than an SSRI. For example, the second active ingredient can be an antioxidant such as vitamin A, vitamin C, vitamin D, or vitamin E. Preferably, the second active agent in the composition is not an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic, such as a local anesthetic, eg, lidocaine.

Preferably, the method is performed using FIASMA formulated as a topical composition capable of delivering an effective amount to target areas of the skin that are directly or incidentally exposed to radiation during radiation therapy or treatment. For example, the active ingredient can be formulated as a liquid composition and administered as drops to the target area of the skin. Alternatively, FIASMA may be formulated in a composition containing a thickening agent or viscosity enhancing agent as a lotion, cream, ointment or gel for topical delivery of FIASMA to the target skin area of the patient. Topical formulations can be applied on or within target areas of the skin before or after radiation therapy.

In methods using solid oral dosage forms, the active ingredient may be provided as particles, granules or beads and manufactured in the form of tablets, capsules, dragees, etc., as will be readily understood in the art. Oral dosage forms may be presented, for example, as controlled release dosage forms, wherein the active ingredient is formulated in a sustained release dosage form, such as an enteric coated tablet, delayed release capsule or dragee, or in a sustained release matrix. It can be formulated into a composition.

In methods using liquid oral dosage forms, the active ingredient can be dissolved, emulsified, or suspended in a compatible and pharmaceutically acceptable carrier. Excipients or other inactive ingredients may be included to provide color, flavor, viscosity, and pleasant mouth-feel to promote patient compliance. Combinations of these dosage forms may also be used. A second active ingredient other than FIASMA may also be included. For example, a local anesthetic useful for reducing pain during and after treatment may be included, or an antiseptic, other anti-inflammatory or antimicrobial agent may also be included.

Accordingly, according to the present invention, a method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, reducing the severity of, or reversing skin radiation injury (CRI) includes prior to radiation treatment: During and after, FIASMA, such as TCA (e.g., amitriptyline), in an effective amount, e.g., from about 0.1% to about 10% w/w, of 0.5 to 50 ml or more, depending on the size of the area to be treated, or Topically administering a composition comprising an SSRI (e.g., sertraline) to a target area of the skin of a patient in need thereof at least once per day.

Methods of preventing, treating, or ameliorating radiation dermatitis also include administering an effective amount, e.g., from about 0.5% to about 10%, of 0.5 to 50 ml or more, depending on the size of the area to be treated, before, during, and after radiation treatment. % w/w of a composition comprising FIASMA, such as a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline), at least once per day to a target area of the skin of a patient in need thereof. It includes administering topically.

The method also includes administering an effective amount of FIASMA, such as TCA, of 0.5 to 50 ml or more, e.g., about 0.5% to about 5% w/w, before, during and after radiation treatment, depending on the size of the area to be treated. Radiation proctopathy is treated by topically administering or delivering a composition comprising (e.g., amitriptyline) or an SSRI (e.g., sertraline) to the target area of a patient in need thereof at least once daily. Includes preventing, treating, or improving.

A method of preventing, treating, or ameliorating oral mucositis includes administering an effective amount, e.g., about 0.5% to about 10%, of 0.5 to 50 ml or more, depending on the size of the area to be treated, before, during, and after radiation treatment. A composition comprising w/w FIASMA, such as a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline), is applied to a target area of the skin or mucosa within the oral cavity of a patient in need thereof for 1 day. It may include oral administration at least once each time. It will be understood that the term “oral mucositis” includes “severe oral mucositis”. A preferred treatment of oral mucositis may use a slowly dissolving adhesive tablet, such as a mucoadhesive tablet, an oral mouth rinse, or a dosage form comprising a thin oral wafer or film, wherein the dosage form is administered into the mouth, For example, placed sublingually or bucally, the dosage form may contain an active ASMase inhibitor, preferably about 1 to 50 mg, for release and delivery of the active agent to protect against oral mucositis, including severe oral mucositis (SOM). Sertraline is formulated to be released over a period of approximately 15 minutes up to 1 hour.

The topical composition used in the method may include 5 to 100 mg of amitriptyline per ml of composition, or 1 to 100 mg of sertraline per ml of composition, or 10 to 90 mg of sertraline per ml of composition. It may contain amitriptyline and 1 to 50 mg of sertraline per ml of the composition. Amitriptyline is preferably used in an amount of less than 40 mg per ml of composition, more preferably about 20 to 30 mg per ml of composition.

The topical composition may also include antioxidants such as vitamin A, vitamin C, vitamin D, and vitamin E.

Preferably, the compositions used in the methods of the invention are formulated as topical dosage forms that deliver an effective dose of the active ingredient orthotopically to the target area of the patient. This can be accomplished using compositions formulated with a pharmaceutically acceptable base to form a lotion, cream, ointment or gel for topical delivery of the active ingredient to the target area of the patient's skin. To treat oral mucositis, the composition may be formulated as an oral solution, emulsion, or suspension, referred to herein as a “rinse.”

Alternatively, the composition may include amitriptyline and a second tricyclic antidepressant other than amitriptyline, such as amineptine, amitriptyline, amoxapine, buttriptyline, clomipramine, desipramine, dibenzepine, dosulepine, doxepin (in combination, not alone), imipramine, iprindole, rofepramine, maprotiline, norclomipramine, nosiaden, nortriptyline, ofipramol, protriptyline, and tia May include neptin, or trimipramine.

Compositions comprising sertraline may include a second selective serotonin reuptake inhibitor other than sertraline, such as citalopram, escitalopram, fluoxetine, fluvoxamine, or paroxetine.

The pharmaceutical compositions of the invention may be presented as a topical pharmaceutical composition comprising an effective amount of one or more active ingredients, such as amitriptyline, sertraline, or a combination thereof, for delivery of the one or more active ingredients to a patient, or as a solid. or it may be a liquid oral dosage form. In a preferred embodiment, the topical compositions of the invention are free, do not contain, or exclude anti-inflammatory agents and anesthetic agents.

Preferred topical pharmaceutical compositions contain 10 to 20 mg of amitriptyline per ml of composition, or 1 to 100 mg of sertraline per ml of composition, or 15 to 20 mg of amitriptyline per ml of composition, and 1 to 20 mg of amitriptyline per ml of composition. Contains 10 mg sertraline. Any of the above may further include an effective amount of an antioxidant, such as vitamin A, vitamin C, vitamin D or vitamin E.

The oral dosage form of the present invention may be formulated as a rapidly dissolving oral dosage form or as a controlled release oral dosage form that is a sustained or delayed release dosage form.

It is understood that the methods and compositions and dosage forms of the present invention may be useful in preventing, treating, or ameliorating other skin conditions such as atopic dermatitis, thermal burns, sunburns, dermatophyto-fibroids, exposure-induced wrinkles, etc. It will be.

1 shows a perspective view of a rectal plug device having a protruding member and a flange member, wherein the protruding member has a pore and contains a soluble dosage form comprising at least one active ingredient, such as a TCA, SSRI, or a combination thereof. It includes a housing shown defining the boundaries of the chamber for receiving it.
Figure 2 shows a cross-section of the rectal plug of Figure 1 illustrating the dosage form placed within the chamber.
Figure 3 shows a perspective view of an alternative embodiment of the rectal plug of the invention comprising a porous compressible foam material impregnated with or coated with a composition comprising a TCA or an SSRI or a combination, shown in its expanded configuration after administration. It is done.
Figure 4 shows a perspective view of the porous compressible foam rectal plug of Figure 3 in its compressed configuration prior to administration.
Figure 5 shows the results of a test of skin damage after 30 Gy focal irradiation. Figure 5A is a summary of skin damage scores for individual mice up to 4 weeks after 30 Gy. Figure 5B is a graphical representation of the observed changes in radiation skin damage score over time. Data are presented as mean +/- SEM. N=5 mice per treatment group.
Figure 6 shows the results of a test of skin damage after 30 Gy focal irradiation. Figure 6A is a summary of skin damage scores for mice treated 3 times with 4% sertraline before irradiation, 2 times with 4% sertraline after irradiation, or 5 times with placebo before and after irradiation. Skin damage scores were tested weekly for up to 6 weeks after irradiation. Figures 6B-6D illustrate comparisons of skin damage scores over time between cohorts of mice that received different treatments. Data are presented as mean +/- SEM. N=5 mice per treatment group. ^* P less than 0.05 by two-way analysis of variance with Bonferroni post hoc test.
Figure 7 shows the percentage of patients treated with RAD-100 or the same vehicle during and after radiation therapy who recorded an RTOG score of 2 or greater.
Figure 8 shows the effect of 1% sertraline on irradiation-induced oral mucositis in mice.

The present invention provides groundbreaking methods for preventing, reducing the incidence or recurrence of, suppressing, treating, ameliorating, reducing the severity of, or reversing skin diseases in mammals, including humans, and providing treatment. The use of novel compositions or dosage forms may be employed to carry out the method. The methods and compositions of the present invention are useful for treating skin radiation damage, or CRI.

In the following, the terms "treat", "treating" or "treatment of" in relation to cutaneous radiation injury or "CRI", or a specific condition considered to be a type of CRI, refer to "preventing" CRI, "the incidence thereof" means or refers to any of the following: "reducing", "reducing its recurrence", "suppressing", "improving", "reducing its severity", "reversing" or "treating" Or, it can be replaced by this. The specific terms "preventing", "reducing its incidence", "reducing its recurrence", "suppressing", "ameliorating", "reducing its severity" or "reversing" CRI refer to treatment only. It may be used where it is intended to designate, or the term may be explicitly excluded from “treatment” when it is not intended to mean that term. For example, “reducing the incidence of” a method may be used to mean not only reducing the incidence of CRI, but also “suppressing” CRI. Alternatively, "a method of treating CRI that excludes reducing the occurrence of CRI" refers to a method of preventing, reducing the incidence of, suppressing, ameliorating, reducing the severity of, or reversing CRI. It can mean.

The term “cutaneous radiation injury” or “CRI” refers to or is derived from exposure to radiation from industrial or military-related sources, e.g., from nuclear power plants or from nuclear weapons, or from radioactive materials used in medical radiotherapy. It is accepted in the medical field that it is defined as damage to the skin or underlying tissue in animals, including mammals and humans, that results in damage to the skin or underlying tissue. Accordingly, the term CRI may include skin diseases observed after medical radiation therapy, such as radiation dermatitis or radiation proctopathy. Mild skin injuries, such as sunburns from overexposure to sunlight, are generally not considered to fall within the definition of CRI.

“Radiation dermatitis” refers to a disorder of the skin that results from radiation therapy to an area of the body. For example, radiation therapy is a known and accepted treatment for cancerous breast tissue in women and men. Inflammation of irradiated skin overlying the targeted cancerous tissue can result in damage to the skin. These signs and symptoms are known as radiation dermatitis. The term is used herein as it is clinically understood by dermatologists and other physicians who treat these disorders.

“Radiation proctopathy” or its synonym, “radiation proctitis”, refers to a disorder of the rectum that results from radiation therapy to the pelvic region and causes alterations in rectal function, including inflammation of the lining of the rectum. Radiation therapy of the pelvic region is a known and accepted treatment procedure for cancers of the genitourinary tissue, for example to treat prostate cancer in men or cervical cancer in women. The term is used herein as it is clinically understood by physicians treating these disorders.

“Oral mucositis” refers to a condition resulting from radiation therapy used to treat head and neck cancer. The more serious condition, aptly named "severe oral mucositis" or "SOM," is often associated with ulcerated tissue in the mouth or may be associated with the patient's inability to swallow food or drink. Oral mucositis is a common, debilitating complication of cancer treatment, especially radiation. This can cause several problems, including pain, nutritional problems as a result of the inability to eat, and an increased risk of infection due to open ulcers on the oral mucosa. Use of the term “oral mucositis” herein includes “severe oral mucositis,” and these terms may be used interchangeably.

“Emulsion” is a general term encompassing macroemulsions, microemulsions or nanoemulsions. Macroemulsions are dynamically stable dispersions of immiscible liquids. Microemulsions are dynamically stable as well as thermodynamically stable dispersions of immiscible liquids with droplet sizes in the micrometer size range. Nanoemulsions are dynamically stable and thermodynamically stable dispersions of immiscible liquids with droplet sizes ranging from about 20 nm to about 200 nm.

One embodiment of the present invention relates to a method of treating cutaneous radiation injury (CRI) by administering an effective amount or dosage of a functional inhibitor of acid sphingomyelinase (FIASMA). Examples of FIASMAs include certain selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, antipsychotics, antidiarrheals, adrenergic receptor blockers (ARBs), beta blockers, and estrogen receptor modulators. do.

Examples of SSRIs useful in accordance with the subject invention are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Preferred SSRIs useful in accordance with the subject invention include fluoxetine, fluvoxamine, paroxetine and sertraline.

Examples of TCAs useful according to the subject invention include amineptine, amitriptyline, amoxapine, buttriptyline, clomipramine, desipramine, dibenzepine, dosulepine, doxepin (in combination, not alone), imipra. These are min, iprindole, lofepramine, maprotiline, norclomipramine, nosiaden, nortriptyline, opipramol, protriptyline, tianeptine and trimipramine. Preferred TCAs useful in accordance with the subject invention are amitriptyline, desipramine and imipramine.

The present invention includes the use of at least one FIASMA, such as a TCA or an SSRI, and may include the use of at least two different FIASMAs from the same class of drugs or at least two different FIASMAs from different classes of drugs. there is. For example, the subject invention provides treatment of CRI using at least two TCAs, at least one TCA and at least one SSRI, or at least one TCA or SSRI and at least one additional active ingredient that is not a TCA or SSRI. It can be included.

The preferred TCA for use according to the subject invention is amitriptyline. Amitriptyline, marketed in the United States under the brand name ELAVIL ^® (AstraZeneca PLC, Cambridge, United Kingdom), is primarily used to treat major depressive disorder, anxiety disorders, and, less commonly, attention deficit hyperactivity disorder (ADHD) and bipolar disorder. It is used to treat a number of mental illnesses, including: Other uses include the prevention of migraines, the treatment of neuropathic pain such as fibromyalgia and postherpetic neuralgia and, less commonly, insomnia.

A preferred SSRI for use according to the subject invention is sertraline. Sertraline, marketed in the United States under the trade name Zoloft ^® (Pfizer, New York, NY, USA), is primarily used to treat depression, panic attacks, obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety disorder (social phobia). and to treat severe forms of premenstrual syndrome (premenstrual dysphoric disorder).

Amitriptyline and sertraline are not previously known to be useful in the prevention or treatment of radiation dermatitis.

In a preferred embodiment, at least one FIASMA can be incorporated into a topical pharmaceutical composition for administration by placement or application on the surface of the skin or mucous membranes for the prevention, amelioration or treatment of skin diseases or disorders, such as radiation dermatitis. The composition may be administered once daily or more or less frequently as prescribed by the patient's physician or health care provider.

Topical compositions or preparations as dosage forms are well known in the art and are commonly used in medical treatment. A preferred embodiment according to the subject invention is the incorporation of FIASMA into a pharmaceutically compatible base composition for preparing topical lotions, creams, gels or ointments comprising at least one FIASMA as active pharmaceutical ingredient (API) or agent. . Another embodiment of the invention is a pharmaceutically compatible combination of at least two different FIASMAs, e.g., at least one TCA and at least one SSRI, as active agents to prepare topical lotions, creams, gels or ointments. Including incorporation into the base composition. A preferred embodiment comprises one or more active ingredients thoroughly mixed into a pharmaceutically acceptable base to provide a homogeneous mixture. For active ingredients that are incompletely solubilized in the base, a suspension may be formed, wherein the suspension comprises the active ingredients thoroughly mixed so as to distribute the active agent uniformly throughout the base. Compositions of the invention may include other pharmaceutically acceptable excipients such as those commonly used in topical dosage forms.

In another embodiment of the invention, the active ingredients, such as one or more TCAs or SSRIs, can be formulated for oral administration. In one embodiment, the oral dosage is a solid oral dosage form provided as an immediate release dosage form. In one embodiment, the solid oral dosage form is provided as a controlled release dosage form. Another oral dosage form is a liquid oral dosage form containing an effective amount of FIASMA, such as an SSRI, sertraline. These liquid oral dosage forms are known as “rinses,” “washes,” “mouthwashes,” or “sprays.” The preferred term used in this disclosure for liquid oral dosage forms is “rinse.” These liquid oral dosage forms will be understood to be in the form of liquid solutions, emulsions or suspensions and may contain thickening or gelling agents to increase the viscosity of the solutions, emulsions or suspensions.

In one embodiment, the solid oral dosage form provided for sublingual or buccal administration of the invention is a pharmaceutical composition in unit dosage form (e.g., lozenges, pills, tablets, films, or strips) comprising at least one FIASMA. The composition comprises a composition, and in a preferred embodiment is prepared as a controlled release dosage form. Regarding the size of the unit dosage form, eg lozenges, simplicity and production costs as well as consumer preferences will also be taken into consideration. The size of the sublingual or buccal dosage form can vary from approximately 5 mm to 20 mm, or approximately 5 mm to 18 mm, or approximately 7 mm to 18 mm, or approximately 10 mm to 15 mm. If the sublingual or buccal dosage form has a round or nearly round shape, the size range is a suitable diameter value. The thickness of the lozenges will in most cases be between 1 mm and 10 mm, more typically between 3 mm and 5 mm.

Sublingual or buccal dosage forms may be in the form of a single layer, double layer, or multilayer. Sublingual or buccal dosage forms with soluble mucoadhesive properties can be prepared by compressing a powder containing a mucoadhesive hydrocolloid. As an example, adhesive pastilles can be prepared by mixing a dry powder comprising gum arabic for adhesive properties and at least one FIASMA as an active ingredient. Residence time in the oral cavity for sublingual or buccal dosage forms can be optimized depending on the dissolution rate and total dissolution time for the product. For example, sublingual or buccal controlled release lozenges, mucoadhesive tablets or films may be prepared to have a residence time in the oral cavity of at least 1 minute, preferably 1 to 30 minutes, more preferably 5 to 15 minutes. You can.

In one aspect of the invention, the sublingual or buccal dosage form is a mucoadhesive tablet. Mucoadhesive tablets for sublingual or buccal administration can be prepared by compressing at least one mucoadhesive polymer to impart mucoadhesive properties and at least one FIASMA as the active ingredient. The mucoadhesive polymer may be one or more selected from the group consisting of cellulose polymers, rubber-type polymers, nonionic polymers, anionic polymers, derivatives thereof, mixtures thereof, etc. The cellulose-based polymer may be hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylethyl cellulose, carboxymethyl cellulose, carboxypropyl cellulose, mixtures thereof, etc. The rubber-type polymer may be xanthan rubber, carrageenan rubber, Karayan rubber, etc. The nonionic polymer may be polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer, polyethylene oxide, etc. Anionic polymers include polyacrylic acid, Carbopol ^® polymer and neutralized polymers thereof, other polyalkylvinylether-maleic acid copolymers (trade name: Gantrez), polyalginic acids and salts thereof, chitosan, hyaluronic acid and derivatives thereof, etc. You can.

Mucoadhesive tablets may have a backing layer to slow the rate of disappearance of the dosage form from the oral cavity by reducing the rate of penetration of saliva. The backing layer may consist of at least one water-insoluble polymer, at least one wax, or a combination thereof. Water-insoluble polymers include: polyvinylacetate; ethyl cellulose; propyl cellulose; polymethyl methacrylate; Methacrylic acid copolymers, such as methacryloylethyl betaine / methacrylate copolymer, methacrylic copolymer (methacrylic acid copolymer; Eudragit L 100, Eudragit L 12,5, Eudragit L Drazit L 100-55, Eudragit L 30D-55), aminoalkyl methacrylate copolymers; Eudragit E 100, Eudragit E 12,5, Eudragit RL 100, Eudragit RL 30D), cellulose acetate phthalate and mixtures thereof. Waxes may include: carnauba wax, yellow wax and white wax, etc. Additionally, any polymer that does not melt at oral conditions of pH 6 to 8 may also be useful as a backing layer.

In another aspect, the invention features a pharmaceutical composition in unit dosage form formulated for oral administration, such as sublingual or buccal administration, wherein the unit dosage form comprises 5 to 100 mg of FIASMA (e.g. , dosage forms are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. mg, 85 mg, 90 mg, 95 mg, 100 mg or more of sertraline). Alternatively, the oral dosage form may be a liquid dosage form comprising from about 1% to about 10% (w/w) FIASMA, e.g., an SSRI, such as sertraline, in a pharmaceutically acceptable and compatible carrier. For example, it may be an oral solution, emulsion or suspension. A preferred oral solution contains 10% sertraline. Controlled release oral dosage forms include delayed release dosage forms produced by coating a solid dosage form with a polymer film that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

The composition of the present invention may contain conventional additives or other excipients such as plasticizers, pigments, colorants, stabilizers, glidants, etc.

In one embodiment, FIASMA is provided in an oral dosage form as a controlled release dosage form allowing delivery of the drug over a period of time compared to an immediate release dosage form which provides delivery of all drug from the dosage form as soon as administered. . Controlled release formulations known in the art include coatings formulated with an active agent, such as enteric coated tablets, beads or pellets, ion exchange resins, waxes, alginates, gelling agents such as cellulose hydrogels (e.g., hydroxyl propyl methyl cellulose or HPMC) or polymeric acrylamide (e.g. ^Carbopol® ), and the use of suitable vehicles.

The present invention provides a method for preventing, improving or treating CRI by administering FIASMA. The method includes providing a composition comprising about 0.001 to 100 grams of the active ingredient and formulating the drug directly on the skin as a topical composition, such as a cream or lotion or ointment, or in an oral dosage form to administer to a patient in need thereof. It includes the step of delivering it to the patient.

According to one preferred embodiment, the FIASMA contained in the topical dosage form is administered as a topical composition at about 0.5% to about 10% w/w, in a dosage of 1 to 1000 mg; More preferably amitriptyline is provided in a dosage of about 5 mg to 150 mg, most preferably in a dosage of about 10 to 100 mg. For example, compositions comprising 1% to 10% active ingredient (10 to 100 mg of active ingredient per ml of composition) may be administered in amounts of about 0.5 ml to about 5 ml or more per topical application depending on the size of the area to be treated. may be administered. Preferably, the composition is administered topically in an amount of about 1 ml to about 2 ml to deliver 10 to 100 mg of active ingredient to the skin to prevent or treat CRI.

In another preferred embodiment, FIASMA contained in a topical dosage form is administered as a topical composition from about 0.1% to about 10% w/w, in a dosage of 1 to 1000 mg; More preferably sertraline is provided in a dosage of about 5 mg to 150 mg, most preferably in a dosage of about 10 to 100 mg. For example, compositions comprising 0.1% to 1% active ingredient (1 to 10 mg of active ingredient per ml of composition) may be administered in amounts of about 0.5 ml to about 5 ml or more per topical application depending on the size of the area to be treated. may be administered. Preferably, the composition is administered topically in an amount of about 1 ml to about 2 ml to deliver 1 to 10 mg of active ingredient to the skin to prevent or treat CRI.

One preferred dose is to administer at least 1 ml of a composition comprising 1% FIASMA as active ingredient according to the subject invention. Another preferred dose is to administer at least 1 ml of a 2% w/w composition comprising the FIASMA active ingredient according to the subject invention. Another preferred dose is to administer at least 1 ml of a 3% w/w composition comprising the FIASMA active ingredient according to the subject invention. Another preferred dose is to administer at least 1 ml of a 4% w/w composition comprising the FIASMA active ingredient according to the subject invention. A further preferred dose is to administer at least 1 ml of a 5% w/w composition comprising the FIASMA active ingredient according to the subject invention. A preferred dose may comprise the administration of at least 1 ml of a composition comprising more than 6%, 7%, 8%, 9%, 10% or 10% w/w of the FIASMA active ingredient according to the subject invention.

It will be appreciated that the concentration of drug may be provided in incremental increases of about 0.1%. As a non-limiting example, FIASMA may be provided in concentrations of 1.1%, 1.2%, 1.3%, etc. up to 10% as desired to achieve the intended effect without negative side effects.

The dosage contained within the dosage form may vary, being lower for dosage forms that deliver the drug to the site more rapidly or higher for dosage forms that release the drug more slowly to the site. Dosage variations may also vary depending on the active ingredient or ingredients contained in the composition. For example, a composition comprising more than one FIASMA comprises less than 10% of each active agent, such as 0.1% to 9.9%, preferably about 0.5% to about 5% of each active agent, and thus the final The composition may comprise from about 1% to less than 10% of the total active ingredients in the composition. This may advantageously lower the dose of each active ingredient administered to the patient, while providing an equivalent or substantially equivalent prophylactic or therapeutic effect. It is also contemplated that a fixed dose combination product comprising at least one TCA and at least one SSRI may provide a synergistic effect, wherein the efficacy is greater than the additive effect expected from each active ingredient used alone. big.

Preferably, FIASMA for topical administration is provided in an immediate release topical formulation that allows targeted administration and immediate delivery of the drug from the composition to the skin upon application or administration of the composition. Retention of the FIASMA component at the site of administration or application may be desirable. Accordingly, the compositions of the present invention enable or promote penetration of the active substances into or under the skin, thereby maintaining the composition and active substances in the skin for a longer period of time compared to compositions containing penetration enhancers that can be absorbed systemically. Penetration enhancers may be excluded in order to remain on the surface. Alternatively, in certain instances, penetration enhancers may be desirable and may be used within the composition.

In a further aspect of the invention, the dosage form may comprise a second active agent, such as a TCA or SSRI component, or may comprise a second active agent that is not a TCA or SSRI, e.g., the second active agent may be of a different class. It is the active ingredient of the drug. In a preferred embodiment, the composition comprises a first active ingredient that is a TCA and a second active ingredient that is a different TCA, is an SSRI, or is a class of compound other than a TCA. For example, the second active ingredient may be an antioxidant such as vitamin A, vitamin C, vitamin D or vitamin E. Preferably, the second active agent in the composition is not an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic, such as a local anesthetic, eg, lidocaine.

In another preferred embodiment, the compositions of the invention comprise a first active ingredient that is an SSRI and a second active ingredient that is a different SSRI, is a TCA, or is a class of compound other than an SSRI. For example, the second active ingredient may be an antioxidant such as vitamin A, vitamin C, vitamin D or vitamin E. Preferably, the second active agent in the composition is not an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic, such as a local anesthetic, eg, lidocaine.

Topical dosage forms may comprise conventional and commercially available pharmaceutical base compositions that are pharmaceutically compatible with one or more FIASMA used as one or more active ingredients and other as commonly used in topical or oral dosage forms. Pharmaceutically acceptable excipients may be additionally included. These commercially available pharmaceutical bases can serve as a vehicle or medium for the active drug substance, and may also contain emollients, penetration enhancers, solvents, gelling agents, thickening or viscosity enhancing agents, preservatives or other suitable excipients commonly used in topical preparations. It may include one or more of the following. In one embodiment, the commercially available pharmaceutical base is PENCream, an oil-in-water vanishing base available from Humco™.

Topical compositions comprising FIASMA useful in accordance with the subject invention may be formulated as commonly known in the pharmaceutical art and may contain one or more additional ingredients or excipients, such as at least one preservative, at least one solvent, at least one thickener. , at least one surfactant, at least one curing agent, at least one emulsifier, at least one antitack agent, mixtures thereof, etc.

Preservatives for topical compositions may include phenoxy-2 ethanol, Alcohol benzylique Improve, etc. Solvents for topical compositions may include glycerin, propanediol-1,2, etc. Thickening agents for topical compositions may include Carpool ETD 2020, xanthan gum, etc. Surfactants for topical compositions may include Brij S721, SP-Brij S2-MBAL, etc. Curing agents for topical compositions may include hydrogenated oils such as Kolliwax HCO and the like. Emulsifiers for topical compositions may include Miglyol 812 N and the like. Anti-tack agents for topical compositions may include Q7-9120 Silicone Fluid, etc.

The present invention provides a method of treating anorectal disorders by orthotopic administration of an active pharmaceutical ingredient of the invention, such as a TCA, such as amitriptyline, an SSRI, such as sertraline, or a combination thereof. The method includes providing a composition comprising about 0.001 to 100 grams of the active ingredient and delivering the drug formulated as a topical composition, such as a cream or ointment, or in a suppository or rectal plug dosage form, directly to the anorectal region. Includes steps. According to a preferred embodiment, the TCA contained in the suppository or rectal plug dosage form is administered in a dosage of 1 to 1000 milligrams (mg); More preferably, it is amitriptyline in a dosage of about 5 mg to 150 mg, most preferably in a dosage of about 10 to 100 mg, with one preferred dosage being a suppository or other dosage form containing about 50 mg. In another preferred embodiment, the SSRI contained in a suppository or rectal plug dosage form is administered in a dosage of 1 to 1000 milligrams (mg); More preferably, it is sertraline in a dosage of about 5 mg to 150 mg, most preferably in a dosage of about 10 to 100 mg, with one preferred dosage being a suppository or other dosage form containing about 100 mg. The dosage contained within the suppository or rectal plug may vary, being lower for dosage forms that deliver the drug to the area more rapidly or higher for dosage forms that release the drug more slowly to the area. Additionally, when two or more active pharmaceutical ingredients are provided in a fixed dose combination suppository product, the respective doses of the active ingredients within the dosage form can be reduced, thereby advantageously lowering the risk or incidence of side effects.

Preferably, the method comprises providing a solid suppository or rectal plug dosage form comprising a composition having a TCA or SSRI as an active ingredient and placing the dosage form in the rectal cavity for a period of time necessary for delivery of the active ingredient to the site. It includes steps to: The composition provided within the rectal plug delivery device may be a suppository.

Alternatively, the drug can be delivered using a rectal delivery device, such as a rectal plug, containing an effective dose of the active ingredient, such as FIASMA or a combination of more than one FIASMA. In one embodiment of the rectal plug device according to the invention, the plug device comprises an insoluble porous housing forming a chamber for containing the active ingredient. The active ingredient may be provided as a dissolvable suppository disposed within a chamber portion formed within a porous rectal plug housing. Suppositories are exposed to body fluids when administered, causing dissolution and orthotopic delivery of the active ingredient from the suppository. In a preferred embodiment, the suppository is formulated as a controlled release dosage form. Alternatively, the active ingredient may be formulated as a viscous, controlled release gel, ointment or cream to fill the chamber within the rectal plug housing.

Different types of rectal plugs are known and can be adapted for use according to the subject invention. For example, rectal plugs formed from porous sponge-like polymeric materials such as polyurethane foam are known for use in fecal incontinence. This rectal plug is marketed under the designation PERISTEEN™ Anal Plug (Coloplast Corp., North Minneapolis, MN). The polyurethane foam can be impregnated with a solution containing an effective amount of FIASMA that can be absorbed onto the material for delivery when inserted into the rectal cavity. These commercially available rectal plugs are generally provided in a compressed structure for ease of insertion, wrapped with a water-soluble film that dissolves after insertion, and can be expanded into an elongated structure. Such compression and expansion are not necessary for orthotopic delivery of the drug according to the subject invention.

1 and 2 illustrate an example of a rectal plug delivery device for use in accordance with the present invention. Figure 1 shows a rectal plug delivery device 100 comprising an elongated member 101 forming the proximal end of the device, which is inserted into the rectal cavity and remains therein during delivery of the active ingredient. The rectal plug delivery device may include a distal flange 102 that prevents the entire rectal plug delivery device from being absorbed into the rectal cavity, thereby maintaining the rectal plug device in place during administration of the active ingredient. The active ingredient, such as a TCA or SSRI, can be provided as a pharmaceutical composition contained within a cavity (not shown) formed within the elongated member. The proximal end of the elongated member 101 includes pores 103 that allow body fluids to enter the cavity formed within the elongated member and allow escape of the active ingredient from the composition contained within the elongated member. The rectal plug delivery device may have an extension piece connected to a distal flange, such as a strap or string, to facilitate removal of the rectal plug delivery device, functionally similar to removal of a tampon.

Figure 2 shows a cross-sectional view of the rectal plug delivery device 100 of Figure 1, illustrating a cavity formed within the proximal end of the elongated member 101, which may contain a composition 104 comprising an active pharmaceutical ingredient. . As illustrated, the composition can be formed as a suppository that dissolves or melts when administered into the rectal cavity. Alternatively, the composition may be an amorphous or amorphous composition including a gel, cream or ointment. Preferably, the composition is provided as a controlled release composition, preferably an extended release composition, which releases the active ingredient from the composition over time.

In another embodiment, the dosage form comprises an anal plug comprising a soft, compressible, porous material (e.g., foam rubber or a polymer sponge-like material), wherein the active ingredient is a porous, compressible plug material. It is infiltrated or injected into, or coated on. This implementation is illustrated in Figures 3 and 4.

Figure 3 shows a rectal plug delivery device 200 comprising a soft, compressible, porous material in an expanded structure. The rectal plug delivery device 200 includes at its proximal end a drug delivery component 201 that expands when inserted into the rectal cavity and conforms to the shape of the rectal cavity. An extension piece 202, such as a strap or string, connects to the drug delivery component to facilitate removal of the rectal plug delivery device, functionally similar to removal of a tampon.

The composition comprising the active ingredient according to the invention can be injected or impregnated into the porous material forming delivery component 201 as a liquid or gel, cream or ointment. Compositions comprising the active ingredient may be presented as controlled release compositions that release the active ingredient over time, preferably extended release compositions.

Figure 4 shows the rectal plug delivery device 200 of Figure 3, wherein the drug delivery component 201 is provided in compressed form for ease of insertion into the rectal cavity. The compressed drug delivery component 201 may include a water-soluble wrapper surrounding the drug delivery component 201. After insertion of the rectal plug delivery device embodiment 200 into the rectal cavity, body fluids dissolve the wrapper and cause the drug delivery component 201 to expand into its expanded structure as shown in FIG. 3 . Figure 4 further shows an extension piece 202, which may be a strap or strip, to facilitate removal of the rectal plug delivery device.

Preferably, the active ingredient is provided in a controlled release dosage form allowing delivery of the drug over a period of time compared to an immediate release dosage form which provides delivery of all drug from the dosage form as soon as administered. Controlled release formulations known in the art include coatings formulated with an active agent, such as enteric coated tablets, beads or pellets, ion exchange resins, waxes, alginates, gelling agents such as cellulose hydrogels (e.g., hydroxyl propyl methyl cellulose or HPMC) or polymeric acrylamide (e.g. ^Carbopol® ), and a suitable vehicle that melts or dissolves in the rectal fluid. Methods for making such formulations and compositions, as well as suppositories or other controlled release compositions, are well known in the art.

In the method according to the invention, the treatment of CRI, such as radiation dermatitis, is carried out with at least one FIASMA, such as TCA, e.g. amitriptyline and/or at least one second FIASMA, such as SSRI, e.g. sertraline. Use a composition containing. Compositions used in the methods of the invention may be provided in topical dosage form. The subject invention also provides methods for treating, ameliorating or preventing a skin disorder or disease, such as radiation dermatitis, using an oral dosage form comprising at least one TCA, such as amitriptyline, and/or at least one SSRI, such as sertraline. Includes.

Preferably, the method comprises providing a topical dosage form comprising a composition having at least one FIASMA as an active ingredient in the composition and targeting an effective amount of the composition to the skin to be treated for a period of time necessary for delivery of the active ingredient to the area. It includes placing on the site. In a preferred embodiment, the active ingredient or ingredients may be formulated as a viscous, controlled release gel, ointment or cream for administration to the skin. Topical compositions of the present invention preferably range from about 0.1% strength (1 mg/ml of composition) up to about 10% strength (100 mg/ml of composition); For example, 0.1%. Available in 0.2%, 0.3%, 0.4%, .05%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% and 1.1%, 1.2%, 1.3%, in 0.1% increments up to approximately 10.0%. Contains each active ingredient. Typical doses are about 0.5 ml to about 2 ml, preferably about 1 ml, but are not so limited, limited to only the area of skin that needs to be treated, such that a dose of 5 ml or more can be applied. Topical formulations can be applied on or within target areas of the skin before or after radiation therapy.

Preferably, FIASMA for topical administration is provided in an immediate release topical formulation that allows targeted administration and immediate delivery of the drug from the composition to the skin upon application or administration of the composition. Retention of the FIASMA component at the site of administration or application may be desirable. Accordingly, the compositions of the present invention enable or promote penetration of the active substances into or under the skin, thereby maintaining the composition and active substances in the skin for a longer period of time compared to compositions containing penetration enhancers that can be absorbed systemically. Penetration enhancers may be excluded in order to remain on the surface.

Alternatively, in certain instances, penetration enhancers may be desirable and may be used within the composition.

It will be appreciated that applying or administering a composition prior to radiation therapy may include retention of the composition in place during a radiation therapy session. The method may be repeated for each radiation therapy session and may include administering or applying the composition at least once per week, several times per week, daily, or multiple times daily before, after or between radiation therapy sessions. You can. The method according to the subject invention may be continued for up to 1 month or up to 1 week after the radiotherapy session has been discontinued. In an alternative embodiment, the method according to the subject matter may be continued for one week after the radiotherapy session has been discontinued.

According to one embodiment of the present invention, the method of the present invention includes the following steps:

Patients in need of an effective dose of one or more active ingredients, i.e. FIASMA, such as those suffering from CRI after exposure to environmental radiation or who will undergo or are undergoing medical radiotherapy and who have radiation dermatitis or radiation rectum. Step of topically administering to the skin of a patient suffering from a disease.

In the method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, reducing the severity of, or reversing oral mucositis or severe oral mucositis, the method may include the following steps: there is:

- providing a solid oral dosage form comprising FIASMA as active ingredient, and

- administering a controlled release sublingual dosage form comprising a pharmaceutically effective amount of one or more active ingredients to a patient in need thereof, such as a patient undergoing radiation therapy for head and neck cancer, wherein at least one active ingredient is FIASMA. step.

In one embodiment, the solid oral dosage form is a modified release dosage form for sublingual administration comprising FIASMA as the active ingredient.

In another method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, reducing the severity of, or reversing oral mucositis or severe oral mucositis, the method comprising the steps of: can do:

- providing a solid oral dosage form comprising FIASMA as active ingredient, and

- administering to a patient in need thereof, such as a patient undergoing radiation therapy for head and neck cancer, a controlled release buccal dosage form comprising a pharmaceutically effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA. step.

In one embodiment, the solid oral dosage form is a modified release dosage form for buccal administration comprising FIASMA as the active ingredient.

In another method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, reducing the severity of, or reversing oral mucositis or severe oral mucositis, the method comprising the steps of: can do:

- providing a liquid oral dosage form or “rinse” comprising FIASMA as the active ingredient, and

- administering an oral rinse dosage form comprising a pharmaceutically effective amount of one or more active ingredients to a patient in need thereof, such as a patient undergoing radiation therapy for head and neck cancer, wherein at least one active ingredient is FIASMA. .

In the method of treating radiation proctopathy, the method of the present invention includes the following steps:

An effective dose of at least one FIASMA drug as an active ingredient, preferably a class of drugs selected from TCAs, SSRIs or combinations thereof, is administered to patients in need thereof, such as patients suffering from radiation proctopathy or proctitis resulting from medical radiation therapy. Anorectal administration into the rectal cavity or rectal tissue.

A preferred method of treating radiation proctopathy involves anorectally administering an effective dose of FIASMA, such as TCA, amitriptyline or an SSRI, sertraline, as the active ingredient. Compositions comprising a fixed dose combination of two or more different FIASMA or one or more FIASMA and non-FIASMA active ingredients may also be used. In a preferred embodiment, the method is performed using amitriptyline, formulated as a composition and provided in a dosage form capable of delivering an effective dose orthotopically to the patient's rectal cavity. For example, amitriptyline can be formulated as a liquid and administered as an enema, or formulated with a thickening agent or viscosity enhancing agent, such as a lotion for topical delivery of amitriptyline to the anorectal region and rectal cavity of the patient; Creams, ointments, or gels may be given.

Alternatively, the method may use semi-solid or solid dosage forms, such as suppositories or rectal plug delivery devices, for orthotopic administration of the drug and delivery of the active pharmaceutical ingredient to the anorectal cavity. Preferably, the dosage form provided with or incorporated into the rectal plug delivery device is of a controlled release type having excipients capable of delaying or delaying the release of the active drug incorporated into the dosage form or coated on the outer surface of the dosage form. It's a formulation.

When the dosage form is a rectal plug delivery device, the device may be an insoluble plug forming a housing with an internal chamber to contain therein a composition comprising the active pharmaceutical ingredient according to the invention. For example, the chamber of the rectal plug can be filled with a viscous composition comprising the active ingredient FIASMA, or can comprise a suppository dosage form comprising FIASMA as the active ingredient.

An alternative embodiment of a rectal plug delivery device useful for carrying out the method of the invention comprises a porous compressible foam material impregnated with, or coated with, a composition comprising an active pharmaceutical ingredient according to the subject invention. The devices described for the methods of the invention may include an effective dose of FIASMA provided in an amount from about 0.1 mg to about 1000 mg or more.

The methods of the invention may further comprise the administration of at least one active ingredient, and an additional or second active ingredient other than FIASMA, to a patient in need thereof. Preferably, the additional active agent is formulated with at least one TCA, at least one SSRI, or a combination of a TCA and an SSRI in a fixed-dose combination drug product.

One preferred embodiment of the composition has the first and second active agents comprising a TCA or SSRI and an anti-inflammatory, anesthetic or antioxidant agent. Anti-inflammatory agents may be steroids or non-steroidal anti-inflammatory drugs (NSAIDs). Alternatively, the second active agent in the composition is not an anti-inflammatory agent, the composition excludes steroid compounds, or the composition excludes non-steroidal anti-inflammatory drugs (NSAIDs). The anesthetic agent may be a local anesthetic commonly used for topical administration, such as lidocaine. Antioxidants can be, for example, vitamin A, vitamin C, vitamin D and vitamin E.

The subject invention includes a composition for the treatment of radiation proctopathy comprising providing an effective amount of FIASMA formulated as a controlled release dosage form for orthotopic delivery of the active ingredient to the rectal cavity. In a preferred embodiment, the composition may be formulated as a controlled release suppository containing as active ingredient or ingredients at least one TCA or at least one SSRI, or at least one TCA and one SSRI. The composition may include additional drugs other than FIASMA as described herein.

The active pharmaceutical ingredient contained in a suppository or rectal delivery device can be administered before, during, or after pelvic radiation therapy. Preferred administration involves inserting the suppository or rectal delivery device into the rectal cavity and allowing the suppository or rectal delivery device to remain within the rectal cavity until delivery of the entire dose is complete. Preferred suppositories according to the invention dissolve slowly and can be maintained for a period of up to about 24 hours, i.e. for daily use. The rectal plug delivery device can be maintained in the rectal cavity for a period of up to about 48 hours, but preferably contains a drug formulation that delivers a dose of the active ingredient or ingredients within about 24 hours. This allows daily use after defecation. Alternatively, the rectal plug can be temporarily removed for defecation and reinserted.

Suppositories containing the active pharmaceutical ingredient are placed to remain in the rectal cavity for the period necessary for dissolution. Because the suppository is completely dissolvable, release of the active ingredient from the suppository will be achieved after retention of the suppository in the rectum. The released active ingredient will be present in high concentration at the site of delivery, thereby enhancing the effectiveness of this therapy for anorectal disorders.

It will be understood that applying or administering a composition prior to radiation therapy may include retention of the composition in place during a radiation therapy session. The method may be repeated for each radiation therapy session and may include administering or applying the composition at least once per week, several times per week, daily, or multiple times daily before, after or between radiation therapy sessions. You can. The method according to the subject invention may be continued for up to 1 month or up to 1 week after the radiotherapy session has been discontinued. In an alternative embodiment, the method according to the subject matter may be continued for one week after the radiotherapy session has been discontinued.

According to alternative embodiments, the suppositories may contain or consist of other drugs or supplements, such as vitamin E and vitamin C, and natural antioxidants, such as fish oil, green tea, cranberry, etc. They can be used as separate suppository preparations or as additional components of the suppositories of the invention.

In these uses and optional embodiments of the invention, suppository forms of these agents are used as clinical treatment for chronic diseases of the anus and rectum.

Any form of the active ingredient contemplated by the invention, which is disposed in suppository form for the treatment of anorectal diseases, is within the scope of the invention. Also contemplated within the present invention is the incorporation of the active pharmaceutical ingredients described herein in combination with other active or inactive ingredients into suppositories for the treatment of anorectal diseases. Also embodied in the present invention is the incorporation of any FIASMA into suppositories as a means of treating anorectal disorders. Finally, other agents such as anti-inflammatory agents, anesthetics, herbs or other vitamins may be included in the suppository to enhance the efficacy of the active ingredient or ingredients. The substances used to produce suppositories include any fatty (or oily) base and/or water-soluble (or miscible) base.

In a particularly preferred embodiment, the medicament contained in the suppository is amitriptyline. In a preferred embodiment, the suppository consists of a fatty (or oily) base and/or a water-soluble (or miscible) base. However, other mechanisms may be used in the present invention to allow passage of the drug into the rectum. More generally, the device can be constructed using any form of suppository base. Additionally, various TCAs can be incorporated into suppositories, allowing direct application of these substances to the rectum and anus. The other above-mentioned substances may also be included in the suppositories to enhance their efficacy in the treatment of anorectal disorders. The contents of the suppository may also consist of various TCAs, alone or in combination with amitriptyline, depending on the purpose of treatment.

Depending on the disease being treated, various doses of amitriptyline may be used. For example, the rectal dose of amitriptyline used for the treatment of radiation proctopathy is 25 to 100 mg per day. Both lower and higher capacities will be used initially in the construction of the device. The optimal dosage to treat these diseases will be determined based on clinical studies.

However, after appropriate clinical evaluation of this treatment, higher or lower doses of amitriptyline may ultimately be used to treat radiation proctopathy as well as other anorectal disorders. For the treatment of anorectal diseases, dosing for amitriptyline and other TCAs in suppositories is expected to be lower than oral doses because these agents will be applied directly to the affected area. However, since delivery by suppositories or rectal devices does not require ingestion and the size of the dosage form can be larger, it is typically administered in oral dosage forms if determined to be safe and effective based on further clinical experience or studies. More capacity than is used may also be used.

Preferably, the method of treating CRI is carried out using FIASMA, e.g., a TCA, such as amitriptyline, or an SSRI, such as sertraline, wherein the TCA or SSRI or both are prepared as a composition, and an effective dose is administered to the patient. It is provided in a dosage form that can be delivered orthotopically to the skin. For example, amitriptyline may be formulated as a liquid and administered in liquid form to a target area of the skin, or may be formulated with a thickening agent or viscosity enhancing agent to treat patients in need thereof, such as those who will be undergoing radiation therapy. , can provide lotions, creams, ointments or gels for topical delivery of amitriptyline to target areas of the skin of patients suffering from radiation dermatitis.

Alternatively, the method may use administration of a solid oral dosage form.

The methods of the invention may further comprise administering to a patient in need thereof at least one FIASMA, and an additional active ingredient other than FIASMA. Preferably, the additional active agent is formulated with at least one FIASMA in a fixed-dose combination drug product for topical administration to the skin.

One preferred embodiment of the composition of the invention with first and second active agents comprises a SSRI as the first active ingredient and a TCA or antioxidant as the second active ingredient. Antioxidants can be, for example, vitamin A, vitamin C, vitamin D and vitamin E. Additional embodiments of the compositions of the present invention may include TCAs, SSRIs, and antioxidants. Examples of active ingredients include amitriptyline as a TCA, sertraline as an SSRI, and vitamin D as an antioxidant.

Depending on the disease being treated, variable doses of one or more active ingredients described herein may be used. For example, the topical dose of amitriptyline used for the prevention or treatment of radiation dermatitis is 1 mg to 100 mg per day.

The optimal dosage to prevent or treat these diseases and the area to be treated will be determined based on clinical studies. However, after appropriate clinical evaluation of this treatment, higher or lower doses of amitriptyline or sertraline may ultimately be used to prevent or treat radiation dermatitis as well as other dermatological inflammatory disorders.

Example

Example 1 - Use of Compositions Containing TCA

Patients receiving or scheduled to receive radiation therapy for the treatment of 25 mm breast tumors will be provided with a composition that is an ointment containing 1% to 2% amitriptyline in a pharmaceutically acceptable base. Areas of skin over the tumor that are or will be exposed to radiation during a course of radiotherapy will be identified and can be marked.

A healthcare worker or patient will administer the composition at least once daily by applying approximately 1 ml of the composition to an area of skin that has been exposed to or is expected to be affected by radiation. Administration of the composition will be repeated at least daily or up to five times per day during a radiation treatment regimen of at least one week. For example, a patient receiving a radiation therapy regimen 5 times a week (Monday through Friday) may apply the cream to the treatment area 90 minutes prior to radiation therapy each day, followed by at bedtime for 7 days. So, before and after radiation treatment on Monday to Friday, and then twice a day on weekends when radiation treatment is not performed. This is repeated for 5 or 6 weeks.

Expected results: Radiation dermatitis is prevented, ameliorated, or reversed by administration of the composition.

Example 2 - Determination of efficacy of a single active agent versus multiple active agents

A group of five patients receiving or scheduled to receive radiation therapy for the treatment of a 25 mm breast tumor will be given a composition that is an ointment comprising any of the following:

■ 1% amitriptyline in a pharmaceutically acceptable base;

■ 1% sertraline in pharmaceutically acceptable bases;

■ 1% amitriptyline and 1% sertraline in pharmaceutically acceptable bases;

■ 0.5% amitriptyline and 0.5% sertraline in pharmaceutically acceptable bases; and

■ Pharmaceutically acceptable mechanism, alone (placebo).

Areas of skin over the tumor that are or will be exposed to radiation during a radiation therapy procedure will be identified and marked. A healthcare practitioner or patient will administer the composition by applying approximately 1 ml of the composition to an area of the skin that is or will be exposed to radiation, at least once daily prior to radiation treatment. Administration of the composition will be repeated at least daily or up to five times per day following radiation treatment for a period of one week.

Expected Results: Efficacy for each composition containing the active ingredients will be determined by scoring the level of radiation dermatitis present in each group of patients. Determination of whether the efficacy of the combination of amitriptyline and sertraline exhibits an additive or synergistic effect can be determined by determining the radiation dermatitis score for a composition containing 1% amitriptyline and 1% sertraline compared to 1% amitriptyline alone. It can be determined by comparing whether the effect is lower, equal, or greater than the effect of the triptyline composition and the 1% sertraline composition alone. Radiation dermatitis scores for fixed dose combination compositions containing 0.5% amitriptyline and 0.5% sertraline in a pharmaceutically acceptable base were significantly higher at lower doses of the combination compared to higher doses of each active agent alone in the composition. It can provide information about the efficacy of each active agent.

Example 3 - Treatment of radiation dermatitis in irradiated mice

Objective : Determination of the effectiveness of topical reconstitution of sertraline as a protective agent against radiation-induced skin damage.

Materials and Methods : Radiation-induced dermatitis experiments were performed in 10-week-old female C57BL/6J mice (The Jackson Laboratory). An approximately 3 x 3 cm area on the dorsal skin of the mice was shaved prior to drug treatment. Mice were randomly assigned to receive topical treatment of 4% sertraline or vehicle (n=5 mice per cohort), and all investigators were blinded to topical treatment.

The study compared active drug-containing compositions with placebo (vehicle). Both the active drug-containing composition and the placebo were manufactured by a third party and provided to the inventors for use in the study. The formulation of the composition is summarized as follows:

4% Sertraline Cream - Hexylene Glycol, Purified Water, Isopropyl Palmitate, Caprylic/Capric Triglyceride, Propylene Glycol, Ceteareth 20, Cetearyl Alcohol, Glyceryl Stearate, PEG 100 Stearate. 4% (w/w) sertraline (as hydrochloride salt) in an oil-in-water vanishing cream base containing salts, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin and phenoxyethanol.

Placebo Cream - Purified Water, Isopropyl Palmitate, Caprylic/Capric Triglyceride, Propylene Glycol, Ceteareth 20, Cetearyl Alcohol, Glyceryl Stearate, PEG 100 Stearate, Dimethicone, Octyldodecanol, Lecithin. , an oil-in-water vanishing cream base containing ethylhexylglycerin and phenoxyethanol.

Both products were packaged in white polypropylene containers with white polypropylene caps with polyvinyl chloride disc liners, for external use only, with instructions not to freeze, and stored at controlled room temperature (20°C to 25°C). Labeled as follows.

The formulations are further described in Composition Table A below:

Composition Table A.

As noted in Composition Table A, a 4% sertraline composition is prepared as the free base. The amount of sertraline HCl added to the formulation is adjusted to compensate for the HCl salt.

PENCream is a commercially available oil-in-water vanishing base purchased from Humco (https://www.humco.com/pharmaceuticals/pencream/). Crimea's NDC code is 0395-6010-56.

Mice received topical treatment once daily for 12 days starting 2 days before irradiation. Image-Guided Small Animal Irradiation Dermatitis was induced by delivering a single dose of 30 Gy of X-rays to a 1 x 1 cm area of shaved skin using an X-Rad 225 Cx.

The occurrence of radiation-induced dermatitis was assessed weekly for 4 weeks before and after irradiation by one observer blinded to treatment group. Skin response to radiation was assessed according to a semiquantitative scoring system previously established for preclinical studies, with scoring based on erythema, desquamation (dry and wet), necrosis, and loss of dermis, ranging from 1.0 to 5.5 (0.5 increments). ) is the range (Table 1).

[Table 1]

Semiquantitative skin damage score

Results : During the first two weeks following 30 Gy irradiation, all mice receiving treatment with 4% sertraline cream had a skin lesion score of 4.5, while mice receiving vehicle treatment had less severe scores of 3.0 to 3.5. had (Figures 1a and 1b). Scratching behavior and sequelae were recorded in the 4% sertraline cohort.

At 21 days post-irradiation, both treatment cohorts had skin damage scores between 3.0 and 3.5. At the end of the experiment, 28 days after irradiation, mice receiving treatment with 4% sertraline had less severe skin damage scores ranging from 1.5 to 2.0, with a mean score of 1.7.

In contrast, vehicle treated mice maintained higher skin damage scores ranging from 1.5 to 3.5, with a mean score of 3.0 (Figures 5A and 5B).

Discussion : Our preliminary results show that skin damage in mice receiving 4% sertraline was substantially improved 4 weeks after 30 Gy, whereas skin damage in vehicle treated mice was still severe. The cause of the higher damage scores for mice treated with 4% sertraline during the first 2 weeks after irradiation is under investigation, but a review of the literature suggests that topical sertraline in mice is not effective in treating mice with 4% sertraline during the first 2 weeks after irradiation. It was found to trigger significant itch-induced scratching (Neuron 87, 124-138, July 1, 2015). Repeating this experiment, removing the cream after 30 minutes, significantly reduced scratching behavior and initial skin damage scores, still showing similar benefits to the data shown above after 2 weeks. Therefore, it is believed that the early toxicity noted in week 1 was related to self-injury due to sertraline-induced scratching.

Conclusion : The results surprisingly support the effectiveness of 4% FIASMA compositions, such as 4% sertraline topical compositions, against radiation-induced skin damage.

Compositions comprising lower concentrations of active drug, e.g., less than 1% sertraline, preferably about 0.5%, can deliver substantially the same amount of drug to the target site as the compositions set forth in Composition Table A above. The composition is formulated with one or more penetration enhancers, solubilizers, softeners, etc. These formulations containing less than 1% active drug are advantageous with regard to dosage to the patient and may therefore be preferred.

Topical gel compositions for delivering a therapeutically effective amount to a target area of a patient's skin may include, for example, a mixture of one or more preservatives, one or more humectants/solvents, one or more rheology modifiers/thickeners, one or more anti-stick agents/fluidizers, etc. It may contain 0.5 to 1.0% of the active agent. An example of a topical gel formulation is provided in Gel Composition Table B below.

Gel composition table B

Topical cream formulations for delivering a therapeutically effective amount to a target area of a patient's skin can be, for example, mixtures with one or more preservatives, one or more humectants/solvents, one or more rheology modifiers/thickeners, one or more anti-stick agents/fluidizers, etc. It may contain 0.5 to 1.0% of the active agent. An example of a topical gel formulation is provided in Cream Composition Table C below.

Gel Composition Table C

Example 4 - Comparison of pre- and post-irradiation treatments

The experiment presented in Example 3 was repeated in mice to compare pre-irradiation treatment with 4% sertraline and post-irradiation treatment. 4% amitriptyline was also tested.

Using the same scoring chart shown in Example 3, the irradiated area on the mice was evaluated.

Methods : Radiation-induced dermatitis experiments were performed using 10-week-old female C57BL/6J mice (The Jackson Laboratory). An approximately 3 x 3 cm area on the dorsal skin of the mice was shaved prior to drug treatment. Dermatitis was induced by delivering a single dose of 30 Gy of X-rays to a 1 x 1 cm area of skin using an image-guided small animal irradiator, X-Rad 225 Cx. Mice were treated with 4% sertraline cream once daily for 3 days prior to irradiation, 4% sertraline cream once daily for 2 days starting 24 hours after irradiation, or 5 days (before and after irradiation). Each cage was randomly assigned to receive topical treatment of placebo once a day.

The occurrence of radiation-induced dermatitis was examined weekly for 6 weeks after irradiation by two observers (S.H. and S.S.) blinded to the treatment cohort. Skin response to irradiation was assessed according to a semiquantitative scoring system previously established for preclinical studies, with scores ranging from 1.0 to 5.5 (0.5) based on erythema, desquamation (dry and wet), necrosis, and loss of dermis. Incremental) range.

The score results at 1, 2, 3, and 4 weeks after irradiation (IR) are shown in Table 2 below:

[Table 2]

Semiquantitative skin damage score

result . At 4 weeks post-irradiation, 9 out of 10 sertraline-treated mice showed lower scores (better improvement) than mice treated with vehicle alone. In general, 4% sertraline cream performed better post-irradiation than pre-irradiation; Pre-irradiation treatment showed some protective effect. 4% sertraline cream administered 24 and 48 hours post-irradiation also produced an earlier response, showing lower scores within 1 week of irradiation and 4 weeks post-irradiation. It continues to show improved scores until.

These results are displayed graphically in Figures 6A-6D. Overall, mice receiving 4% sertraline twice post-irradiation showed accelerated recovery from acute radiation dermatitis starting in the first week post-irradiation (Figures 6A and 2). The skin damage score for the subsequent 2 group was significantly lower than the placebo group at weeks 3 to 6 after 30 Gy (Figure 6b). On the other hand, the skin damage score for the previous 3-dose group was significantly lower than the placebo alone group only at week 5 after 30 Gy (Figure 6c). Notably, mice receiving three doses of 4% sertraline before irradiation showed significantly slower recovery from acute radiation dermatitis compared to mice receiving two doses of 4% sertraline after irradiation (Figure 6D).

In particular, administration of 4% amitriptyline cream and 4% fluoxetine cream had deleterious effects in mice, and this group of experiments was discontinued. This supports the idea that 4% cream formulations containing tricyclic antidepressants (TCAs) are excessive doses and that lower doses are needed to determine their efficacy.

Example 5 - Oral Solution or Rinse Containing an SSRI for Treating Oral Mucositis Associated with Head and Neck Radiation Therapy

Purpose: The purpose of this proposed study is to evaluate the effectiveness of an oral solution or rinse containing an SSRI (sertraline) for the treatment of oral mucositis and xerostomia associated with head and neck radiotherapy.

A. Optimal radiation dose to induce oral mucositis in mouse model

Preliminary experiments will be performed to determine the optimal dose of irradiation to study radiation-induced oral mucositis and xerostomia in 8-week-old female C57BL/6J mice. The head and neck region of mice will be treated with single doses of 0, 16, 18, 20, and 22 Gy X-rays using the Small Animal Radiation Research Platform (SARRP) (n=10 per radiation dose). .

Two measurements will be performed to assess the duration and severity of oral mucositis:

(a) The body weight of the mice will be measured daily from days 7 to 16 post-irradiation and then three times a week for up to 21 days post-irradiation;

(b) Tongue pathomorphological changes will be evaluated using an otoscope on days 9, 12, and 16 after irradiation.

Pain management medications and supportive care may be provided if needed.

To assess the severity of xerostomia, saliva production for each mouse will be measured 30 and 60 days after irradiation according to previously described methods. Ashcraft et al. (2015) “Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model.” International Journal of Radiation Oncology, Biology, Physics 93 (4): 892-900]; Saiki et al. (2018) “Aldehyde Dehydrogenase 3A1 Activation Prevents Radiation-Induced Xerostomia by Protecting Salivary Stem Cells from Toxic Aldehydes.” Proceedings of the National Academy of Sciences of the United States of America 115 (24): 6279-84].

B. Determination of the effectiveness of sertraline oral solution on the development of radiation-induced oral mucositis and xerostomia.

Using the optimal radiation dose determined in A above, 8-week-old female C57BL/6J mice will be randomly assigned to receive:

head and neck radiotherapy plus vehicle alone (control);

Head and neck radiotherapy plus 2% sertraline in vehicle;

Head and neck radiotherapy + 4% sertraline in vehicle and

Head and neck radiotherapy + 6% sertraline in vehicle (n=20 mice/treatment cohort).

Mice will be treated with sertraline oral solution once daily for 5 consecutive days (2 days before irradiation, the day immediately before irradiation, and 2 days after irradiation).

Two measurements will be performed to assess the duration and severity of oral mucositis:

(a) Mice will be weighed daily from days 7 to 16 post-irradiation and then three times a week for up to 21 days post-irradiation.

(b) Tongue pathomorphological changes will be evaluated using an otoscope on days 9, 12, and 16 after irradiation. Pain management medications and supportive care may be provided if needed. To assess the severity of xerostomia, saliva production will be measured for each mouse 30 and 60 days after irradiation (Ashcraft et al. 2015; Saiki et al. 2018). Fibrosis of the salivary glands will be assessed 60 days after irradiation by histology (Ashcraft et al. 2015).

It is hypothesized that oral treatment with sertraline will reduce the severity and/or duration of radiation-induced oral mucositis and xerostomia by reducing acute inflammation. It is expected that the results will be dose-dependent and that sertraline oral solution will be effective in the treatment of oral mucositis and/or xerostomia.

Example 6 - Treatment of radiation dermatitis in patients undergoing and recovering from radiation therapy

Objective : To determine the effectiveness of RAD-100 in preventing or reducing radiation-induced dermatitis in postoperative breast cancer patients receiving a standard course of radiotherapy.

Materials and Methods : Patients who have recently undergone breast cancer surgery, i.e., breast-conserving surgery (lumpectomy) or mastectomy, for 25 to 30 sessions over a period of 5 to 6 weeks, performed as daily treatments on 5 consecutive days per week. A randomized, double-blind study was conducted using subjects 18 years of age or older who were scheduled to receive a course of standard radiation therapy of 1.8 to 2.0 GY per dose.

Subjects were excluded from the study if they met any of the following exclusion criteria:

· Ulcerated breast tissue or open breast wounds at the start of radiotherapy.

· Skin lesions in the area scheduled for irradiation prior to initiation of irradiation.

· Known allergy, hypersensitivity or reaction to any of the ingredients of the cream or to sertraline.

· Any neurological or psychiatric condition that, in the opinion of the treating physician, would render the subject ineligible for participation in the study.

· Any other significant comorbidities that, in the opinion of the investigator, may affect study results (e.g., uncontrolled diabetes, renal failure, liver dysfunction, cardiovascular disease, etc.).

· BMI greater than 35.0

· Subjects included in an investigational drug trial within the past thirty (30) days.

· Subjects taking monoamine oxidase inhibitors.

· Subjects receiving concurrent treatment with chemotherapy drugs.

· Pregnant or lactating

Subjects who met all inclusion criteria and none of the exclusion criteria were enrolled in the study, read, understood, and signed an informed consent form, completed a medical questionnaire, underwent a complete physical examination, and underwent fasting for chemistry and hematology. You were asked to provide a blood sample and a urine sample for urinalysis.

The study consisted of a cohort of 14 subjects who were randomized 2:1 to receive RAD-100 (sertraline topical cream 4.00% w/w) or vehicle cream twice daily (BID). Subjects were asked to apply the cream twice daily, once in the morning and once in the evening, and to continue the daily regimen during radiation treatment and for 14 days after the last radiation treatment.

The cream was dispensed on the Friday before the first week of radiation therapy, with instructions to subjects to begin application of the cream on the Sunday evening before their first radiation treatment. One day prior to starting the standard course of radiotherapy, all subjects were asked to begin application of the cream to the defined area where radiotherapy would be administered. This included the entire breast for breast conservation subjects and defined regions in mastectomy subjects.

Subjects were asked to apply the cream twice daily, once in the morning and once in the evening, and to continue this regimen daily during radiation treatment and for 14 days after the last radiation treatment. All subjects received medication blindly coded according to a predetermined random assignment code of a ratio of 2 active agent to 1 vehicle control unknown to both the subject and the investigator/evaluator. All subjects were provided with a diary to record the time they applied the cream and to record any concomitant medications and adverse events. Photographs of the application site were taken twice weekly, on Tuesday and Thursday before radiation treatment, and on days 7 and 14 after radiation treatment.

After an initial 1-day preparation, all subjects reported daily to the radiology department 5 days a week to receive their radiation dose. Immediately prior to radiation therapy treatment on Tuesdays and Fridays, the Principal Investigator (PI) or the PI's designated assistant assesses the skin at the radiation treatment site using the revised Radiation Therapy Oncology Group (RTOG) scoring system. Scores were recorded using . Subjects were queried weekly regarding the irradiated area and asked to report pain levels as well as any adverse or unusual events. Subjects were reminded to continue applying the cream during the 2 days per week they were not receiving radiation treatment and to record any changes in the radiation treatment area in a diary. Upon completion of the radiation phase of the study, all subjects were asked to continue their daily treatment regimen for the next 14 days. Subjects returned on days 7 and 14 for evaluation. At the end of this 14-day post-radiation period, subjects were released from the study with a request to voluntarily report any subsequent changes in the irradiation site.

Results : Dermatitis did not develop earlier than day 26 except in a few subjects. Results showed a P-value in favor of the treatment group throughout the treatment period and into the post-irradiation period. Radiation-induced dermatitis, as recorded in the RTOG score, worsened in the placebo group over the 7-day post-radiation period, whereas the mean score stabilized in the treatment group. Table 3 shows mean RTOG score data after Day 26.

[Table 3]

Average RTOG Score

The distribution of RTOG scores within each group at different times was also assessed. Dermatitis worsened earlier in the placebo group compared to the treatment group, and all P-values were in favor of the treatment group. In the post-irradiation period, the treatment group appeared to heal more rapidly. Table 4 shows the distribution of RTOG scores by category.

[Table 4]

Categorical RTOG score (% of subjects with specific score)

RTOG includes a score of more than 2 points, but radiation treatment is designed not to exceed 2 points. Although data are presented as the percentage of patients with a score of 2 or higher in each group, no actual score exceeded 2.

The data in Table 5 (below) shows categorized data for this study. During the radiation treatment phase, the placebo group had a higher percentage of 2.0 points on days 33 and 36, approaching statistical significance on day 33. The placebo group also had poorer recovery.

[Table 5]

Categorized RTOG data (% of subjects with scores of 2 or greater than 2)

The results in Table 5 are graphically displayed in Figure 7.

Conclusion : The results of this study showed that treatment with RAD100 improved the course of dermatitis during both the radiation treatment phase and the recovery phase, achieving some P-values near significance. While a larger number of subjects will inevitably improve the statistical data of this study, the current values predict that a larger study will achieve high statistical significance. Overall, the delayed development of dermatitis as well as the faster healing rate in the treatment groups complement the data generated using the mice in Examples 3 and 4. Like the human data, the mouse data show improved healing rates in the RAD100 treated group.

Example 7 - Treatment for tissue toxicity associated with head and neck radiotherapy

Objective: To determine the effect of sertraline on the development of radiation-induced oral mucositis in mice by testing the effect of sertraline oral solution on the development of radiation-induced oral mucositis in mice.

Experimental Procedure: 10-week-old female C57BL/6 mice were randomly assigned per cage to receive 16 Gy oral irradiation + placebo or 16 Gy oral irradiation + 1% sertraline solution. Placebo or sertraline solution was applied to the oral cavity of mice once daily for 5 consecutive days (2 days before irradiation, 30 minutes to 1 hour on the day before irradiation, and 2 days after irradiation). The development of radiation-induced severe oral mucositis was followed for 21 days after irradiation.

Results: Results showed that 16 Gy oral irradiation in the placebo group caused death in 66% of mice (4 of 6) due to acute irradiation toxicity of the oral mucosa, whereas in the 1% sertraline group it caused death in 33% of mice (4 out of 6). Only 2 out of 6 animals were found to have died (Figure 8). These findings support the development of oral sertraline treatment as a new approach to ameliorate radiation-induced severe oral mucositis.

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The foregoing description of the invention is illustrative only and is not intended to limit the scope of the invention to the precise terms presented. Moreover, although the invention has been described in detail with reference to specific exemplary embodiments, variations and modifications are within the scope and purpose of the invention as set forth and defined in the following claims.

The above disclosure and examples are generally descriptive of the invention and are provided for purposes of illustration and are not intended to limit the scope of the invention. The invention described herein may be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, in each example herein, any one of the terms “comprising,” “consisting essentially of,” and “consisting of” may be replaced with either of the other two terms. Terms and expressions are used as terms of description and not of limitation, and in the use of such terms and expressions there is no intention to exclude any equivalents of the features shown and described or portions thereof, but within the scope of the invention as claimed. It is recognized that various variations are possible. Accordingly, although the present invention has been specifically disclosed in terms of preferred embodiments and optional features, modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and such modifications and variations are within the scope of the invention as defined by the claims. It must be understood that it is considered within.

Claims (20)

A method of treating skin radiation injury (CRI), said method comprising:
0.5 to 10 ml of a composition comprising an effective amount of at least one functional inhibitor of acid sphingomyelinase (FIASMA) is administered to a target skin of a patient in need of treatment for cutaneous radiation injury (CRI) before, during or after radiation therapy. A method comprising administering to a site at least once per day. The method of claim 1 , wherein treating CRI comprises preventing CRI, reducing the incidence or recurrence thereof, suppressing, treating, ameliorating, reducing the severity of, or reversing CRI. The method of claim 1 , wherein the CRI results from medical radiation treatment for cancer. The method of claim 1 , wherein CRI is radiation dermatitis. The method of claim 1 , wherein the CRI is oral mucositis. The method of claim 1, wherein the CRI is radiation proctopathy. The method of claim 1 , wherein the composition is a topical cream, gel, or ointment. The method of claim 1 , wherein the composition is a solid oral dosage form. 9. The method according to claim 8, wherein the mucoadhesive tablet is a solid oral dosage form. The method of claim 1 , wherein the composition is an oral solution. 11. The method of claim 10, wherein the oral solution is a rinse comprising 1 to 100 mg/ml of an SSRI. The method of claim 1 , wherein FIASMA is selected from the group of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmic agents, adrenergic receptor blockers (ARBs) and beta blockers. 1. A pharmaceutical composition for treating cutaneous radiation injury (CRI), wherein the composition comprises an effective amount of at least one functional inhibitor of acid sphingomyelinase (FIASMA). The pharmaceutical composition of claim 13, wherein treating CRI comprises preventing CRI, reducing the incidence or recurrence thereof, inhibiting, treating, ameliorating, reducing the severity of, or reversing CRI. . 14. The pharmaceutical composition of claim 13, wherein CRI is radiation dermatitis. 14. The pharmaceutical composition according to claim 13, wherein the CRI is oral mucositis. 14. The pharmaceutical composition of claim 13, wherein the CRI is radiation proctopathy. 14. The pharmaceutical composition according to claim 13, wherein FIASMA is selected from the group of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenergic receptor blockers (ARBs) and beta blockers. 14. The pharmaceutical composition according to claim 13, wherein the composition is an oral dosage form comprising 1 to 100 mg/ml of an SSRI. 20. The composition of claim 19, wherein the oral dosage form is a mucoadhesive tablet.

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