Compositions and methods for preventing and treating skin radiation injury - Patents.com

Abstract

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

Description

[Technical field]

[0001] The present invention relates to compounds, compositions and methods for treating skin conditions or damage induced by radiation exposure. [Background technology]

[0002] Cutaneous radiation injury (CRI) is damage to the skin or underlying tissue in animals, including mammals and humans, induced by or resulting from radiation exposure from industrial or military-related sources, such as radioactive materials used in nuclear power plants or nuclear weapons. Although minor skin damage, such as sunburn due to overexposure to sunlight, is generally not considered to fall within the definition of CRI; the term CRI can include skin conditions such as radiation dermatitis, or other conditions such as radiation proctopathy, oral mucositis, or severe oral mucositis, each of which may be observed after medical radiation therapy administered to certain areas of the body.

[0003] Radiation therapy in medicine has been used successfully in the treatment of localized or locally advanced cancers and can be used as a sole treatment or as an adjunct to chemotherapy or surgery. However, radiation exposure in such treatments can cause severe burns of the skin and surrounding tissues, as well as permanent changes in pigmentation. As many as 95% of patients treated with cancer radiation therapy will experience skin reactions. For example, a particular skin reaction resulting from radiation therapy administered to breast cancer patients is called "radiation dermatitis."

[0004] Patients with head and neck cancer may suffer from oral mucositis due to damage to the epithelial cells lining the oral cavity after radiation therapy to treat head and neck cancer. When radiation therapy causes ulcerative lesions to form in the oral cavity or when the patient is unable to swallow solid food, the condition is considered "severe oral mucositis," or "SOM."

[0005] Radiotherapy administered to the pelvic region can cause damage to rectal tissue. A variety of disorders resulting from radiotherapy targeted to the pelvic region can affect the anorectal region and may involve one or more of inflammatory, ischemic, infectious, traumatic, or neoplastic conditions. Symptoms of anorectal disease include anal or rectal pain, urgency to move the bowel, fecal incontinence, diarrhea, rectal bleeding, and difficulty emptying the rectum. These conditions are referred to as "radiation proctitis" and, more recently and more accurately, as "radiation proctopathy."

[0006] Given the prevalence of these conditions in cancer patients undergoing radiation therapy, several strategies and treatments have been proposed for patients suffering from radiation dermatitis, but without great success. Aloe vera and topical vitamin C have been tried, but without any improvement in the outcome of irradiated breast tissue.

[0007] Other reports have shown that prophylactic and continued use of topical corticosteroids or dexpanthenol-containing emollients may reverse but not prevent radiation dermatitis. Other reports have shown that moist skin care with 3% urea lotion delayed and reduced the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors. The negative side effects of corticosteroids are well documented and their use is preferably avoided. Topical corticosteroids have little to no effect on pigmentation changes.

[0008] Biafine and Lipiderm have been shown to have no radioprotective effect, whereas a retrospective analysis showed significant skin cytoprotection from the use of amifostine.

[0009] Misoprostol, a prostaglandin E(l) analogue, has been found to be an effective radioprotectant in animal studies, preventing oncogenic transformation of Syrian hamster embryos exposed to radiation in utero, but has not produced successful results in humans.

[0010] Attempts to prevent or treat radiation proctopathy or proctitis have also been largely unsuccessful. Many topical treatments used for anorectal or lower intestinal conditions appear to be ineffective. For example, the use of the anti-inflammatory drug 5-aminosalicylic acid (5-ASA), previously used to treat inflammatory bowel disease (IBD), with or without steroids such as hydrocortisone, has been unsuccessful in treating radiation proctopathy or proctitis. Sucralfate has been recommended for radiation proctopathy but has proven ineffective.

[0011] Local therapies such as nitroglycerin and calcium channel blockers have also been found to be ineffective in treating radiation rectal injury. Short chain fatty acid enemas have also been used to treat radiation rectal injury, but are not readily available and are difficult to administer.

[0012] Recently, antioxidants such as vitamin A, vitamin C, and vitamin E formulated in suppositories have been described for the treatment of radiation rectal injury or proctitis. Suppositories are solid dosage forms containing medicines that are placed in the anus or vagina for the treatment of certain systemic conditions, but can also be used for the local treatment of anorectal and gynecological disorders. For example, one common use of rectal suppositories is for the treatment of constipation.

[0013] Rectal suppositories are also used as an alternative form of drug delivery in patients unable to accept medications through the oral cavity, whereby the medication is absorbed by the mucous membranes and distributed throughout the body. Examples of this type of rectal suppository include those for the treatment of nausea and pain.

[0014] It has been proposed that damage to healthy tissues from radiation therapy may involve an endothelial response associated with signaling from the plasma membrane via the acid sphingomyelinase / ceramide pathway (Corre, I., et al., Inti. J. Mol. Sci. (2013) 14, 22678-22696). Protection against endothelial damage, for example by inhibiting acid sphingomyelinase (ASMase) activity, has been suggested as a means to limit radiation toxicity in normal tissues. Corre, supra, at 22685. Inhibitors of ASMase are known, but none have been developed for topical administration and have not been shown to be effective in preventing or treating CRI in general, or radiation dermatitis or radiation rectal injury in particular.

[0015] Amitriptyline has been formulated into a suppository form. However, amitriptyline suppositories have only been prepared for systemic delivery and for the treatment of depression (a known indication for amitriptyline). Another indication for amitriptyline suppositories for systemic delivery is insomnia, taking advantage of the sleep-inducing side effect observed with amitriptyline. Amitriptyline suppositories have not previously been known to be administered to patients undergoing or having undergone pelvic radiation therapy, or for the treatment of radiation proctopathy or proctitis, or for any other in situ treatment in the lower intestinal tract.

[0016] Tricyclic antidepressants have generally not been known before for the treatment of anorectal disorders such as radiation rectal injury or proctitis.Dosage forms containing tricyclic antidepressants such as amitriptyline have also not been formulated for anal or rectal administration or for in situ (or non-systemic) treatment of radiation rectal injury or proctitis.More specifically, amitriptyline has not been previously formulated into dosage forms, such as suppositories or other anorectal delivery devices, for the local treatment of radiation rectal injury or proctitis.Tricyclic antidepressants, such as amitriptyline, have also not been formulated as controlled release formulations that bypass release in low pH environments (acidic pH below 7), such as in the stomach, so that drug release occurs primarily in the intestine, preferably in the lower intestine, for in situ delivery of drugs for the treatment of radiation rectal injury or proctitis.

[0017] No selective serotonin reuptake inhibitors (SSRIs) are known to be available in suppository form; nor are SSRIs known to have been used in the treatment of radiation proctopathy or proctitis.

[0018] There are many anorectal diseases that may benefit from the local administration of TCA such as amitriptyline or SSRI such as sertraline.These conditions include (but are not limited to) inflammatory bowel disease (IBD), including ulcerative proctitis and Crohn's disease, anal fissure, internal hemorrhoids, radiation proctopathy, anal and rectal tumors, anal warts, anal dysplasia, solitary rectal ulcer syndrome, perianal pruritus and anorectal ischemia.These conditions are diverse and significant clinical problems with limited currently available treatment options.

[0019] The continuing and increasing use of radiation therapy in the treatment of cancer, and the lack of available preventative or therapeutic medications for CRI, including radiation dermatitis or radiation proctopathy, is a long-standing unmet patient need that affects millions of patients. Summary of the Invention [Means for solving the problem]

[0020] The subject invention relates to methods for preventing, reducing the incidence or recurrence rate, inhibiting, treating, ameliorating or reducing the severity, or reversing cutaneous radiation injury (CRI), including radiation dermatitis or radiation proctopathy, resulting from environmental exposure to radiation from industrial or military radiation sources, or from therapeutic radiation treatments in cancer treatment. 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 fat layer. Radiation dermatitis and radiation proctopathy are included in the definition of CRI, but are generally considered to be conditions associated with damage to the dermis.

[0021] The method according to the invention comprises topically administering or applying to the skin surface of a patient suffering from a CRI, including radiation dermatitis or radiation proctopathy, a composition comprising at least one acid sphingomyelinase (ASMase) inhibitor. Functional inhibitors of acid sphingomyelinase, known in the art by the acronym FIASMA, include certain selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenoceptor blockers (ARBs), beta-blockers, and the like.

[0022] SSRIs useful in the methods of the invention include one or more of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. A preferred SSRI is sertraline. According to a preferred embodiment, the dosage form of the invention includes amitriptyline in a dosage amount of 0.1 mg to 1000 mg; more preferably, in a dosage amount of about 1 mg to 100 mg, and most preferably, in a dosage amount of about 5 mg to 50 mg. A preferred dosage is contemplated to be about 10 to 50 mg of the SSRI formulated in a 1 to 5% (w / w) composition. Dosages may vary, with lower dosage forms delivering the drug to the site more rapidly, or higher dosage forms releasing the drug more slowly.

[0023] Tricyclic antidepressants (TCAs) useful in the methods or compositions of the invention include one or more of: amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin (alone but in combination), imipramine, iprindole, lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, opipramol, protriptyline, tianeptine, or trimipramine. A preferred TCA is amitriptyline. According to a preferred embodiment, the dosage form of the invention comprises amitriptyline in a dosage amount of 0.1-1000 mg; more preferably in a dosage amount of about 1 mg-100 mg, and most preferably in a dosage amount of about 5 mg-50 mg. A preferred dosage is about 10-50 mg of the TCA formulated in a 1-5% (w / w) composition. The dosage may vary, with a lower dosage form delivering the drug to the site more rapidly, or a higher dosage form releasing the drug more slowly.

[0024] More specifically, the method of the present invention comprises: - providing a topical composition comprising as an active ingredient a pharma- ceutical effective amount of at least one FIASMA, or a combination of two or more FIASMA agents; - locally administering or applying an effective amount of the composition to a patient in need thereof prior to radiation therapy, or after radiation therapy, or both; Includes.

[0025] In a method for preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating or reducing the severity of, or reversing radiation rectal injury, the method comprises: - anorectally administering to a patient in need thereof, such as a patient undergoing radiation therapy of the pelvic area or a patient suffering from radiation proctopathy or proctitis, a dosage form comprising a pharmacologic effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA. may include.

[0026] 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 comprises: - providing a sublingual controlled release dosage form comprising FIASMA as an active ingredient; - administering to a patient in need thereof, such as a patient undergoing radiation therapy for head and neck cancer, a controlled release sublingual dosage form comprising a pharma- tically effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA; and may include.

[0027] Controlled release dosage forms for sublingual administration are known in the art and can slow the dissolution of the dosage form, thereby extending the release of the drug over a period of time, maintaining the presence of the active drug in the oral cavity, or increasing its residence time. Such controlled release dosage forms can be tablets, capsules, lozenges, pastilles, troches, or thin film strips, as will be appreciated by those skilled in the pharmaceutical arts.

[0028] It will be appreciated that applying or administering the composition prior to radiation therapy may include holding the composition in place during the 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 per day before, after, or during the radiation therapy session.

[0029] Alternatively, the subject method may include orally administering a composition comprising an effective amount of at least one FIASMA. Such oral compositions may be in immediate release or controlled release dosage forms. For conditions affecting the oral cavity, such as oral mucositis or severe oral mucositis, oral dosage forms that dissolve in the oral cavity and are not swallowed whole are preferred.

[0030] In patients with radiation rectal injury receiving radiation therapy in the pelvic region, a preferred method may involve providing a solid suppository or rectal plug dosage form containing a composition comprising FIASMA and placing the dosage form in the rectal cavity for the period of time necessary to deliver the active ingredient to the site.

[0031] The subject invention also provides compositions useful for preventing, reducing the incidence or recurrence of, treating, ameliorating or reducing the severity of, or reversing cutaneous radiation injury (CRI), including radiation dermatitis or radiation proctopathy. At least one Acid sphingomyelin Ze's Machine Activity inhibitors (FIASMA) The present invention relates to a topical pharmaceutical composition comprising as an active drug or substance.

[0032] The present invention may also include a suppository form for use in preventing, reducing the incidence or recurrence of, treating, ameliorating or reducing the severity of, or reversing radiation rectal injury. The suppository form may include 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 may further include other pharmacologic acceptable excipients conventionally used in suppository forms.

[0033] In the method of using a suppository or rectal plug delivery device for delivery of FIASMA to the anorectal cavity and administration of drugs in situ, the dosage form has one or more excipients that can delay the release of the active drug, which are provided with or incorporated into the rectal plug delivery device as a controlled release formulation, incorporated into the dosage form or coated on the outer surface of the dosage form, or particles, granules or beads in the dosage form that contain the active ingredient. The controlled release dosage form can also be provided for oral administration, where the oral dosage form is formulated as 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 above 7.0. Such a controlled release dosage form can be formulated with an enteric coating on a tablet, provided in a delayed release capsule or caplet, formulated in a delayed release matrix composition, or a combination of the above.

[0034] When the dosage form is a rectal plug delivery device, the device may be an insoluble plug forming a housing having an internal chamber for containing therein a composition comprising a FIASMA, which may be a TCA, an SSRI, or various combinations thereof. For example, the chamber of the rectal plug may be filled with a viscous composition comprising a TCA, or may contain a suppository formulation comprising a TCA active ingredient.

[0035] An alternative embodiment of a rectal plug delivery device useful for practicing the methods of the invention comprises a porous compressible foam material infused or coated with a composition comprising a TCA, e.g., amitriptyline, an SSRI, e.g., sertraline, or a combination thereof. The devices described in the methods of the invention can contain an effective dose of a FIASMA or FIASMA combination of about 0.1 mg to about 1000 mg or more.

[0036] Compositions according to the invention may also include compositions containing two or more active pharmaceutical ingredients formulated or mixed together in a single fixed dose composition, such as two or more different TCAs, two or more different SSRIs, or one or more TCAs in combination with one or more SSRIs.

[0037] Compositions for use in the methods of the invention may contain about 0.1 to 1000 milligrams (mg) of FIASMA. Topical compositions useful in the methods of the 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 invention is the SSRI, sertraline. Another FIASMA useful as an active ingredient in the compositions and methods of the invention is the TCA, amitriptyline. Other FIASMA compounds may be substituted or provided in combination with other FIASMA compounds in the compositions or methods of the invention.

[0038] The topical dosage form may comprise conventional and commercially available pharmaceutical carrier compositions that are pharma- ceutical compatible with one or more FIASMAs used as one or more active ingredients, and may further comprise other pharma- ceutical acceptable excipients conventionally used in topical or oral dosage forms. These commercially available pharmaceutical carriers may function as vehicles or media for the active drug substances and may comprise one or more of emollients, permeation enhancers, solvents, gelling agents, thickening or viscosity enhancing agents, preservatives, or other suitable excipients commonly used in topical formulations.

[0039] Preferably, the FIASMA is provided in an immediate release topical formulation that allows targeted administration and immediate delivery of the drug from the composition to the skin after application or administration of the composition. It may be preferable for the FIASMA component to be retained at the site of administration or application. Thus, the composition of the present invention may exclude a penetration enhancer to maintain the composition and active substance on the surface of the skin for a longer period of time than a composition that includes a penetration enhancer, which allows or promotes the penetration of the active substance into or under the skin where it can be absorbed systemically. Alternatively, in certain cases, a penetration enhancer may be preferred and used in the composition.

[0040] Oral dosage forms of the composition may be immediate release or may be formulated with excipients such as polymers, gels, gums, waxes, or may be incorporated into a matrix or may contain a coating for slow, delayed, sustained, or extended release of the active ingredient from the composition after oral administration. For example, a solid dosage form for sublingual administration of FIASMA in the treatment of oral mucositis may be formulated to dissolve in the oral cavity and may contain excipients that control, delay, sustain, or extend the release of the drug from the dosage form.

[0041] According to a further aspect of the present invention, the dosage form can include a second active, such as a TCA or SSRI component, or can include a second active that is not a TCA or SSRI, for example, an active component of a different drug class. In a preferred embodiment, the composition includes a first active component that is a TCA and a second active component that is a different TCA or an SSRI, or is a compound of another class that is not a TCA. For example, the second active component can be an antioxidant, such as vitamin A, vitamin C, vitamin D, or vitamin E. Preferably, the second active component in the composition is not an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic agent, such as a local anesthetic, for example, lidocaine.

[0042] In another preferred embodiment, the composition of the present invention comprises a first active ingredient that is an SSRI and a second active ingredient that is a different SSRI or a TCA, or is a compound of another class that is not 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 in the composition is not an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic agent, such as a local anesthetic, such as lidocaine.

[0043] Preferably, the method is carried out with FIASMA formulated in a topical composition capable of delivering an effective dose to the target area of ​​the skin directly or concomitantly exposed to radiation during radiation therapy or treatment. For example, the active ingredient may be formulated as a liquid composition and administered as liquid drops to the target area of ​​the skin. Alternatively, FIASMA may be formulated in a composition containing a thickening or viscosity enhancing agent as a lotion, cream, ointment or gel for local delivery of FIASMA to the target skin area of ​​the patient. The topical formulation may be rubbed onto or into the target area of ​​the skin before or after radiation therapy.

[0044] In methods using solid oral dosage forms, the active ingredient is provided as particles, granules, or beads, which can be manufactured in the form of tablets, capsules, caplets, etc., as is readily understood in the art. The oral dosage form can be provided, for example, as a controlled release dosage form, where the active ingredient can be formulated in a delayed release dosage form, such as an enteric coated tablet, delayed release capsule or caplet, or formulated in a delayed release matrix composition. Combinations of these controlled release dosage forms can also be used.

[0045] Thus, in accordance with the present invention, a method for preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating or reducing the severity of cutaneous radiation injury (CRI) comprises topically administering to a target area of ​​the skin of a patient in need thereof at least once per day before, during, and after radiation treatment an effective amount, for example, from about 0.5% to about 5% w / w of a composition comprising a FIASMA, such as a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline), of 0.5 to 50 ml or more depending on the size of the area to be treated.

[0046] Methods for preventing, treating, or ameliorating radiation dermatitis also include topically administering to a target area of ​​the skin of a patient in need thereof at least once per day before, during, and after radiation treatment, e.g., 0.5 to 50 ml or more of a composition comprising about 0.5% to about 5% w / w of a FIASMA, such as a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline), depending on the size of the area to be treated.

[0047] The method also includes preventing, treating, or ameliorating radiation rectal damage by locally administering or delivering an effective amount, e.g., about 0.5% to about 5% w / w of a composition comprising a FIASMA, e.g., a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline), to a target area of ​​a patient in need thereof at least once per day before, during, and after radiation treatment, from 0.5 to 50 ml or more depending on the size of the area to be treated.

[0048] The topical composition used in the present method can contain 5-50 mg of amitriptyline per ml of composition, or can contain 5-50 mg of sertraline per ml of composition, or can contain 10-40 mg of amitriptyline per ml of composition and 10-40 mg of sertraline per ml of composition.

[0049] The topical compositions can also include antioxidants such as vitamin A, vitamin C, vitamin D, and vitamin E.

[0050] Preferably, the compositions used in the methods of the present invention are formulated as topical dosage forms that deliver an effective dose of the active ingredient to the target area of ​​the patient in situ. This may be done with the composition formulated with a pharma- ceutically acceptable carrier to form a lotion, cream, ointment, or gel for topical delivery of the active ingredient to the target area of ​​the patient's skin.

[0051] Alternatively, the composition may include amitriptyline and a second tricyclic antidepressant that is not amitriptyline, such as amitriptyline, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin (in combination, not alone), imipramine, iprindole, lofepramine, maprotiline, norclomipramine, nortiaden, nortriptyline, opipramol, protriptyline, tianeptine, or trimipramine.

[0052] A composition that includes sertraline can include a second selective serotonin reuptake inhibitor that is not sertraline, such as citalopram, escitalopram, fluoxetine, fluvoxamine, or paroxetine.

[0053] The pharmaceutical compositions of the present invention can be provided as topical pharmaceutical compositions containing 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 can be in oral dosage form. In a preferred embodiment, the topical compositions of the present invention do not have, do not include, or exclude anti-inflammatory and anesthetic agents.

[0054] Preferred topical pharmaceutical compositions contain 10-20 mg of amitriptyline per ml of composition, or 10-50 mg of sertraline per ml of composition, or 15-20 mg of amitriptyline per ml of composition and 20-40 mg of sertraline per ml of composition, any of the above may further contain an effective amount of an antioxidant such as vitamin A, vitamin C, vitamin D, or vitamin E.

[0055] The oral dosage forms of the present invention can be formulated as controlled release oral dosage forms.

[0056] It will be appreciated 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, burns, sunburn, dermatomyofibroma, sun-induced wrinkles, and the like. [Brief description of the drawings]

[0057] [Figure 1] FIG. 1 shows a perspective view of a rectal plug device having a protruding member and a flange member, the protruding member including a housing having a pore and shown to bound a chamber for containing a soluble dosage form including at least one active ingredient, such as a TCA, an SSRI, or a combination thereof. [Diagram 2] 2 illustrates a cross-sectional view of the rectal plug of FIG. 1 showing a dosage form disposed within the chamber. [Diagram 3] FIG. 1 shows a perspective view of an alternative embodiment of a rectal plug of the present invention comprising a porous compressible foam material injected with or coated with a composition comprising a TCA or SSRI or combination, and shown in its expanded configuration after administration. [Figure 4] FIG. 4 illustrates a perspective view of the porous compressible foam rectal plug of FIG. 3 in a compressed configuration prior to administration. [Diagram 5] Results are shown by examination of skin injury following 30 Gy focal irradiation. Panel A of FIG. 5 is a summary of individual mouse skin injury scores up to 4 weeks following 30 Gy. Panel B is a graph of the observed changes in radiation skin injury scores over time. Data are presented as mean + / - SEM. n=5 mice / treatment group. [Figure 6] Results of examination of skin injury following 30 Gy focal irradiation are shown. Panel A of FIG. 6 is a summary of skin injury scores for mice treated with 3 doses of 4% sertraline prior to irradiation, 2 doses of 4% sertraline after irradiation, or 5 doses of placebo prior to and after irradiation. Skin injury scores were examined weekly for up to 6 weeks following irradiation. Panels B-D of FIG. 6 show a comparison of skin injury scores over time between cohorts of mice receiving different treatments. Data are presented as mean + / - SEM. n=5 mice / treatment group. *P<0.05 by 2-way ANOVA with Bonferroni post-hoc test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] The present invention provides innovative methods for preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating or reducing the severity of, or reversing skin conditions in mammals, including humans, and can involve the use of novel compositions or dosage forms to carry out the methods of treatment.

[0059] Hereinafter, the terms "treat", "treating", or "treatment" in relation to cutaneous radiation injury, i.e., "CRI", or a particular condition considered to be a type of CRI, may mean, refer to, or be substituted with any one of "preventing", "reducing its incidence", "reducing its recurrence", "inhibiting", "reversing", "reducing its severity", "reversing" or "treating" CRI. The specific terms "preventing", "reducing its incidence", "reducing its recurrence", "inhibiting", "reversing", "reducing its severity", or "reversing" CRI are used when intended to specify only the treatment thereof, or these terms may be expressly excluded from "treatment" when that term is not intended to be meant. For example, a method for "reducing its incidence" may only mean reducing the incidence of CRI, and not "inhibiting" CRI. Alternatively, "a method for treating CRI other than reducing the occurrence of CRI" may mean a method for preventing, reducing the incidence, inhibiting, ameliorating, reducing the severity, or reversing CRI.

[0060] The term "cutaneous radiation injury", or "CRI", is accepted in the medical field as being defined as damage to the skin or underlying tissue in animals, including mammals and humans, induced by or resulting from exposure to radiation from radioactive materials used in industrial or military related sources, such as nuclear power plants, or in nuclear weapons, or in medical radiation therapy. Thus, the term CRI can include skin conditions such as radiation dermatitis or radiation rectal injury observed after medical radiation therapy. Minor skin damage, such as sunburn due to overexposure to sunlight, is generally not considered to be included in the definition of CRI.

[0061] "Radiation dermatitis" refers to skin disorders resulting from radiation therapy of areas of the body. For example, radiation therapy is a known and accepted treatment for cancerous breast tissue in women and men. Inflammation of the skin overlying the targeted cancerous tissue and exposure to radiation 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 such disorders.

[0062] "Radiation rectal injury" or its synonym, "radiation proctitis," refers to injury to the rectum resulting from radiation therapy of the pelvic region, including inflammation of the rectal lining, resulting in altered rectal function. Radiation therapy of the pelvic region is a known and accepted therapeutic treatment for cancers of the urogenital tissues, such as the treatment of prostate cancer in men, or cervical cancer in women. The term is used herein as it is clinically understood by physicians who treat such injuries.

[0063] "Oral mucositis" refers to a condition resulting from radiation therapy used to treat head and neck cancer, and a more severe condition aptly termed "severe oral mucositis" or "SOM" is often associated with ulcerated tissue in the mouth or may be associated with the patient being unable to swallow food or drink. Oral mucositis is a common and debilitating complication of cancer treatment, especially radiation. It can lead to several problems including pain, nutritional problems as a result of the inability to eat, and increased risk of infection due to open wounds in the mucosa.

[0064] One embodiment of the present invention relates to a method for treating cutaneous radiation injury (CRI) by administering an effective amount or dose of a functional inhibitor of acid sphingomyelinase (FIASMA), examples of which include certain selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, antipsychotics, antidiarrheals, adrenoceptor blockers (ARBs), beta-blockers, estrogen receptor modulators, and the like.

[0065] 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.

[0066] Examples of useful TCAs according to the subject invention are amitriptyline, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin (alone but in combination), imipramine, iprindole, lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, opipramol, protriptyline, tianeptine, and trimipramine. Preferred TCAs useful according to the subject invention are amitriptyline, desipramine, and imipramine.

[0067] The invention includes the use of at least one FIASMA, such as a TCA or and an SSRI, and can include the use of at least two different FIASMAs from the same drug class, or at least two different FIASMAs from different drug classes. For example, the subject invention can include the 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 an SSRI.

[0068] A preferred TCA for use with the subject invention is amitriptyline. Amitriptyline, sold in the United States under the trade name ELAVIL® (AstraZeneca PLC, Cambridge England), is primarily used to treat a number of psychiatric disorders, including major depressive disorder, anxiety disorders, and less commonly, attention-deficit hyperactivity disorder (ADHD) and bipolar disorder. Other uses include the prophylaxis of migraines, neuropathic pain such as fibromyalgia and post-herpetic neuralgia, and less commonly, the treatment of insomnia.

[0069] A preferred SSRI for use with the subject invention is sertraline. Sold in the United States under the trade name Zoloft® (Pfizer, New York, NY USA), sertraline is primarily used to treat depression, panic attacks, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder (social phobia), and severe forms of premenstrual syndrome (premenstrual dysphoric disorder).

[0070] Amitriptyline and sertraline were not previously known to be useful in the prevention or treatment of radiation dermatitis.

[0071] In a preferred embodiment, at least one FIASMA may be incorporated into a topical pharmaceutical composition for administration by placement or application onto the surface of the skin for the prevention, amelioration or treatment of a skin condition or disorder, such as radiation dermatitis. The composition may be administered more or less frequently than once daily, as prescribed by the patient's physician or health care professional.

[0072] Topical compositions or formulations as dosage forms are well known in the art and are conventionally used in medical treatment. A preferred embodiment according to the subject invention is to incorporate FIASMA into a pharma- ceutically compatible base composition to make a topical lotion, cream, gel, or ointment containing at least one FIASMA as an active pharmaceutical ingredient (API) or drug. Another embodiment of the invention includes incorporating at least two different FIASMAs as active drugs, such as a combination of at least one TCA and at least one SSRI, into a pharma- ceutically compatible base composition to make a topical lotion, cream, gel, or ointment. A preferred embodiment includes thoroughly mixing one or more active ingredients in a pharma- ceutically acceptable base to provide a homogenous mixture. In the case of an active ingredient that is incompletely dissolved in the base, a suspension can be formed, which contains the active ingredient thoroughly mixed so that the active material is evenly distributed throughout the base. The compositions of the present invention can include other pharma- ceutically acceptable excipients conventionally used in topical dosage forms.

[0073] In another embodiment of the present invention, the active ingredient, such as one or more TCAs or SSRIs, can be formulated for oral administration.In one embodiment, the oral dose is provided as an immediate release dosage form.In one embodiment, the oral dose is provided as a controlled release dosage form.

[0074] In one embodiment, the oral dosage form for sublingual administration of the present invention comprises a pharmaceutical composition in a unit dosage form (e.g., lozenge, pill, tablet, film, or strip) containing at least one FIASMA, and in a preferred embodiment, is prepared as a controlled release formulation. With regard to the size of the unit dosage form, e.g., lozenge, ease and cost of manufacture, as well as consumer preference, will be considered. The size of the sublingual dosage form may vary from about 5 mm to 20 mm, or from about 5 mm to 18 mm, or from about 7 mm to 18 mm, or from about 10 mm to 15 mm. When the sublingual dosage form is circular or approximately circular, the size range is the appropriate diameter value. In most cases, the thickness of the lozenge will be 1 mm to 10 mm, more commonly 3 mm to 5 mm.

[0075] Sublingual dosage forms may be in the form of a single layer or a double layer. Sublingual dosage forms with soluble mucoadhesive properties may be prepared by pressing a powder containing a mucoadhesive hydrocolloid. As an example, an adhesive tablet (pastil) may be prepared by mixing a dry powder containing gum arabic for adhesion and at least one FIASMA as an active ingredient. The residence time of the sublingual dosage form in the oral cavity may be optimized according to the dissolution rate and total dissolution time of the product. For example, a sublingual controlled release lozenge or film may be prepared to have a residence time of at least 1 minute, preferably 1 to 30 minutes, more preferably 5 to 15 minutes in the oral cavity after administration.

[0076] In another aspect, the invention features a pharmaceutical composition in a unit dosage form formulated for sublingual administration, where the unit dosage form contains 5 to 50 mg of FIASMA (e.g., the dosage form contains 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of sertraline.

[0077] Controlled release oral dosage forms include delayed release formulations made by coating a solid dosage form with a polymeric film that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

[0078] The compositions of the present invention may contain conventional additives or other excipients such as plasticizers, pigments, colorants, stabilizers, glidants, and the like.

[0079] The present invention provides a method of preventing, ameliorating, or treating CRI by administration of FIASMA, comprising providing a composition comprising about 0.001 to 100 grams of active ingredient and delivering the drug to a patient in need thereof as a topical composition, such as a cream or lotion or ointment, directly to the skin, or formulated into an oral dosage form.

[0080] According to one preferred embodiment, the FIASMA contained in the topical dosage form is amitriptyline provided in a dosage of 1-1000 mg; more preferably in a dosage of about 5 mg-150 mg, and most preferably in a dosage of about 10-100 mg, administered as about a 0.5% to about 5% w / w topical composition. For example, a composition containing 1% to 5% active ingredient (10-50 mg active ingredient per ml of composition) may be administered in a volume of about 0.5 ml to about 5 ml per topical application. Preferably, the composition is administered topically in a volume of about 1 ml to about 2 ml to deliver 10-100 mg of active ingredient to the skin to prevent or treat CRI.

[0081] One preferred dose is administration of at least 1 ml of a composition containing 1% of FIASMA according to the subject invention as an active ingredient. Another preferred dose is administration of a 2% w / w composition containing at least 1 ml of a FIASMA active ingredient according to the subject invention. Yet another preferred dose is administration of a 3% w / w composition containing at least 1 ml of a FIASMA active ingredient according to the subject invention. Yet another preferred dose is administration of a 4% w / w composition containing at least 1 ml of a FIASMA active ingredient according to the subject invention. Yet another preferred dose is administration of a 5% w / w composition containing at least 1 ml of a FIASMA active ingredient according to the subject invention. It will be understood that the concentration of the drug may be provided in incremental increments of about 0.1%. By way of non-limiting example, FIASMA may be provided in a concentration of 1.1%, 1.2%, 1.3%, etc. up to 5%, as desired, to obtain the intended effect without having negative side effects.

[0082] The dosage contained in the dosage form may vary, with a lower dosage form delivering the drug to the site more rapidly, or a higher dosage form releasing the drug more slowly. The variation in dosage may also depend on the active ingredients contained in the composition. For example, a composition containing more than one FIASMA may contain less than 1% of each active, such as 0.1% to 0.9%, preferably about 0.5%, of each active, such that the final composition contains less than 1% to 2% of the total active ingredients in the composition. This may advantageously reduce 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 containing at least one TCA and at least one SSRI may provide a synergistic effect, where the efficacy is greater than the expected additive effect of each active ingredient when used alone.

[0083] In one embodiment, the FIASMA is provided in an oral dosage form as a controlled release formulation, which allows for delivery of the drug over a period of time, as compared to immediate release formulations, which provide for delivery of all of the drug from the dosage form upon administration. Controlled release formulations known in the art include the use of coatings, such as enteric coated tablets, beads, or pellets, ion exchange resins, waxes, alginates, gelling agents, such as cellulose hydrogels (e.g., hydroxypropylmethylcellulose, or HPMC) or polymeric acrylamides (e.g., Carbopol®), formulated with the active agent, and a suitable vehicle.

[0084] The present invention provides a method for treating anorectal disorders by in situ administration of an active pharmaceutical ingredient of the present invention, e.g., a TCA, e.g., amitriptyline, an SSRI, e.g., sertraline, or a combination thereof. The method includes the steps of providing a composition comprising about 0.001 to 100 grams of the active ingredient, and formulating the drug as a topical composition, e.g., a cream or ointment, or into a suppository or rectal plug dosage form to deliver directly to the anorectal area. According to a preferred embodiment, the TCA contained in the suppository or rectal plug dosage form is amitriptyline in a dosage amount of 1 to 1000 milligrams (mg); more preferably, a dosage amount of about 5 mg to 150 mg, and most preferably, a dosage amount of about 10 to 100 mg, where one preferred dosage amount is a suppository or other dosage form containing about 50 mg. In another preferred embodiment, the SSRI contained in the suppository or rectal plug dosage form is sertraline in a dosage amount of 1 to 1000 milligrams (mg); more preferably, a dosage amount of about 5 mg to 150 mg, and most preferably, a dosage amount of about 10 to 100 mg, with one preferred dosage amount being a suppository or other dosage form containing about 50 mg. The dosage amount contained in the suppository or rectal plug may vary, with a lower dosage form delivering the drug to the site more rapidly, or a higher dosage form releasing the drug more slowly. Additionally, when two or more active pharmaceutical ingredients are provided in a fixed-dose combination suppository product, the dosage of each of the active ingredients may be reduced in the dosage form, thereby advantageously reducing the risk or incidence of side effects.

[0085] 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 within the rectal cavity for a period of time necessary to deliver the active ingredient to the site. The composition provided in the rectal plug delivery device can be a suppository.

[0086] Alternatively, the drug may be delivered using a rectal delivery device, such as a rectal plug, that contains an effective dose of an active ingredient, such as a FIASMA, or a combination of more than one FIASMA. In one embodiment of the rectal plug device according to the present invention, the plug device comprises an insoluble porous housing that forms a chamber for containing the active ingredient. The active ingredient may be provided as a soluble suppository disposed within a chamber portion formed within the porous rectal plug housing. The suppository is exposed to bodily fluids when administered, dissolving the active ingredient from the suppository and delivering it in situ. In a preferred embodiment, the suppository is formulated as a controlled release formulation. Alternatively, the active ingredient may be formulated as a viscous controlled release gel, ointment, or cream that fills the chamber within the rectal plug housing.

[0087] Other types of rectal plugs are known and may be adapted for use with the subject invention. For example, rectal plugs formed from porous sponge-like polymeric materials, such as polyurethane foams, are known for use in fecal incontinence. Such rectal plugs are sold under the name PERISTEEN™ anal plug (Coloplast Corp., North Minneapolis, MN, USA). The polyurethane foam can be infused with a solution containing an effective amount of FIASMA and adsorbed onto the material for delivery upon insertion into the rectal cavity. These commercially available rectal plugs are generally provided in a compressed configuration for ease of insertion and are wrapped in a water-soluble film that dissolves after insertion and can expand to an enlarged configuration. Such compression and expansion are not necessary for in situ delivery of drugs according to the subject invention.

[0088] 1 and 2 show an example of a rectal plug delivery device for use according to the invention. FIG. 1 shows a rectal plug delivery device 100 including an elongated member 101 forming a proximal end of the device that is inserted into the rectal cavity and resides there during delivery of the active ingredient. The rectal plug delivery device may include a distal flange 102 to prevent the entire rectal plug delivery device from being entrapped within the rectal cavity, thereby keeping the rectal plug device in place during administration of the active ingredient. The active ingredient, e.g., a TCA or SSRI, may be provided as a pharmaceutical composition housed in a cavity (not shown) formed within the elongated member. The proximal end of the elongated member 101 includes a pore 103 to allow for the ingress of bodily fluids into the cavity formed within the elongated member and for the egress of the active ingredient from the composition contained within the elongated member. The rectal plug delivery device may have an extension piece, e.g., a strap or string, connected to the distal flange to facilitate removal of the rectal plug delivery device, functioning similarly to the removal of a tampon.

[0089] Figure 2 shows a cross-sectional view of the rectal plug delivery device 100 of Figure 1 showing a cavity formed within the proximal end of the elongate member 101 that can contain a composition 104 including an active pharmaceutical ingredient. As shown, the composition can be formed as a suppository that dissolves or melts when administered into the rectal cavity. Alternatively, the composition can be an amorphous or non-formed composition including a gel, cream, or ointment. Preferably, the composition is provided as a controlled release composition, preferably an extended release composition, that releases the active ingredient from the composition over time.

[0090] In another embodiment, the dosage form comprises an anal plug comprising a soft, compressible, porous material (e.g., foam rubber or a polymeric sponge-like material) and the active ingredient is impregnated or injected into or coated onto the porous, compressible plug material. This embodiment is shown in Figures 3 and 4.

[0091] 3 shows a rectal plug delivery device 200 comprising a soft, compressible porous material in an expanded configuration. The rectal plug delivery device 200 includes a drug delivery component 201 at its proximal end that expands and conforms to the shape of the rectal cavity upon insertion therein. An extension piece 202, such as a strap or string, is connected to the drug delivery component to facilitate removal of the rectal plug delivery device, functioning similarly to the removal of a tampon.

[0092] The composition comprising the active ingredient according to the present invention may be injected or infiltrated as a liquid or gel, cream, or ointment into the porous material forming the delivery component 201. The composition comprising the active ingredient may be provided as a controlled release composition, preferably an extended release composition, which releases the active ingredient over time.

[0093] Figure 4 illustrates the rectal plug delivery device 200 of Figure 3, where the drug delivery component 201 is provided in a compressed form to facilitate insertion into the rectal cavity. The compressed drug delivery component 201 may include a water-soluble wrapper surrounding the drug delivery component 201. After inserting the rectal plug delivery device embodiment 200 into the rectal cavity, bodily fluids dissolve the wrapper, allowing the drug delivery component 201 to expand to its expanded configuration shown in Figure 3. Figure 4 further illustrates an extension member 202, which may be a strap or tie, to facilitate removal of the rectal plug delivery device.

[0094] Preferably, the active ingredient is provided in a controlled release formulation that allows delivery of the drug over a period of time, compared to an immediate release formulation that provides delivery of all the drug from the dosage form as soon as it is administered.Controlled release formulations known in the art include the use of coatings, such as enteric coated tablets, beads, or pellets, ion exchange resins, waxes, alginates, gelling agents, such as cellulose hydrogels (e.g., hydroxypropylmethylcellulose, i.e., HPMC), or polymeric acrylamides (e.g., Carbopol®), formulated with the active agent, and suitable vehicles that melt or dissolve in rectal fluid.Such formulations and compositions, as well as methods for making suppositories or other controlled release compositions, are well known in the art.

[0095] In the method according to the invention, treating a CRI such as radiation dermatitis uses a composition comprising at least one FIASMA, e.g., a TCA, e.g., amitriptyline, and / or at least one second FIASMA, e.g., an SSRI, e.g., sertraline. The composition used in the method of the invention can be provided in a topical dosage form. Additionally, the subject invention includes a method for treating, ameliorating, or preventing a skin disorder or condition, such as radiation dermatitis, using an oral dosage form comprising at least one TCA, e.g., amitriptyline, and / or at least one SSRI, e.g., sertraline.

[0096] Preferably, the method includes providing a topical dosage form comprising a composition having at least one FIASMA as an active ingredient in the composition, and placing an effective amount of the composition on the target area of ​​the skin to be treated for a period of time necessary to deliver the active ingredient to the site. In a preferred embodiment, the active ingredient can be formulated as a viscous controlled release gel, ointment, or cream for administration to the skin. The topical compositions of the present invention preferably contain each active ingredient provided in a concentration of about 0.1% (1 mg per ml of composition) up to about 5% (50 mg per ml of composition); for example, 0.1%, 0.2%, 0.3%, 0.4%, .05%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, and 1.1%, 1.2%, 1.3%, etc., in increments of 0.1% up to about 5.0%. A typical dose is from about 0.5 ml to about 2 ml, preferably about 1 ml, but is not so limited, limited only by the area of ​​skin requiring treatment, and thus doses of 5 ml or more can be applied.

[0097] According to one embodiment of the present invention, the method of the present invention comprises: The method includes topically administering an effective dose of one or more active ingredients, i.e., a drug that is a FIASMA, to the skin of a patient in need thereof, such as a patient suffering from CRI after exposure to environmental radiation, or a patient undergoing or having undergone medical radiation therapy and suffering from radiation dermatitis or radiation rectal injury.

[0098] 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 comprises: - providing a sublingual controlled release dosage form comprising FIASMA as an active ingredient; - administering a controlled release sublingual dosage form comprising a pharma- tically effective amount of one or more active ingredients to a patient in need thereof, e.g., a patient undergoing radiation therapy for head and neck cancer; may include At least one active ingredient is a FIASMA.

[0099] In a method for treating radiation rectal injury, the method of the present invention comprises: The method includes anorectally administering an effective dose of one or more FIASMA drugs, preferably drugs from a class selected from TCAs, SSRIs, or combinations thereof, as an active ingredient to the rectal cavity or rectal tissue of a patient in need thereof, such as a patient suffering from radiation rectal injury or proctitis resulting from medical radiation therapy.

[0100] A preferred method of treating radiation rectal injury includes anorectal administration of an effective dose of FIASMA, such as TCA, amitriptyline, or SSRI, sertraline, as an active ingredient. A composition containing a fixed dose combination of two or more different FIASMAs, or one or more FIASMAs and a non-FIASMA active ingredient, can also be used. In a preferred example, the method is carried out using amitriptyline formulated as a composition and provided in a dosage form that can deliver an effective dose in situ to the rectal cavity of a patient. For example, amitriptyline can be formulated as a liquid and administered as an enema, or formulated with a thickening or viscosity enhancing agent to provide a lotion, cream, ointment, or gel for local delivery of amitriptyline to the anorectal area and rectal cavity of a patient.

[0101] Alternatively, the method may use a semi-solid or solid dosage form, such as a suppository or a rectal plug delivery device, to deliver the active pharmaceutical ingredient to the anorectal cavity and for in situ administration of the drug. Preferably, the dosage form provided with or incorporated into the rectal plug delivery device is a controlled release formulation having excipients capable of delaying or retarding the release of the active drug incorporated into the dosage form or coated on the outer surface of the dosage form.

[0102] Where the dosage form is a rectal plug delivery device, the device may be an insoluble plug forming a housing having an internal chamber that contains therein a composition comprising an active pharmaceutical ingredient according to the present invention. For example, the chamber of the rectal plug may be filled with a viscous composition comprising a FIASMA active ingredient, or may contain a suppository dosage form that includes FIASMA as the active ingredient.

[0103] An alternative embodiment of a rectal plug delivery device useful in practicing the methods of the invention comprises a porous compressible foam material infused with or coated with a composition comprising an active pharmaceutical ingredient according to the subject invention. The devices described in the methods of the invention can contain an effective dose of FIASMA provided in an amount of from about 0.1 mg to about 1000 mg or more.

[0104] The method of the present invention can further comprise administering to a patient in need thereof at least one active ingredient and an additional or second active ingredient that is not a FIASMA. Preferably, the additional active agent is formulated in a fixed-dose combination formulation together with at least one TCA, at least one SSRI, or a combination of a TCA and an SSRI.

[0105] A preferred embodiment of the composition comprising a first and a second active agent comprises a TCA or SSRI and an anti-inflammatory agent, an anesthetic agent, or an antioxidant agent. The anti-inflammatory agent can be a steroid or a non-steroidal anti-inflammatory drug (NSAID). Alternatively, the second active agent in the composition is not an anti-inflammatory agent, the composition excludes a steroid compound, or the composition excludes a non-steroidal anti-inflammatory drug (NSAID). The anesthetic agent can be a local anesthetic agent commonly used for topical administration, such as lidocaine. The antioxidant agent can be, for example, vitamin A, vitamin C, vitamin D, and vitamin E.

[0106] The subject invention includes a composition for treating radiation rectal injury, comprising providing an effective amount of FIASMA formulated as a controlled release formulation for in situ delivery of the active ingredient to the rectal cavity. In a preferred embodiment, the composition may be formulated as a controlled release suppository containing at least one TCA or at least one SSRI, or at least one TCA and one SSRI as the active ingredient. The composition may include an additional drug that is not a FIASMA as described herein.

[0107] The active pharmaceutical ingredient contained in the suppository or rectal delivery device can be administered before, during or after pelvic radiotherapy. A preferred administration involves inserting the suppository or rectal delivery device into the rectal cavity and allowing the suppository or rectal delivery device to remain in the rectal cavity until delivery of the entire dose is complete. A preferred suppository according to the present invention dissolves slowly and can remain in the rectal cavity for a period of up to about 24 hours, i.e., can be used daily. A rectal plug delivery device can remain in the rectal cavity for a period of up to about 48 hours, but preferably contains a drug formulation that delivers a dose of active ingredient within about 24 hours. This provides for daily use after defecation. Alternatively, the rectal plug may be temporarily removed for defecation and reinserted.

[0108] The suppository containing active pharmaceutical ingredients is arranged to remain in the rectal cavity for the period required for dissolution.Since the suppository is completely soluble, the release of the active ingredient from the suppository is achieved after the suppository is retained in the rectum.The released active ingredient occurs in high concentration at the site of delivery, thereby enhancing the effectiveness of this treatment for anorectal disorders.

[0109] According to alternative embodiments, the suppository may comprise or consist of other drugs or supplements, such as antioxidants including vitamin E and vitamin C, as well as natural antioxidants such as fish oil, green tea, cranberry, etc. These may be used as separate suppository formulations or as additional components of the suppositories of the present invention.

[0110] In any of these uses and embodiments of the present invention, suppository forms of these agents are used as clinical treatments for chronic disorders of the anus and rectum.

[0111] Any form of the active ingredient contemplated by the present invention that is placed in suppository form for the treatment of anorectal disease is within the scope of the present invention.Furthermore, it is embodied within the scope of the present invention to incorporate the active pharmaceutical ingredient described herein in combination with other active or inactive ingredients into a suppository for treating anorectal disease.Furthermore, it is embodied within the scope of the present invention to incorporate any FIASMA into a suppository as a means of treating anorectal disorders.Finally, other drugs, such as anti-inflammatory drugs, anesthetics, herbs, or other vitamins, can be included in the suppository to enhance the effectiveness of the active ingredient.The materials used to prepare the suppository include any fatty (or oily) base and / or water-soluble (or miscible) base.

[0112] In a particularly preferred embodiment, the medicament contained in the suppository is amitriptyline. In a preferred embodiment, the suppository is composed of a fatty (or oily) base and / or a water-soluble (or miscible) base. However, other bases can be used in the present invention to allow the passage of the medicament into the rectum. More generally, any form of suppository base can be used to construct the device. Furthermore, various TCAs can be incorporated into the suppository to allow these substances to be applied directly to the rectum and anus. Other previously mentioned substances can also be included in the suppository to enhance their effectiveness in treating anorectal disorders. The contents of the suppository can also consist of various TCAs, alone or in combination with amitriptyline, depending on the goal of treatment.

[0113] Depending on the condition being treated, various doses of amitriptyline can be used. For example, the rectal dose of amitriptyline used to treat radiation rectal injury is 25-100 mg per day. In the construction of the device, both lower and higher doses will be used initially. The optimal dosage for treating these conditions will be determined based on clinical trials.

[0114] However, after clinical evaluation of this treatment, higher or lower doses of amitriptyline may eventually be used to treat radiation rectal injury and other anorectal disorders. The dosage of amitriptyline and other TCAs in suppositories is expected to be lower than oral dosages for the treatment of anorectal diseases, since these drugs are applied directly to the affected area. However, because delivery by suppository or rectal device does not need to be ingested and the dosage form can be larger in size, higher dosages than typically used in oral dosage forms may also be used if determined to be safe and effective based on further clinical experience or testing.

[0115] Preferably, the method for treating CRI is carried out using a FIASMA, for example, a TCA, such as amitriptyline, or an SSRI, for example, sertraline, and the TCA or SSRI or both are prepared as a composition and provided in a dosage form that can deliver an effective dose to the skin of a patient in situ.For example, amitriptyline can be formulated as a liquid and administered to the skin application area in liquid form, or can be formulated with a thickening or viscosity enhancing agent to provide a lotion, cream, ointment or gel for local delivery of amitriptyline to the target area of ​​the skin of a patient in need thereof, for example, a patient undergoing radiation therapy or suffering from radiation dermatitis.

[0116] Alternatively, the method can employ administration of a solid oral dosage form.

[0117] The method of the invention can further comprise administering to a patient in need thereof at least one FIASMA and an additional active ingredient that is not a FIASMA. Preferably, the additional active is formulated together with the at least one FIASMA in a fixed dose combination formulation for topical administration to the skin.

[0118] A preferred embodiment of the composition of the present invention having a first and a second active agent comprises an SSRI as the first active agent and a TCA or an antioxidant as the second active agent. The antioxidant may be, for example, vitamin A, vitamin C, vitamin D, and vitamin E. A further embodiment of the composition of the present invention may comprise a TCA, an SSRI, and an antioxidant. An example of an active agent is amitriptyline as the TCA, sertraline as the SSRI, and vitamin D as the antioxidant.

[0119] Depending on the condition being treated, various doses of one or more of the active ingredients described herein can be used. For example, topical doses of amitriptyline used to prevent or treat radiation dermatitis range from 1 mg to 100 mg daily.

[0120] The optimal dosage and range to be treated for preventing or treating these conditions will be determined based on clinical trials, however, after appropriate clinical evaluation of the treatment, higher or lower doses of amitriptyline or sertraline may ultimately be used to prevent or treat radiation dermatitis and other inflammatory skin disorders. EXAMPLES

[0121] Example 1 – Use of a composition containing TCA A patient undergoing or scheduled to undergo radiation therapy for the treatment of a 25 mm breast tumor is provided with a composition, the composition being an ointment containing 1% to 2% amitriptyline in a pharma- ceutically acceptable base, and areas of the skin on the tumor that are or will be exposed to radiation during the radiation therapy treatment may be identified and marked.

[0122] The medical professional or patient administers the composition by applying about 1 ml of the composition at least once per day to the area of ​​skin expected to be exposed to or affected by radiation. The administration of the composition is repeated at least once per day, or up to 5 times per day, for at least one week during the radiation therapy regimen. For example, a patient undergoing a radiation therapy regimen 5 days per week (Monday through Friday) may apply the cream daily to the treatment area 90 minutes before radiation therapy, then at bedtime for 7 days. Before and after radiation therapy Monday through Friday, then twice a day on weekends when the patient is not receiving radiation. This is repeated for 5 or 6 weeks.

[0123] Expected Results: Radiation dermatitis is prevented or ameliorated or reversed by administration of the composition.

[0124] Example 2 - Determining the efficacy of single active vs. multiple actives The five patient groups receiving or scheduled to receive radiation therapy for the treatment of 25 mm breast tumors were: ■ 1% amitriptyline in a pharma- ceutically acceptable vehicle; ■ 1% sertraline in a pharma- ceutically acceptable vehicle; ■ 1% amitriptyline and 1% sertraline in a pharma- ceutically acceptable base; ■ 0.5% amitriptyline and 0.5% sertraline in a pharma- ceutically acceptable carrier; and ■ Pharmaceutically acceptable base alone (placebo)

[0023] A composition is provided which is an ointment comprising either

[0125] Areas of skin on the tumor that are or will be exposed to radiation during radiation therapy treatment can be identified and marked. A medical professional or patient administers the composition by applying about 1 ml of the composition to the areas of skin that are expected to be exposed to or affected by radiation at least once per day prior to radiation therapy. Administration of the composition is repeated at least once per day, or up to 5 times per day for one week following radiation therapy.

[0126] Expected Results: The effectiveness of each composition containing active ingredients is determined by scoring the level of radiation dermatitis present in each group of patients. The determination of whether the effectiveness of the use of the combination of amitriptyline and sertraline shows additive or synergistic effects can be determined by comparing whether the radiation dermatitis scores of the composition containing 1% amitriptyline and 1% sertraline are lower than, equal to, or higher than the effect of the 1% amitriptyline composition alone and the 1% sertraline composition alone. The radiation dermatitis scores of the fixed dose combination composition containing 0.5% amitriptyline and 0.5% sertraline in a pharma- ceutically acceptable carrier can provide information regarding the effectiveness of lower doses of each active combination compared to higher doses of each active alone in the composition.

[0127] Example 3 – Treatment of radiation dermatitis in irradiated mice Objective: To determine the efficacy of a topical reformulation of sertraline as a protective agent against radiation-induced skin injury.

[0128] Materials and Methods: Radiation-induced dermatitis experiments were performed in 10-week-old female C57BL / 6J mice (The Jackson Laboratory). An area of ​​approximately 3x3cm on the dorsal skin of the mice was shaved before drug treatment. Mice were randomly assigned to receive topical treatment with 4% sertraline or vehicle (n=5 mice per cohort), and all investigators were blinded to the topical treatment.

[0129] The study compared an active drug-containing composition to a placebo (vehicle). Both the active drug-containing composition and the placebo were prepared by a third party and provided to the inventors for use in the study. The formulation of the composition is outlined below:

[0130] 4% Sertraline Cream - 4% (w / w) sertraline (as the hydrochloride salt) in an oil-in-water vanishing cream base containing hexylene glycol, purified water, isopropyl palmitate, caprylic / capric triglyceride, propylene glycol, ceteareth 20, cetearyl alcohol, glyceryl stearate, PEG 100 stearate, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin, and phenoxyethanol.

[0131] Placebo Cream - An oil-in-water vanishing cream base containing purified water, isopropyl palmitate, caprylic / capric triglyceride, propylene glycol, ceteareth 20, cetearyl alcohol, glyceryl stearate, PEG 100 stearate, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin, and phenoxyethanol.

[0132] Both products were packaged in white polypropylene bottles having a white polypropylene closure with a polyvinyl chloride disc liner, labeled for external use only, and instructed to store at controlled room temperature (20°C to 25°C) and avoid freezing.

[0133] The formulations are further described in the composition table below:

[0134] [Table 1]

[0135] 4% sertraline compositions are prepared as free base as shown in the composition table. The amount of sertraline HCl added to the formulation is adjusted to compensate for the HCl salt.

[0136] PENCream is a commercially available oil-in-water vanishing base purchased from Humco (https: / / www.humco.com / pharmaceuticals / pencream / ). The NDC code for this cream is 0395-6010-56.

[0137] Mice received topical treatment once daily for 12 days, starting 2 days before irradiation. Dermatitis was induced by delivering a single dose of 30 Gy of X-rays to a 1x1 cm area of ​​shaved skin using an image-guided small animal irradiation X-Rad 225 Cx.

[0138] The occurrence of radiation-induced dermatitis was examined before irradiation and weekly for 4 weeks after irradiation by a single observer blinded to treatment group. Skin reactions to radiation were assessed according to a semiquantitative scoring system previously established for preclinical studies - scoring ranges from 1.0 to 5.5 (increments of 0.5) based on erythema, desquamation (dry and moist), necrosis, and dermis loss (Table 1).

[0139] [Table 2]

[0140] Results: During the first 2 weeks after 30 Gy irradiation, all mice treated with 4% sertraline cream had skin lesion scores of 4.5, whereas vehicle-treated mice had milder scores of 3.0-3.5 (Figure 1, Panels A and B). Scratching behavior and sequelae were observed in the 4% sertraline cohort.

[0141] At day 21 post-irradiation, both treatment cohorts had skin injury scores of 3.0-3.5. At the end of the experiment at day 28 post-irradiation, mice treated with 4% sertraline had milder skin injury scores ranging from 1.5-2.0, with a mean score of 1.7.

[0142] In contrast, vehicle-treated mice maintained higher skin injury scores ranging from 1.5 to 3.5, with a mean score of 3.0 (Figure 5, panels A and B).

[0143] Discussion: Our preliminary results show that skin lesions in mice receiving 4% sertraline improved substantially 4 weeks after 30 Gy, while skin lesions in vehicle-treated mice remained severe. Although the cause of the higher lesion scores in mice treated with 4% sertraline during the first 2 weeks after irradiation is under investigation, a literature search confirmed that topical sertraline induces significant itch-induced scratching in mice, as shown in a previously established animal study (Neuron 87, 124-138, July 1, 2015). By repeating this experiment with removal of the cream after 30 minutes, the scratching behavior and initial skin lesion scores were substantially reduced, but still showed similar benefits after 2 weeks, as shown in the data above. Therefore, the early toxicity observed at 1 week is likely related to self-injury due to sertraline-induced scratching.

[0144] Conclusion: The results surprisingly suggest that a 4% FIASMA composition, for example a 4% sertraline topical composition, is effective against radiation-induced skin injury.

[0145] Example 4 - Comparison before and after radiation treatment The experiment described in Example 3 was repeated in mice to compare 4% sertraline administered before and after radiation treatment. 4% amitriptyline was also tested.

[0146] The same scoring chart as shown in Example 3 was used to evaluate the irradiated sites on the mice.

[0147] Methods: Radiation-induced dermatitis experiments were performed using 10-week-old female C57BL / 6J mice (The Jackson Laboratory). An approximately 3x3 cm area on the dorsal skin of the mice was shaved before drug treatment. A single dose of 30 Gy of X-rays was delivered to a 1x1 cm area of ​​the skin using an image-guided small animal irradiator X-Rad 225 Cx to induce dermatitis. Mice were randomized by cage to receive topical treatment with 4% sertraline cream once daily for 3 days before irradiation, 4% sertraline cream once daily for 2 days starting 24 hours after irradiation, or placebo once daily for 5 days (before and after irradiation).

[0148] The development of radiation-induced dermatitis was examined weekly for 6 weeks after irradiation by two observers (SH and SS) blinded to the treatment cohort. Skin reactions to radiation were assessed according to a semiquantitative scoring system previously established for preclinical studies - scoring ranges from 1.0 to 5.5 (increments of 0.5) based on erythema, desquamation (dry and moist), necrosis and loss of dermis.

[0149] The scores at 1, 2, 3 and 4 weeks after radiation treatment (IR) are shown in Table 2 below:

[0150] [Table 3]

[0151] Results: Four weeks after radiation treatment, 9 of 10 sertraline-treated mice showed lower scores (better improvement) than mice treated with vehicle alone. In general, 4% sertraline cream performed better when administered after radiation treatment compared to before radiation treatment; however, before radiation treatment showed some preventative effects. 4% sertraline cream administered 24 and 48 hours after radiation treatment also showed an earlier response, showing lower scores within one week of radiation treatment and continuing to show improved scores up to the fourth week after radiation treatment.

[0152] These results are shown graphically in Figure 6, panels A-D. Overall, mice that received 4% sertraline twice after irradiation showed accelerated recovery from acute radiation dermatitis starting 1 week after irradiation (Figure 6, A and 2). Skin injury scores in the post-treatment 2x group were significantly lower than the placebo group at 3-6 weeks after 30 Gy (Figure 6, panel B). Meanwhile, skin injury scores in the pre-treatment 3x group were significantly lower than the placebo group at only 5 weeks after 30 Gy (Figure 6, panel C). Notably, mice that received 4% sertraline three times before irradiation showed significantly slower recovery from acute radiation dermatitis compared to mice that received 4% sertraline two times after irradiation (Figure 6, panel D).

[0153] In particular, administration of 4% amitriptyline cream and 4% fluoxetine cream had deleterious effects on the mice and this experimental arm was discontinued, suggesting that the 4% cream formulations containing tricyclic antidepressants (TCAs) were overdosed and that lower doses were needed to determine their effectiveness.

[0154] The foregoing description of the invention is merely illustrative and is not intended to limit the scope of the invention to the precise terms set forth. Moreover, although the invention has been described in detail with reference to certain exemplary embodiments, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims.

[0155] The above disclosure and examples generally describe the present invention and are provided for illustrative purposes and are not intended to limit the scope of the present invention. The present invention described herein can be practiced in the absence of any element or limitation not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprise", "consist essentially of" and "consist of" can be replaced with either of the other two terms. The terms and expressions are used as descriptive terms and not limiting, and there is no intention in the use of these terms and expressions to exclude the features shown and described or equivalents of some of them, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, although the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be utilized by those skilled in the art, and such modifications and variations are considered to be within the scope of the present invention as defined by the claims. <Appendix 1> 1. A method for treating cutaneous radiation injury (CRI), the method comprising: A method comprising administering 0.5 to 5 ml of a topical composition comprising an effective amount of one or more functional inhibitors of acid sphingomyelinase (FIASMA) to a target area of ​​the skin of a patient in need thereof at least once daily before, during or after radiation treatment. <Appendix 2> The method of claim 1, wherein treating CRI includes preventing CRI, reducing the incidence or recurrence rate of CRI, inhibiting, treating, ameliorating or reducing the severity of CRI, or reversing CRI. <Appendix 3> 2. The method of claim 1, wherein the CRI results from exposure to environmental radiation. <Appendix 4> 2. The method of claim 1, wherein the CRI results from exposure to radiation from a military weapon. <Appendix 5> 2. The method of claim 1, wherein the CRI results from medical radiation treatment of cancer. <Appendix 6> The method of claim 1, wherein the CRI is radiation dermatitis. <Appendix 7> The method of claim 1, wherein the CRI is oral mucositis. <Appendix 8> 2. The method of claim 1, wherein the CRI is radiation rectal injury. <Appendix 9> The method of claim 1, wherein the FIASMA is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenoceptor blockers (ARBs), and beta blockers. <Appendix 10> The method of claim 1, wherein the FIASMA is an SSRI. <Appendix 11> The method of claim 1, wherein the FIASMA is a TCA. <Appendix 12> The method of claim 1, wherein the FIASMA is a TCA other than doxepin. <Appendix 13> The method of claim 1, wherein the FIASMA is sertraline. <Appendix 14> The method of claim 1, wherein the FIASMA is amitriptyline. <Appendix 15> 2. The method of claim 1, wherein the composition comprises from 5 to 50 mg of FIASMA. <Appendix 16> 2. The method of claim 1, wherein the composition contains up to 20 mg of amitriptyline per ml of the composition. <Appendix 17> The method of claim 1, wherein the composition contains up to 40 mg of sertraline per ml of composition. <Appendix 18> 2. The method of claim 1, wherein the composition comprises 10-20 mg of amitriptyline per ml of the composition and further comprises 5-50 mg of sertraline per ml of the composition. <Appendix 19> 2. The method of claim 1, wherein the composition further comprises an antioxidant selected from vitamin A, vitamin C, vitamin D, and vitamin E. <Appendix 20> 2. The method of claim 1, wherein the composition is formulated as a local dosage form that delivers an effective dose of the active ingredient to the target area of ​​the patient in situ. <Appendix 21> 2. The method of claim 1, wherein the composition is formulated with a pharma- ceutical acceptable carrier to form a lotion, cream, ointment, or gel for localized delivery of the active ingredient to a target area of ​​the patient's skin. <Appendix 22> The method of claim 1, wherein the composition is formulated as a sublingual dosage form. <Appendix 23> The method of claim 1, wherein the composition is provided in a suppository form. <Appendix 24> The method of claim 1, wherein the composition is administered by a rectal plug device to deliver the FIASMA to the anorectal cavity. <Appendix 25> A pharmaceutical composition for treating cutaneous radiation injury (CRI), said composition comprising an effective amount of at least one functional inhibitor of acid sphingomyelinase (FIASMA). <Appendix 26> The pharmaceutical composition of claim 25, wherein treating CRI includes preventing CRI, reducing the incidence or recurrence rate of CRI, inhibiting, treating, ameliorating or reducing the severity of CRI, or reversing CRI. <Appendix 27> The pharmaceutical composition of claim 25, wherein the CRI is radiation dermatitis. <Appendix 28> The pharmaceutical composition of claim 25, wherein the CRI is oral mucositis. <Appendix 29> The pharmaceutical composition of claim 25, wherein the CRI is radiation rectal injury. <Appendix 30> The pharmaceutical composition of claim 25, wherein the FIASMA is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenoceptor blockers (ARBs), and beta-blockers. <Appendix 31> 26. The pharmaceutical composition of claim 25, wherein the FIASMA is an SSRI. <Appendix 32> 26. The pharmaceutical composition of claim 25, wherein the FIASMA is a TCA. <Appendix 33> 26. The pharmaceutical composition of claim 25, wherein the FIASMA is a TCA other than doxepin. <Appendix 34> 26. The pharmaceutical composition of claim 25, wherein the FIASMA is sertraline. <Appendix 35> 26. The pharmaceutical composition of claim 25, wherein the FIASMA is amitriptyline. <Appendix 36> 26. The pharmaceutical composition of claim 25, wherein the composition comprises 5 to 50 mg of at least one FIASMA. <Appendix 37> 26. The pharmaceutical composition of claim 25, wherein the composition contains up to 20 mg of amitriptyline per ml of the composition. <Appendix 38> 26. The pharmaceutical composition of claim 25, wherein the composition contains up to 40 mg of sertraline per ml of the composition. <Appendix 39> 26. The pharmaceutical composition of claim 25, wherein the composition comprises 10-20 mg of amitriptyline per ml of the composition and further comprises 5-50 mg of sertraline per ml of the composition. <Appendix 40> 26. The pharmaceutical composition of claim 25, wherein the composition further comprises an antioxidant selected from vitamin A, vitamin C, vitamin D, and vitamin E. <Appendix 41> 26. The pharmaceutical composition of claim 25, wherein the composition is formulated as a local dosage form that delivers an effective dose of the active ingredient to the target area of ​​the patient in situ. <Appendix 42> 26. The pharmaceutical composition of claim 25, wherein the composition is formulated with a pharma- ceutically acceptable carrier to form a lotion, cream, ointment, or gel for localized delivery of the active ingredient to a target area of ​​the patient's skin. <Appendix 43> 26. The pharmaceutical composition of claim 25, wherein the composition is administered in a sublingual dosage form. <Appendix 44> 26. The pharmaceutical composition of claim 25, wherein the composition is provided in the form of a suppository. <Appendix 45> The pharmaceutical composition of claim 25, wherein the composition is administered by a rectal plug device for delivering the FIASMA to the anorectal cavity. <Appendix 46> 26. A pharmaceutical composition according to claim 25, comprising an effective amount of FIASMA and not including an anti-inflammatory agent and not including an anesthetic agent.

Claims

1. A pharmaceutical composition for treating cutaneous radiation injury (CRI), said composition comprising an effective amount of sertraline.

2. 2. The pharmaceutical composition of claim 1, wherein treating CRI comprises preventing CRI, reducing the incidence or recurrence rate of CRI, inhibiting, treating, ameliorating or reducing the severity of, or reversing CRI.

3. The pharmaceutical composition of claim 1 , wherein the CRI is radiation dermatitis.

4. The pharmaceutical composition of claim 1 , wherein the CRI is oral mucositis.

5. The pharmaceutical composition of claim 1 , wherein the CRI is radiation proctopathy.

6. 10. The pharmaceutical composition of claim 1, wherein the composition comprises 5 to 50 mg of sertraline.

7. 2. The pharmaceutical composition of claim 1, wherein the composition comprises up to 40 mg of sertraline per ml of the composition.

8. 10. The pharmaceutical composition of claim 1, wherein the composition comprises 10-20 mg of amitriptyline per ml of the composition and further comprises 5-50 mg of sertraline per ml of the composition.

9. 10. The pharmaceutical composition of claim 1, wherein the composition further comprises an antioxidant selected from vitamin A, vitamin C, vitamin D, and vitamin E.

10. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated as a topical dosage form that delivers an effective dose of sertraline in situ to targeted areas of the skin of a patient in need of treatment for CRI.

11. 10. The pharmaceutical composition of claim 1, wherein the composition is formulated with a pharma- ceutically acceptable carrier to form a lotion, cream, ointment, or gel for localized delivery of sertraline to targeted areas of the skin of a patient in need of treatment for CRI.

12. The pharmaceutical composition of claim 1 , wherein the composition is administered in a sublingual dosage form.

13. The pharmaceutical composition of claim 1 , wherein the composition is provided in the form of a suppository.

14. 10. The pharmaceutical composition of claim 1, wherein the composition is administered by a rectal plug device for delivering the sertraline to the anorectal cavity.

15. 10. The pharmaceutical composition of claim 1, comprising an effective amount of sertraline and free of anti-inflammatory and anesthetic agents.

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