Compositions and methods for preventing and treating skin radiation injury

Abstract

Skin radioactive injury (CRI) is injury to the skin or subterranean tissue of animals, including mammals and humans, induced or caused by exposure to radiation of industrially or military related sources, such as radioactive substances used in nuclear power plants or nuclear weapons. Light skin lesions (e.g., sunburn due to overexposure to sunlight) are generally not considered to fall within the definition of CRI; however, the term CRI may include a dermatological condition (such as radiodermatitis) or other condition (such as radiorectal disease, oral mucositis, or severe oral mucositis), each of which may be observed following administration of medical radiation therapy to the body region for the treatment of cancer or other condition treatable with radiation. Disclosed are compositions and methods for treating skin radiation injury (CRI), including radiodermatitis, radiation rectal disease, or oral mucositis, with one or more acid sphingomyelinase function inhibitors (FIASMA).

Description

Technical Field

[0001] The present invention relates to compounds, compositions, and methods for treating skin conditions or disorders caused by radiation exposure. Background Art

[0002] Cutaneous radiation injury (CRI) is damage to the skin or underlying tissues of animals (including mammals and humans) induced or caused by exposure to radiation from industrial or military-related sources (e.g., radioactive materials used in nuclear power plants or nuclear weapons). Mild skin damage (e.g., sunburn caused by overexposure to sunlight) is generally not considered to fall within the definition of CRI; however, 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 can be observed after the administration of medical radiotherapy to a body region for the treatment of cancer or other radiation-treatable conditions.

[0003] Radiotherapy in the medical field has been successfully used to treat locally or regionally advanced cancers and can be used as a standalone treatment or as an adjunct to chemotherapy or surgery. However, radiation exposure in such treatments can cause severe burns to the skin and surrounding tissues as well as permanent changes in pigmentation. Up to 95% of patients receiving cancer radiotherapy will experience skin reactions. For example, certain skin reactions caused by radiotherapy administered to breast cancer patients are referred to as "radiation dermatitis."

[0004] Patients with head and neck cancers may experience an inflammatory response in the mouth due to damage to the epithelial cells of the oral lining after radiotherapy used to treat head and neck cancers, thereby causing conditions such as oral mucositis. When ulcerative lesions form in the mouth due to radiotherapy, or if the patient becomes unable to swallow solid food, the condition is considered "severe oral mucositis" or "SOM."

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

[0006] Given the prevalence of these conditions in cancer patients undergoing radiotherapy, several strategies and treatments have been proposed for patients suffering from radiation dermatitis, but these strategies and treatments have not shown great success. Aloe vera and topical vitamin C have been tried, but there has been no improvement in the results for irradiated breast tissue.

[0007] Other reports have shown that prophylactic and continuous use of topical corticosteroids or emollients containing dexpanthenol can improve but not prevent radiation dermatitis. Other reports have shown that moist skin care with 3% urea lotion delays the onset and reduces the grade of acute skin reactions in head and neck cancer patients irradiated through the skin. The negative side effects of corticosteroids are well-documented and their use is preferably avoided. Topical corticosteroids have little effect on pigmentation changes.

[0008] Biafine and Lipiderm have shown no radioprotective effect, while in retrospective analyses, significant cytoprotective effects on the skin have been shown since the use of amifostine.

[0009] Misoprostol, a prostaglandin E(1) analogue, has been found to be an effective radioprotectant in animal studies, preventing the carcinogenic transformation of Syrian hamster embryos exposed to radiation in utero. However, successful results have not been obtained in humans.

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

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

[0012] Recently, antioxidants formulated in suppositories such as vitamins A, C, and E have been described for the treatment of radiation proctopathy or proctitis. Suppositories are solid dosage forms that contain drugs for placement in the anus or vagina for the treatment of certain systemic conditions but can be used for topical treatment of anorectal and gynecological disorders. For example, a 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 who cannot receive drugs orally, whereby the drug is absorbed by the mucosa and distributed systemically. Examples of these types of rectal suppositories include the treatment of nausea and pain.

[0014] It has been proposed that damage to healthy tissue by radiotherapy may involve an endothelial response associated with signaling from the plasma membrane via the acid sphingomyelinase / ceramide pathway (Corre, I. et al., Intl. J. Mol. Sci. (2013) 14, 22678 - 22696). It has been proposed to protect against endothelial damage, for example, by inhibiting acid sphingomyelinase (ASM enzyme) activity as a means of limiting radiation toxicity in normal tissues. Corre, ibid., at 22685. Although ASM enzyme inhibitors are known, they have not been developed for topical administration and have not been shown to be effective in preventing or treating general CRI, or particularly radiation dermatitis, radiation proctopathy or oral mucositis.

[0015] It has not been previously known to use a class of ASM enzyme inhibitors called tricyclic antidepressants for treating 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 in situ (or non - systemic) treatment of radiation proctopathy or proctitis. Amitriptyline has been formulated in a suppository dosage form. However, amitriptyline suppositories have only been prepared for systemic delivery and treatment of depression - the known indication for amitriptyline. Another indication for amitriptyline suppositories for systemic delivery is insomnia, which takes advantage of the sleep - inducing side effect observed with amitriptyline. It has not been previously known to administer amitriptyline suppositories to patients who are undergoing or have undergone pelvic radiotherapy, or for treating radiation proctopathy or proctitis or any other in situ treatment within the lower bowel.

[0016] More specifically, amitriptyline has not been previously formulated in a dosage form (such as a suppository or other anorectal delivery device) for local treatment of radiation proctopathy or proctitis. Nor have tricyclic antidepressants such as amitriptyline been formulated as controlled - release formulations to bypass release in an environment such as the low pH environment (acidic pH less than 7) in the stomach, such that drug release occurs primarily in the intestine, preferably the lower intestine, for in situ delivery of the drug for treating radiation proctopathy or proctitis.

[0017] It has not been known that another class of ASM enzyme inhibitors, selective serotonin reuptake inhibitors (SSRI), are available in suppository form; nor has it been previously known to use SSRI for treating radiation proctopathy or proctitis.

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

[0019] It is not known that ASM enzyme inhibitors, such as TCAs (e.g., amitriptyline), or other tricyclic compounds (such as tricyclic antihistamines (e.g., loratadine or its metabolite desloratadine), or SSRIs (e.g., sertraline)) have been used to treat CRI conditions, such as radiation dermatitis or oral mucositis. These drugs (tricyclic antidepressants, and antihistamines and SSRIs) are typically formulated as solid oral dosage forms. However, it is not known that liquid oral dosage forms, such as oral solutions, suspensions, or emulsions (collectively or individually referred to herein as "mouthwashes" or simply "washes") containing tricyclic active ingredients or SSRIs have been formulated for the treatment of oral mucositis.

[0020] Patients who have reduced saliva production due to radiation damage to the salivary glands and have difficulty swallowing oral dosage forms or rapidly disintegrating solid oral dosage forms for oral dissolution may benefit from oral solutions, suspensions, or emulsions that can be used as mouthwashes or gargles to deliver the active ingredient to the mouth and damaged tissues within the oral cavity.

[0021] The continued and increasing use of radiotherapy in the treatment of cancer, and the lack of available prophylactic or therapeutic drugs for CRI, including radiation dermatitis or radiation proctopathy, are long-standing unmet patient needs affecting millions of patients. SUMMARY OF THE INVENTION

[0022] The present invention relates to a method for ameliorating or reducing the severity of, preventing, reducing the occurrence or recurrence of, inhibiting, treating, or reversing the following conditions: cutaneous radiation injury (CRI) caused by environmental exposure to radiation from industrial or military radioactive sources, or radiation dermatitis, radiation proctopathy, or oral mucositis (including severe oral mucositis or SOM) caused by therapeutic radiation procedures in cancer treatment. The term CRI generally includes radioactive damage to the outer layer of the skin or the dermis, but may also include damage to deeper skin layers, such as the subcutaneous or adipose layers. Radiation dermatitis, radiation proctopathy, and oral mucositis fall within the definition of CRI, but are generally considered conditions associated with dermal injury.

[0023] The method according to the invention comprises topically applying or spreading a composition comprising at least one inhibitor of acid sphingomyelinase (ASM enzyme) to the skin surface or mucosa of a patient suffering from CRI, including radiation dermatitis, radiation proctopathy or oral mucositis. Acid sphingomyelinase function inhibitors, known in the art by the acronym FIASMA, include certain selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), tricyclic antihistamines, antiarrhythmic agents, adrenergic receptor blockers (ARB), beta blockers, etc.

[0024] The SSRI that can be used in the method of the invention includes one or more of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline. The preferred SSRI is sertraline. According to a preferred embodiment, the dosage form of the invention comprises an ASM enzyme inhibitor, such as SSRI, in the following dosages: a dosage between 0.1 mg - 1000 mg; more preferably a dosage of about 1 mg - 500 mg, and most preferably a dosage of about 5 mg - 100 mg. It is contemplated that the preferred dosage is about 10 - 100 mg of SSRI, formulated as a 0.5% - 10% (w / w) composition. The topical composition generally comprises 0.5% - 5% of at least one FIASMA, preferably about 1% to about 4% of at least one FIASMA, more preferably about 1% to about 3% of at least one FIASMA, most preferably about 1.5% to about 2% of at least one FIASMA.

[0025] The dosage can vary, being lower in dosage forms that deliver the drug more rapidly to the site, or higher in dosage forms that release the drug slowly.

[0026] Tricyclic antidepressants (TCAs) that can be used in the methods or compositions of the present invention include one or more of the following: amineptine, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin (in combination rather than individually), 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 present invention contains amitriptyline in the following dosages: dosages between 0.1 - 1000 mg; more preferably dosages of about 1 mg - 100 mg, and most preferably dosages of about 5 mg - 50 mg. The preferred dosage is about 10 - 50 mg of TCA, formulated as a 1% - 5% (w / w) composition. The dosage can vary, being lower in dosage forms that deliver the drug more rapidly to the site, or higher in dosage forms that release the drug slowly.

[0027] More specifically, the method of the present invention comprises the following steps: - Providing a topical composition that contains a pharmaceutically effective amount of at least one FIASMA as an active ingredient, 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 before radiotherapy, after radiotherapy, or in both cases.

[0028] In a method of preventing radiation proctopathy, reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, improving the condition, or reducing the severity of the condition, or reversing the condition, the method may comprise the following steps: - Anorectal administration to a patient in need thereof, such as a patient undergoing radiotherapy in the pelvic region or suffering from radiation proctopathy or proctitis, of a dosage form that contains a pharmaceutically effective amount of one or more active ingredients, wherein at least one active ingredient is a FIASMA.

[0029] In a method of preventing oral mucositis or severe oral mucositis, reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, ameliorating the condition, or reducing the severity of the condition, or reversing the condition, the method may comprise the steps of: - providing a solid oral dosage form comprising FIASMA as an active ingredient, and - administering to a patient in need thereof, such as a patient undergoing radiotherapy for head and neck cancer, the solid oral dosage form comprising a pharmaceutically effective amount of one or more active ingredients, 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 an active ingredient.

[0030] In another method of preventing oral mucositis or severe oral mucositis, reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, ameliorating the condition, or reducing the severity of the condition, or reversing the condition, the method may comprise the steps of: - providing a liquid oral dosage form or "mouthwash" comprising one or more FIASMA as active ingredients in the form of a solution, suspension or emulsion, and - administering to a patient in need thereof, such as a patient undergoing radiotherapy for head and neck cancer, the liquid oral dosage form comprising a pharmaceutically effective amount of one or more FIASMA as active ingredients in the liquid oral dosage form.

[0031] Controlled release dosage forms for sublingual administration are known in the art and may slow the dissolution of the dosage form such that the release of the drug is prolonged over time, thereby maintaining the presence of the active drug in the oral cavity or increasing the residence time of the active drug in the oral cavity. Such controlled release dosage forms may be tablets, capsules, lozenges, pastilles, troches or film strips, etc., as would be recognized by one of ordinary skill in the pharmaceutical art. It is also known that controlled release dosage forms for sublingual administration dissolve or disintegrate rapidly in the oral cavity to provide immediate administration of the active ingredient in the dosage form. Thus, "controlled release" is not limited to slowing dissolution, but may be "controlled" in such a way as to rapidly disintegrate in the mouth and dissolve faster than the standard dissolution rate of an "immediate release" solid dosage form, where "immediate release" generally refers to release in the stomach with no significant delivery of the active substance prior to swallowing the dosage form.

[0032] One embodiment of the method according to the invention comprises topically applying or administering a composition comprising an effective amount of at least one FIASMA. It should be understood that applying or administering the composition before radiotherapy may comprise maintaining the composition in place before, during or after radiotherapy. The method may be repeated for each radiotherapy session and may comprise administering or applying the composition at least once a week, several times a week, daily or several times a day, before, after or between radiotherapy sessions. The method according to the invention may continue after completion of radiotherapy, for example, for 1-5 days after radiotherapy, for one to three weeks after radiotherapy or for one or more months after radiotherapy. Typically, the method comprises administering the composition from about one week to about one month after cessation of the radiotherapy session.

[0033] Another method according to the invention may comprise orally administering a composition comprising an effective amount of at least one FIASMA. Such oral compositions may be immediate release or controlled release solid dosage forms. For conditions affecting the oral cavity, such as oral mucositis or severe oral mucositis, an oral dosage form that is preferably dissolved in the oral cavity and not swallowed whole may be preferred.

[0034] In certain patients suffering from damage to the salivary glands and unable to produce sufficient saliva to dissolve solid dosage forms in the oral cavity, a liquid oral dosage form comprising FIASMA as the active ingredient may be the preferred dosage form. Such liquid oral dosage forms are referred to as "mouthwashes", "gargles", "rinses", "oral rinses", or may be used as "sprays". The preferred term used in this disclosure for liquid oral dosage forms is "mouthwash". These liquid oral dosage forms should be understood to be in the form of a liquid solution, emulsion or suspension and may contain thickening agents or gelling agents to increase the viscosity of the solution, emulsion or suspension.

[0035] In patients undergoing radiotherapy in the pelvic region, suffering from radiation proctopathy, the preferred method may comprise providing a solid suppository or rectal insert dosage form comprising a composition containing FIASMA and placing the dosage form in the rectal cavity for the period of time required to deliver the active ingredient to the site.

[0036] The invention also relates to a topical pharmaceutical composition comprising at least one functional inhibitor of acid sphingomyelinase (FIASMA) as the active drug or active substance, which can be used for preventing cutaneous radiation injury (CRI) (including radiodermatitis or radiation proctopathy), reducing the occurrence or recurrence of the condition, treating the condition, improving the condition, or reducing the severity of the condition, or reversing the condition.

[0037] The present invention may also include a suppository dosage form for use in preventing radiation proctopathy, reducing the occurrence or recurrence of the condition, treating the condition, ameliorating the condition, or reducing the severity of the condition, or reversing the condition.

[0038] The dosage forms of the present invention may comprise a soluble base and a TCA (e.g., amitriptyline), a tricyclic antihistamine (such as loratadine), an SSRI (such as sertraline), or a combination of one or more TCAs, tricyclic antihistamines, or SSRIs, and may further comprise other pharmaceutically acceptable excipients conventionally employed in pharmaceutically acceptable dosage forms.

[0039] In a method of delivering FIASMA to the anorectal cavity and administering the drug in situ using a suppository or rectal plug delivery device, the dosage form may be provided with or incorporated into a rectal plug delivery device as a controlled-release formulation having one or more excipients that can retard the release of the active drug, the active drug being incorporated into the dosage form or coated on the outer surface of the dosage form or on particles, pellets, or beads within the dosage form containing the active ingredient. A controlled-release dosage form for oral administration may also be provided, wherein the oral dosage form is formulated as a delayed-release dosage form that bypasses the acidic environment of the stomach and releases the active ingredient in the intestine at a pH higher than 7.0. Such controlled-release dosage forms may be formulated using an enteric coating on a tablet, provided within a delayed-release capsule or caplet, formulated in a sustained-release matrix composition, or a combination of the above.

[0040] In the case where 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 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 containing a TCA, or may accommodate a suppository dosage form containing a TCA active ingredient.

[0041] Alternative embodiments of rectal plug delivery devices useful for performing the methods of the present invention include porous compressible foam materials that are infused with or coated with a composition comprising a TCA (e.g., amitriptyline), an SSRI (e.g., sertraline), or a combination thereof. The devices described for the methods of the present invention may accommodate an effective dose of FIASMA or FIASMA combination between about 0.1 mg and about 1000 mg or greater.

[0042] The compositions according to the present invention may also comprise two or more active pharmaceutical ingredients formulated or mixed together in a single fixed-dose composition, such as compositions comprising two or more different TCAs, two or more different SSRIs, or a combination of one or more TCAs and one or more SSRIs, etc.

[0043] The composition for use in the method of the present invention may comprise one or more FIASMAs in an amount between about 0.1 - 1000 milligrams (mg). The topical composition useful in the method according to the present invention may be provided as a topical liquid, but is preferably formulated as a topical cream, gel, lotion or ointment. A preferred FIASMA that can be used as an active ingredient in the composition and method of the present invention is the SSRI sertraline. Another FIASMA that can be used as an active ingredient in the composition and method of the present invention is the TCA amitriptyline. Yet another FIASMA that can be used as an active ingredient in the composition and method of the present invention is the tricyclic antihistamine loratadine, or its metabolite desloratadine. Other FIASMA compounds may be substituted or may be provided in combination in the composition or method of the present invention.

[0044] The topical dosage form may comprise a conventional and commercially available pharmaceutical base composition that is pharmaceutically compatible with one or more FIASMAs used as one or more active ingredients, and may further comprise other pharmaceutically acceptable excipients conventionally employed in topical or oral dosage forms. These commercially available pharmaceutical bases can act as carriers or vehicles for the active pharmaceutical ingredient and may comprise one or more of emollients, penetration enhancers, solvents, gelling agents, thickening or viscosity increasing agents, preservatives or other suitable excipients commonly used in topical formulations.

[0045] Preferably, the FIASMA for topical administration is provided in an immediate release topical formulation that allows targeted drug delivery and immediately delivers the drug from the composition to the skin upon application or administration of the composition. The FIASMA component can preferably be retained at the site of application or administration. Thus, the composition of the present invention may exclude penetration enhancers to retain the composition and the active substance at the skin surface for a longer period of time relative to a composition that contains a penetration enhancer that allows or facilitates penetration of the active substance into or beneath the skin where it can be systemically absorbed. Alternatively, in certain cases, a penetration enhancer may be preferred and employed within the composition.

[0046] The oral dosage form of the composition can be immediate release or can be formulated with excipients (such as polymers, gels, gums, waxes, etc.), or incorporated into a matrix or include a coating to slow, delay, sustain, or extend the 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 can be formulated to dissolve in the oral cavity and can contain excipients that control, delay, slow, sustain, or extend the release of the drug from the dosage form. Alternatively, a solid oral dosage form can be formulated to dissolve or disintegrate rapidly in the oral cavity, for example, in the treatment of oral mucositis. A preferred dosage form for the treatment of oral mucositis is a liquid oral solution, emulsion, or suspension containing FIASMA, and preferably formulated as a mouthwash containing an SSRI such as sertraline.

[0047] According to another aspect of the invention, the dosage form can contain a second active substance, such as a TCA or SSRI component, or can contain a non-TCA or SSRI, for example, an active ingredient belonging to a different class of drugs, i.e., a second active ingredient other than tricyclic or SSRI. In a preferred embodiment, the composition contains a first active ingredient as a TCA and a second active ingredient as a different TCA or as an SSRI or a non-TCA compound of another class. 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 substance in the composition is not an anti-inflammatory agent (such as a non-steroidal anti-inflammatory drug (NSAID)), nor an anesthetic (such as a local anesthetic (e.g., lidocaine)).

[0048] In another preferred embodiment, the composition of the invention contains a first active ingredient as an SSRI and a second active ingredient as a different SSRI or as a TCA or a non-SSRI compound of another class. 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 substance in the composition is not an anti-inflammatory agent (such as a non-steroidal anti-inflammatory drug (NSAID)), nor an anesthetic (such as a local anesthetic (e.g., lidocaine)).

[0049] Preferably, the method is carried out using FIASMA formulated in a topical composition that can deliver an effective dose to a target skin area directly or indirectly exposed to radiation during radiotherapy or treatment. For example, the active ingredient can be formulated as a liquid composition and applied as drops to the target skin area. Alternatively, FIASMA can be formulated in a composition containing a thickening or viscosity-increasing agent to be used as a lotion, cream, ointment, or gel for topical application and to deliver FIASMA topically to the target skin area of the patient. Before or after radiotherapy, the topical formulation can be rubbed onto or into the target skin area.

[0050] In methods employing solid oral dosage forms, the active ingredient can be provided as granules, pellets, beads or other conventional forms and manufactured into dosage forms such as tablets, capsules, caplets, etc. as would be readily understood in the art. The oral dosage form can be provided as, for example, a controlled release dosage form where the active ingredient is formulated to be released from the final dosage form in a delayed manner after administration, such as in enteric coated tablets, delayed release capsules or caplets, or one or more active ingredients are formulated to be released slowly from the dosage form after administration, such as in a matrix composition.

[0051] In methods employing 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 can be included to provide color, flavor, viscosity and a pleasant taste for the patient to facilitate compliance. Combinations of these dosage forms can also be employed. A second active ingredient that is not a FIASMA can also be included. For example, a local anesthetic that can be used to relieve pain during and after treatment can be included, or a bactericide, other anti-inflammatory agent or antimicrobial agent can also be included.

[0052] Thus, according to the present invention, a method for preventing cutaneous radiation injury (CRI), reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, improving the condition or reducing the severity of the condition, or reversing the condition comprises topically administering to a skin target area of a patient in need thereof at least once daily before, during and after radiotherapy 0.5 - 50 ml or more (depending on the size of the area to be treated) of a composition comprising an effective amount, such as from about 0.1% to about 10% w / w of a FIASMA, such as a TCA (e.g., amitriptyline), a tricyclic antihistamine (e.g., loratadine), an SSRI (e.g., sertraline), or a combination of two or more FIASMA.

[0053] A method for preventing, treating or improving radiation dermatitis also comprises topically administering to a skin target area of a patient in need thereof at least once daily before, during and after radiotherapy 0.5 - 50 ml or more (depending on the size of the area to be treated) of a composition comprising an effective amount, such as from about 0.5% to about 10% w / w of a FIASMA, such as a TCA (e.g., amitriptyline), a tricyclic antihistamine (e.g., loratadine), an SSRI (e.g., sertraline), or a combination of two or more FIASMA.

[0054] The method further comprises preventing, treating or ameliorating radiation proctopathy by topically administering or delivering, to a target area of a patient in need thereof, at least once daily before, during and after radiotherapy, 0.5 - 50 ml or more (depending on the size of the area to be treated) of a composition comprising an effective amount, such as from about 0.5% to about 5% w / w of FIASMA, such as TCA (e.g., amitriptyline) or SSRI (e.g., sertraline).

[0055] A method for preventing, treating or ameliorating oral mucositis may comprise orally administering, to a skin target area or oral mucosa of a patient in need thereof, at least once daily before, during and after radiotherapy, 0.5 - 50 ml or more (depending on the size of the area to be treated) of a composition comprising an effective amount, such as from about 0.5% to about 10% w / w of FIASMA, such as TCA (e.g., amitriptyline) or SSRI (e.g., sertraline). It should be understood that the term "oral mucositis" includes "severe oral mucositis".

[0056] Preferred treatment of oral mucositis may employ dosage forms including slowly dissolving adhesive tablets (such as mucoadhesive tablets), oral rinses, or oral wafers or films, wherein the dosage form is disposed intraorally, for example, via the tongue or buccal surface, and wherein the dosage form is formulated to release the active ASM enzyme inhibitor, preferably about 1 - 50 mg of sertraline, over a period of about 15 minutes to one hour to release and deliver an active substance for protection from oral mucositis (including severe oral mucositis (SOM)).

[0057] One embodiment of an oral dosage form for treating oral mucositis or SOM comprises a lozenge or troche which is held in the mouth and slowly dissolved, so that the active ingredient is slowly released from the dosage form to provide local or in situ protection against CRI caused by radiotherapy in patients with head and neck cancer. It should be understood that the lozenge or troche may be formed to include a rod or handle that can be used as a handle for inserting and removing the dosage form, similar to a lollipop (''sucker'') or other persistent confectionery with a stick.

[0058] Such a ''lollipop'' system for delivering pharmaceutical ingredients to the oral mucosa is described. For example, U.S. Patent No. 6,103,257 describes a hard candy matrix mounted on a handle to form a lollipop, a method of making the hard candy and forming embodiments of the lollipop, and a method of using the hard candy or lollipop embodiments to deliver a local anesthetic to the oral mucosa. The disclosure of this U.S. Patent No. 6,103,257 is hereby incorporated by reference herein.

[0059] The topical composition employed in the method may contain 5 - 100 mg amitriptyline / ml of the composition, or may contain 1 - 100 mg sertraline / ml of the composition, or may contain 10 - 90 mg amitriptyline / ml of the composition and 1 - 50 mg sertraline / ml of the composition. Amitriptyline is preferably used at less than 40 mg / ml of the composition and more preferably at about 20 - 30 mg / ml of the composition.

[0060] The above topical composition may further contain antioxidants such as vitamin A, vitamin C, vitamin D, and vitamin E.

[0061] Preferably, the composition used in the method of the present invention is formulated into a topical dosage form that will deliver an effective dose of the active ingredient in situ to the target area of the patient. This can be done using the following composition, which is formulated with a pharmaceutically acceptable base to form a lotion, cream, ointment, or gel for topically delivering the active ingredient to the target area of the patient's skin. For the treatment of oral mucositis, the composition can be formulated into an oral solution, emulsion, or suspension, which will be referred to herein as a "mouthwash".

[0062] Alternatively, the composition may contain amitriptyline and a second tricyclic antidepressant that is not amitriptyline, such as amineptine, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin (in combination rather than alone), imipramine, iprindole, lofepramine, maprotiline, nortriptyline, norclomipramine, nordosulepin, protriptyline, thienepine, or trimipramine.

[0063] The composition containing sertraline may contain a second selective serotonin reuptake inhibitor that is not sertraline, such as citalopram, escitalopram, fluoxetine, fluvoxamine, or paroxetine.

[0064] The pharmaceutical composition of the present invention can be provided as a topical pharmaceutical composition or can be an oral dosage form (solid or liquid), and the pharmaceutical composition contains an effective amount of one or more active ingredients, such as amitriptyline, sertraline, or a combination thereof, in order to deliver the one or more active ingredients to the patient. In a preferred embodiment, the topical composition of the present invention does not contain, does not include, or excludes anti-inflammatory agents and anesthetics.

[0065] The preferred topical pharmaceutical composition contains 10 - 20 mg amitriptyline / ml of the composition, or 1 - 100 mg sertraline / ml of the composition, or 15 - 20 mg amitriptyline / ml of the composition and 1 - 10 mg sertraline / ml of the 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.

[0066] The oral dosage forms of the present invention can be formulated into controlled-release oral dosage forms, which are fast-dissolving oral dosage forms or slow or delayed-release dosage forms.

[0067] It should be understood that the methods, compositions, and dosage forms of the present invention can be used to prevent, treat, or improve other skin conditions, such as atopic dermatitis, thermal burns, sunburns, dermatofibromas, exposure-induced wrinkles, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 shows the results of skin injury examinations after 30 Gy focal irradiation. Panel A of Figure 1 is a summary of the skin injury scores of individual mice up to 4 weeks after 30 Gy. Panel B is a graphical representation of the change in the observed radioactive skin injury scores over time. Data are presented as mean ± SEM. N = 5 mice / treatment group.

[0069] Figure 2 shows the results of skin injury examinations after 30 Gy focal irradiation. Panel A of Figure 2 is a summary of the skin injury scores of mice treated with 4% sertraline three times before irradiation, 4% sertraline two times after irradiation, or placebo five times before and after irradiation. Skin injury scores were examined weekly up to 6 weeks after irradiation. Panels B - D of Figure 2 show the 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 two-way ANOVA with Bonferroni post-test.

[0070] Figure 3 Shows the percentage of patients treated with RAD-100 or the same vehicle during and after radiotherapy who had an RTOG score of 2 or higher.

[0071] Figure 4 Shows the effect of 1% sertraline on radiation-induced oral mucositis in mice. DETAILED DESCRIPTION

[0072] The present invention provides an innovative method for preventing skin conditions, reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, improving the condition, or reducing the severity of the condition, or reversing the condition in mammals (including humans), and novel compositions or dosage forms can be used for the use of the treatment method. The methods and compositions of the present invention can be used to treat cutaneous radiation injury or CRI.

[0073] As used herein, the term "treat, treating, treatment of" in relation to cutaneous radiation injury or "CRI" or a specific medical condition regarded as a type of CRI may mean or refer to any one of the following or may be replaced by any one of the following: "prevent CRI", "reduce the incidence of CRI", "reduce the recurrence of CRI", "inhibit CRI", "ameliorate CRI", "reduce the severity of CRI", "reverse CRI", or "treat CRI". The specific terms "prevent CRI", "reduce the incidence of CRI", "reduce the recurrence of CRI", "inhibit CRI", "ameliorate CRI", "reduce the severity of CRI", or "reverse CRI" are used when it is intended to specify only that treatment, or when it is intended not to imply a term, that term may be expressly excluded from "treatment". For example, a method for "reducing the incidence of..." may be used to mean only reducing the incidence of CRI and not "inhibiting" CRI. Alternatively, "exclude methods for treating CRI that reduce the incidence of CRI" may mean methods for preventing CRI, reducing the incidence of CRI, inhibiting CRI, ameliorating CRI, reducing the severity of CRI, or reversing CRI.

[0074] The term "cutaneous radiation injury" or "CRI" is recognized in the medical field as being defined as injury to the skin or underlying tissue of an animal (including mammals and humans) induced by exposure to radiation from industrial or military-related sources (e.g., radioactive materials used in nuclear power plants or nuclear weapons or medical radiotherapy). Thus, the term CRI can include medical conditions observed after medical radiotherapy, such as radiation dermatitis or radiation proctopathy. Mild skin injury (e.g., sunburn caused by excessive exposure to sunlight) is generally not considered to fall within the definition of CRI.

[0075] "Radiation dermatitis" refers to a skin disorder caused by radiotherapy to a body area. For example, radiotherapy is a known and accepted treatment for cancerous breast tissue in both females and males. Inflammation of the skin covering the targeted cancerous tissue and exposed to radiation can lead to injury to the skin. These signs and symptoms are referred to as radiation dermatitis. The term is used herein as it is clinically understood by dermatologists and other physicians treating such disorders.

[0076] "Radiation proctopathy" or its synonym "radiation proctitis" refers to a rectal disorder (including inflammation of the rectal mucosa) that causes a change in rectal function and is caused by radiotherapy to the pelvic region. Radiotherapy to the pelvic region is a known and accepted treatment procedure for genitourinary tissue cancers, such as treating prostate cancer in males or treating cervical cancer in females. The term is used herein as it is clinically understood by physicians treating such disorders.

[0077] "Oral mucositis" refers to a condition caused by radiotherapy used to treat head and neck cancer. A more severe condition, appropriately referred to as "severe oral mucositis" or "SOM", is usually associated with ulcerated tissue in the mouth or the patient's inability to swallow food or drink. Oral mucositis is a common and debilitating complication of cancer treatment, especially radiotherapy. It can cause a number of problems, including pain, nutritional problems due to inability to eat, and an increased risk of infection due to open ulcers in the oral mucosa. The term "oral mucositis" as used herein includes "severe oral mucositis", and these terms may be used interchangeably.

[0078] "Emulsion" is a general term encompassing macroemulsions, microemulsions or nanoemulsions. A macroemulsion is a kinetically stable dispersion of immiscible liquids. A microemulsion is a kinetically and thermodynamically stable dispersion of immiscible liquids with droplet sizes in the micrometer size range. A nanoemulsion is a kinetically and thermodynamically stable dispersion of immiscible liquids with droplet sizes ranging from about 20 nm to about 200 nm.

[0079] 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 FIASMA include certain selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), antihistamines (preferably tricyclic antihistamines such as loratadine or its metabolite desloratadine), antiarrhythmic drugs, antipsychotic drugs, antidiarrheal drugs, adrenergic receptor blockers (ARB), beta blockers, estrogen receptor modulators, etc.

[0080] Examples of SSRI available according to the present invention are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Preferred SSRI available according to the present invention include fluoxetine, fluvoxamine, paroxetine and sertraline.

[0081] Examples of TCA available according to the present invention are amonaptiline, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin (in combination rather than alone), imipramine, iprindole, lofepramine, maprotiline, nortriptyline, norclomipramine, nordosulepin, nortriptyline, opipramol, protriptyline, tianeptine and trimipramine. Preferred TCA available according to the present invention are amitriptyline, desipramine and imipramine.

[0082] Examples of tricyclic antihistamines useful according to the present invention include promethazine, cyproheptadine, latrepiridine, rupatadine, loratadine, and desloratadine. A preferred tricyclic antihistamine useful according to the present invention is loratadine.

[0083] The present invention includes the use of at least one FIASMA (such as a TCA), a tricyclic antihistamine, or an SSRI, and may include the use of at least two different FIASMA from the same drug class or at least two different FIASMA from different drug classes. For example, the present invention may include the use of at least two TCAs, at least one TCA and at least one SSRI or tricyclic antihistamine, or at least one of a TCA, tricyclic antihistamine, or SSRI, and at least one additional active ingredient that is not a TCA, tricyclic antihistamine, or SSRI to treat CRI.

[0084] A preferred TCA for use according to the present invention is amitriptyline. Amitriptyline, sold in the United States under the trade name (AstraZeneca PLC, Cambridge, UK), is mainly used to treat a variety of mental illnesses, including major depressive disorder, anxiety disorders, and less commonly attention deficit hyperactivity disorder (ADHD) and bipolar disorder. Other uses include preventing migraines, treating neuropathic pain (such as fibromyalgia and postherpetic neuralgia), and less commonly insomnia.

[0085] A preferred SSRI for use according to the present invention is sertraline. Sertraline, sold in the United States under the trade name (Pfizer, New York, NY, USA), is mainly 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).

[0086] Preferred tricyclic antihistamines useful according to the present invention are loratadine (the active ingredient in the antihistamine product Claritin), or the loratadine metabolite desloratadine (the active ingredient in the antihistamine product Clarinex).

[0087] It has not previously been known that amitriptyline, loratadine, and sertraline can be used to prevent or treat cutaneous radiation injury (CRI), including radiation dermatitis.

[0088] In a preferred embodiment, at least one FIASMA can be incorporated into a topical pharmaceutical composition for administration by placement or application onto the surface of the skin or mucosa to prevent, ameliorate, or treat a skin condition or disorder, such as radiation dermatitis or oral mucositis. This composition can be administered once daily, or more or less frequently as prescribed by the patient's physician or healthcare provider.

[0089] Topical compositions or formulations as dosage forms are well known in the art and are routinely used in medical treatment. A preferred embodiment of the present invention is to incorporate FIASMA into a pharmaceutically compatible base composition to form a topical lotion, cream, gel, or ointment containing at least one FIASMA as the active pharmaceutical ingredient (API) or agent. Another embodiment of the present invention includes incorporating at least two different FIASMA (e.g., a combination of at least one TCA and at least one SSRI) as active agents into a pharmaceutically compatible base composition to form a topical lotion, cream, gel, or ointment. Preferred embodiments include thoroughly mixing one or more active ingredients into a pharmaceutically acceptable cream or lotion base to provide a homogeneous mixture. For active ingredients that are not completely soluble in the base, a suspension can be formed, wherein the suspension contains the thoroughly mixed active ingredient to uniformly disperse the active ingredient throughout the base. The compositions of the present invention can contain other pharmaceutically acceptable excipients conventionally employed in topical dosage forms. For example, stabilizers, emulsifiers, and penetration enhancers can be included as needed and in accordance with conventional topical pharmaceutical formulation practices.

[0090] In another embodiment of the present invention, active ingredients, such as one or more TCAs, tricyclic antihistamines, or SSRIs, can be formulated for oral administration. In one embodiment, the oral dose is provided as a solid oral dosage form in an immediate release formulation. In one embodiment, the solid oral dosage form is provided as a controlled release formulation. Yet another oral dosage form is a liquid oral dosage form containing an effective amount of FIASMA, such as the SSRI sertraline. It has been determined that tricyclic antihistamines can provide a preferred flavor profile or taste for oral dosage forms for in situ oral or buccal treatment. These liquid oral dosage forms are referred to as "mouthwashes", "gargles", "oral rinses", or "sprays". The preferred term used in this disclosure for liquid oral dosage forms is "mouthwash". These liquid oral dosage forms should be understood to be in the form of a liquid solution, emulsion, or suspension, and can contain thickening agents or gelling agents to increase the viscosity of the solution, emulsion, or suspension, thereby prolonging the retention or residence time of the composition at the target site.

[0091] In one embodiment, the solid oral dosage form provided by the present invention for sublingual or buccal administration comprises a pharmaceutical composition in unit dosage form (e.g., lozenge or troche, pill, tablet, film or strip) comprising at least one FIASMA, and is prepared as a controlled release formulation in a preferred embodiment. Regarding the size of the unit dosage form (e.g., lozenge), the simplicity and cost of production, as well as consumer preferences, will also be considered. The size of the sublingual or buccal dosage form can 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. If the sublingual or buccal dosage form has a circular or nearly circular shape, the size range is the appropriate diameter value. In most cases, the thickness of the lozenge will be from 1 mm to 10 mm, and more generally from 3 mm to 5 mm.

[0092] The sublingual or buccal dosage form can be in the form of a single layer, bilayer or multilayer. The sublingual or buccal dosage form having soluble mucoadhesive properties can be made by compressing powders (including mucoadhesive hydrocolloids). For example, an adhesive lozenge can be made by mixing dry powders including gum arabic for the adhesive property and at least one FIASMA as the active ingredient. The residence time of the sublingual or buccal dosage form in the oral cavity can be optimized according to the dissolution rate and total dissolution time of the product. For example, a sublingual or buccal controlled release lozenge, mucoadhesive tablet or film can be prepared to have a residence time in the oral cavity of at least 1 minute, preferably between 1 and 30 minutes and more preferably 5 - 15 minutes after administration.

[0093] In one aspect of the present invention, the sublingual or buccal dosage form is a mucoadhesive tablet. The mucoadhesive tablet for sublingual or buccal administration can be made by compressing at least one mucoadhesive polymer for imparting mucoadhesion and at least one FIASMA as the active ingredient. The mucoadhesive polymer can be one or more selected from the group consisting of: cellulose-based polymers, gum-type polymers, nonionic polymers, anionic polymers, their derivatives, their mixtures, etc. The cellulose-based polymers can be hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, carboxymethyl cellulose, carboxypropyl cellulose, their mixtures, etc. The gum-type polymers can be xanthan gum, carrageenan, karaya gum, etc. The nonionic polymers can be polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide, etc. The anionic polymers can be polyacrylic acid, the polymer and its neutralized polymer, other polyalkyl vinyl ether-maleic acid copolymers (trade name Gantrez), polyalginic acid and its salts, chitosan, hyaluronic acid and its derivatives, etc.

[0094] Mucosal adhesive tablets may have a backing layer to delay the rate of disappearance of the formulation in 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: polyvinyl acetate; ethyl cellulose; propyl cellulose; polymethyl methacrylate; methacrylic acid copolymers, such as methacryloyloxyethyl betaine / methacrylate copolymer, methacrylic acid copolymer (methacrylic acid copolymer; Eudragit L 100, Eudragit L 12,5, Eudragit L 100-55, Eudragit L 30D-55), aminoalkyl methacrylate copolymer; Eudragit E 100, Eudragit E 12,5, Eudragit RL100, Eudragit RL 30D), cellulose acetate phthalate, and mixtures thereof. Waxes may include: carnauba wax, yellow wax, white wax, etc. Additionally, any polymer that does not melt under oral conditions between pH 6 and 8 can also be used as the backing layer.

[0095] In another aspect, the present invention features a pharmaceutical composition formulated in a unit dosage form for oral administration, such as sublingual or buccal administration, the unit dosage form comprising from about 5 to 100 mg of FIASMA (e.g., a dosage form comprising 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, 85 mg, 90 mg, 95 mg, 100 mg or more sertraline).

[0096] In another aspect, the present invention features a pharmaceutical composition formulated in a unit dosage form for oral administration, such as sublingual or buccal administration, the unit dosage form comprising from about 5 to 100 mg of FIASMA (e.g., a dosage form comprising 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, 85 mg, 90 mg, 95 mg, 100 mg or more loratadine, or its metabolite desloratadine). In a preferred embodiment, the dosage form for oral administration for sublingual or buccal administration can be provided in the form of a lollipop, the shape of which can be determined as needed, and comprising a stick or handle made of paper or plastic as a grip to facilitate insertion into and removal from the oral cavity.

[0097] Alternatively, the oral dosage form can be a liquid dosage form, such as an oral solution, emulsion or suspension, which contains about 1% to about 10% (w / w) of FIASMA in a pharmaceutically acceptable and compatible carrier, such as an SSRI like sertraline. A preferred oral solution contains 10% sertraline. The controlled-release oral dosage form includes a delayed-release formulation 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.

[0098] The compositions of the present invention may contain conventional additives or other excipients, such as plasticizers, pigments, colorants, stabilizers, glidants, etc.

[0099] In one embodiment, FIASMA is provided in an oral dosage form as a controlled-release formulation, which allows for the delivery of the drug over a period of time compared to an immediate-release formulation that provides immediate delivery of all 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., hydroxypropyl methylcellulose, or HPMC) or polyacrylamide (e.g., )) formulated with an active agent and a suitable vehicle.

[0100] The present invention provides a method for preventing, ameliorating or treating CRI by administering FIASMA. The method includes the steps of providing a composition containing between about 0.001 - 100 grams of the active ingredient, and delivering the drug to a patient in need thereof, the drug being delivered directly to the skin as a topical composition (such as a cream or lotion or ointment), or formulated in an oral dosage form.

[0101] According to a preferred embodiment, the FIASMA contained in the topical dosage form is amitriptyline, which is provided in the following doses: a dose between 1 - 1000 mg; more preferably a dose of about 5 mg - 150 mg, and most preferably a dose of about 10 - 100 mg, administered as a topical composition of about 0.5% to about 10% w / w. For example, a composition containing 1% to 10% active ingredient (10 - 100 mg active ingredient / 1 ml composition) can be topically applied in an amount of about 0.5 ml to about 5 ml per application or a greater amount, depending on the size of the area to be treated. Preferably, the composition is topically administered in an amount of about 1 ml to about 2 ml to deliver 10 - 100 mg of the active ingredient to the skin for the prevention or treatment of CRI.

[0102] In another preferred embodiment, the FIASMA contained in the topical dosage form is sertraline, which is provided in the following dosages: dosages between 1 - 1000 mg; more preferably dosages of about 5 mg - 150 mg, and most preferably dosages of about 10 - 100 mg, administered as a topical composition of about 0.1% to about 10% w / w. For example, a composition containing 0.1% to 10% active ingredient (1 - 100 mg active ingredient / 1 ml composition) can be topically applied in an amount of about 0.5 ml to about 5 ml per application or a greater amount, depending on the size of the area to be treated. Preferably, the composition is topically administered in an amount of about 1 ml to about 2 ml to deliver 1 - 200 mg of active ingredient to the skin for the prevention or treatment of CRI.

[0103] One preferred dosage is to administer at least 1 ml of a composition according to the invention containing 1% of FIASMA as the active ingredient. Another preferred dosage is to administer at least 1 ml of a composition according to the invention containing 2% w / w of FIASMA active ingredient. Still another preferred dosage is to administer at least 1 ml of a composition according to the invention containing 3% w / w of FIASMA active ingredient. Yet another preferred dosage is to administer at least 1 ml of a composition according to the invention containing 4% w / w of FIASMA active ingredient. Additional preferred dosages are to administer at least 1 ml of a composition according to the invention containing 5% w / w of FIASMA active ingredient. Preferred dosages can include administering at least 1 ml of a composition according to the invention containing 6%, 7%, 8%, 9%, 10% or greater than 10% w / w of FIASMA active ingredient.

[0104] It should be understood that the concentration of the drug can be provided in increments of about 0.05%. By way of non-limiting illustration, FIASMA can be provided at concentrations of 1.05%, lollipop%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, etc., up to 10% to achieve the desired effect without negative side effects.

[0105] The dosage contained within the dosage form can vary, being lower in dosage forms that deliver the drug more rapidly to the site or higher in dosage forms that deliver the drug slowly to the site. The dosage variation may also depend on one or more active ingredients contained within the composition. For example, a composition containing more than one FIASMA can contain less than 10% of each active substance, such as 0.1% - 9.9%, preferably about 0.5% to about 5% of each active substance, such that the final composition contains about 1% to less than 10% of the total active ingredient. This can advantageously reduce the dosage 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 can provide a synergistic effect, where the efficacy is greater than the expected additive effect from the corresponding active ingredients used alone.

[0106] Preferably, the FIASMA for topical administration is provided in an immediate-release topical formulation that allows for targeted drug delivery and immediately delivers the drug from the composition to the skin upon application or administration of the composition. The FIASMA component can preferably be retained at the site of application or administration. Thus, the compositions of the present invention can exclude penetration enhancers to retain the composition and the active substance at the skin surface for a longer period of time relative to compositions containing penetration enhancers that allow or facilitate the penetration of the active substance into or beneath the skin, where it can be systemically absorbed. Alternatively, in certain cases, a penetration enhancer can be preferred and employed within the composition.

[0107] In another aspect of the present invention, the dosage form can contain a second active substance, such as a TCA, tricyclic antihistamine, or SSRI component, or can contain a second active substance that is not a TCA, tricyclic antihistamine, or SSRI, e.g., the second active substance is an active ingredient in a different drug class. In a preferred embodiment, the composition contains a first active ingredient that is a TCA and a second active ingredient that is a different TCA, tricyclic antihistamine, or SSRI or a non-TCA compound of another class. 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 substance in the composition is not an anti-inflammatory agent (such as a non-steroidal anti-inflammatory drug (NSAID)) or an anesthetic (such as a local anesthetic (e.g., lidocaine)).

[0108] 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, tricyclic antihistamine, or other non-SSRI compound of another class. 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 substance in the composition is not an anti-inflammatory agent (such as a non-steroidal anti-inflammatory drug (NSAID)), nor an anesthetic (such as a local anesthetic (e.g., lidocaine)).

[0109] The topical formulation can comprise a conventional and commercially available pharmaceutical base composition that is pharmaceutically compatible with one or more FIASMAs used as one or more active ingredients and can further comprise other pharmaceutically acceptable excipients conventionally employed in topical or oral formulations. These commercially available pharmaceutical bases can serve as carriers or media for the active pharmaceutical ingredients and can comprise one or more of emollients, penetration enhancers, solvents, gelling agents, thickening agents, or tackifiers, preservatives, or other suitable excipients commonly used in topical formulations. In one embodiment, the commercially available pharmaceutical base is PENCream, an oil-in-water vanishing base available from Humco TM obtained.

[0110] The topical compositions containing FIASMAs useful according to the present invention can be formulated as is conventionally known in the pharmaceutical art and can comprise one or more additional ingredients or excipients, such as at least one preservative, at least one solvent, at least one thickening agent, at least one surfactant, at least one hardening agent, at least one emulsifying agent, at least one anti-tack agent, mixtures thereof, and the like.

[0111] Preservatives for topical compositions can include phenoxy-2-ethanol, benzyl alcohol Emprove, etc. Solvents for topical compositions can include glycerol, propylene glycol-1,2, etc. Thickening agents for topical compositions can include Carpool ETD2020, xanthan gum, etc. Surfactants for topical compositions can include Brij S721, SP-Brij S2-MBAL, etc. Hardening agents for topical compositions can include hydrogenated oils, such as Kolliwax HCO, etc. Emulsifying agents for topical compositions can include Miglyol 812N, etc. Anti-tack agents for topical compositions can include Q7-9120 silicone fluid, etc.

[0112] The present invention provides a method for treating anorectal disorders by in situ administration of an active pharmaceutical ingredient of the present invention, such as TCA (e.g., amitriptyline), tricyclic antihistamines (e.g., loratadine), SSRI (e.g., sertraline), or a combination thereof. The method comprises the steps of providing a composition comprising between about 0.001 - 100 grams of the active ingredient, and delivering the drug directly to the anorectal region, the drug being in the form of a topical composition, such as a cream or lotion or ointment, or formulated in a suppository or rectal plug dosage form. According to a preferred embodiment, the TCA contained within the suppository or rectal plug dosage form is amitriptyline in the following dosages: between 1 - 1000 milligrams (mg); more preferably between about 5 mg - 150 mg, and most preferably between about 10 - 100 mg, where one preferred dosage is a suppository or other dosage form containing about 50 mg. In another preferred embodiment, the SSRI contained within the suppository or rectal plug dosage form is sertraline in the following dosages: between 1 - 1000 milligrams (mg); more preferably between about 5 mg - 150 mg, and most preferably between about 10 - 100 mg, where one preferred dosage is a suppository or other dosage form containing about 100 mg. The dosage contained within the suppository or rectal plug may vary, being lower in dosage forms that deliver the drug more rapidly to the site, or higher in dosage forms that deliver the drug slowly to the site. Additionally, in cases where two or more active pharmaceutical ingredients are provided in a fixed-dose combination suppository product, the dosage of each active ingredient may be reduced within the dosage form and thereby advantageously reduce the risk or occurrence of side effects.

[0113] Preferably, the method comprises providing a solid suppository or rectal plug dosage form comprising a composition having TCA or SSRI as the active ingredient, and placing the dosage form within the rectal cavity for a period of time required to deliver the active ingredient to the site. The composition provided within the rectal plug delivery device may be a suppository.

[0114] Alternatively, the drug may be delivered using a rectal delivery device such as a rectal plug, the rectal delivery device containing an effective dose of an active ingredient, such as 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 forming a chamber for containing the active ingredient. The active ingredient may be provided as a soluble suppository, the soluble suppository being disposed within a portion of the chamber formed within the porous rectal plug housing. The suppository is exposed to body fluids upon administration to cause dissolution and in situ delivery of the active ingredient from the suppository. 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 for filling the chamber within the rectal plug housing.

[0115] Other types of rectal plugs are known and can be adapted for use in accordance with the present invention. For example, rectal plugs formed from porous spongy polymeric materials such as polyurethane foam are known for use in fecal incontinence. Such rectal plugs are sold under the name PERISTEEN TM Anorectal Plug (Coloplast Corp., North Minneapolis, MN, USA). A solution containing an effective amount of FIASMA can be infused into the polyurethane foam, and the FIASMA can be adsorbed to the material for delivery upon insertion into the rectal cavity. These commercially available rectal plugs are typically provided in a compressed configuration for ease of insertion and are wrapped in a water-soluble film that dissolves after insertion and can expand into an extended configuration. This compression and expansion are not required for in situ delivery of the drugs according to the present invention.

[0116] The rectal plug delivery device can include a distal flange 102 to prevent the entire rectal plug delivery device from being introduced into the rectal cavity, thereby holding the rectal plug device in place during administration of the active ingredient. The active ingredient, such as TCA or SSRI, can be provided as a pharmaceutical composition that is housed within a cavity (not shown) formed within the elongate member. The proximal end of the elongate member 101 includes a hole 103 for allowing body fluid to enter the cavity formed within the elongate member and for allowing the active ingredient to be discharged from the composition contained within the elongate member. The rectal plug delivery device can have an extension (such as a strap or cord) attached to the distal flange to facilitate removal of the rectal plug delivery device, which functions similar to the removal of a tampon.

[0117] The composition for rectal administration can be formed as a suppository that dissolves or melts when administered within the rectal cavity. Alternatively, the composition can be an amorphous or unformed composition including a gel, cream, or ointment. Preferably, the composition is provided as a controlled release composition, preferably an extended release composition, such that the active ingredient is released from the composition over time.

[0118] In another embodiment, the dosage form includes an anal plug comprising a soft, compressible porous material (e.g., foam rubber or polymeric spongy material), wherein the active ingredient is infiltrated or infused within, or coated onto, the porous compressible plug material.

[0119] The rectal plug delivery device of the present invention can include a soft, compressible, and porous material in an expanded configuration. In this embodiment, the rectal plug delivery device includes a drug delivery component at its proximal end that expands upon insertion into the rectal cavity and conforms to the shape of the rectal cavity. Attached to the drug delivery component is an extension (such as a strap or cord) to facilitate removal of the rectal plug delivery device, which functions similar to the removal of a tampon.

[0120] A composition comprising an active ingredient according to the present invention can be injected or infiltrated into a porous material forming a delivery component as a liquid or a gel, cream or ointment. The composition comprising the active ingredient can be provided as a controlled release composition, preferably an extended release composition, so as to release the active ingredient over time.

[0121] A rectal suppository delivery device comprising a porous material can be provided in a compressed form to facilitate insertion into the rectal cavity. The compressed drug delivery component can include a water-soluble wrapper surrounding the drug delivery component. After the rectal suppository delivery device embodiment is inserted into the rectal cavity, body fluids dissolve the wrapper and allow the drug delivery component to expand to its expanded configuration. An extension (such as a strap or string) can be provided to facilitate removal of the rectal suppository delivery device.

[0122] In a preferred embodiment, the active ingredient is provided in a controlled release formulation which allows for the delivery of the drug over a period of time as compared to an immediate release formulation which provides for the delivery of all of the drug from the dosage form immediately 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., hydroxypropyl methylcellulose, or HPMC) or polyacrylamide (e.g., )) formulated with an active agent and a suitable vehicle which melts or dissolves in rectal fluid. Such formulations and compositions and methods of making suppositories or other controlled release compositions are well known in the art.

[0123] In the method according to the present invention, treating CRI such as radiation dermatitis employs a composition comprising at least one FIASMA such as TCA (e.g., amitriptyline), and / or at least one second FIASMA such as a tricyclic antihistamine (e.g., loratadine), or an SSRI (e.g., sertraline). The composition employed in the method of the present invention can be provided in a topical dosage form. Additionally, the present 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 (such as amitriptyline) and / or at least one SSRI (such as sertraline).

[0124] Preferably, the method comprises providing a topical dosage form that comprises a composition having at least one FIASMA as an active ingredient in the composition and placing an effective amount of the composition onto a target skin area to be treated for a period of time required to continuously deliver the active ingredient to the site. In a preferred embodiment, one or more active ingredients can be formulated into a viscous controlled release gel, ointment or cream for application to the skin. The topical composition of the present invention preferably comprises from about 0.1% concentration (1 mg / ml of the composition) to about 10% concentration (100 mg / ml of the composition) of each provided active ingredient; for example, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0% and 1.05%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6% etc., in 0.05% increments up to about 10.0%. Typical doses are from about 0.5 ml to about 5 ml, preferably from about 1 ml to about 2 ml, but are not limited thereto and are limited only by the skin area to be treated such that doses of about 3 ml, 4 ml, 5 ml or greater can be applied. The topical formulation can be rubbed onto or into the target skin area before or after radiotherapy.

[0125] In another preferred embodiment, the FIASMA for topical administration is provided in an immediate release topical formulation that allows targeted drug delivery and immediately delivers the drug from the composition to the skin upon application or administration of the composition. The FIASMA component can preferably be retained at the site of application or administration. Thus, the compositions of the present invention can exclude penetration enhancers to retain the composition and the active substance on the skin surface for a longer period of time relative to compositions that contain penetration enhancers that allow or facilitate penetration of the active substance into or beneath the skin where it can be systemically absorbed.

[0126] Alternatively, in some cases, penetration enhancers can be preferred and employed within the composition.

[0127] It should be understood that applying or administering the composition before radiotherapy may include maintaining the composition in place during the radiotherapy period. The method may be repeated for each radiotherapy period and may include applying or administering the composition at least once a week, several times a week, daily or multiple times a day, before, after or between radiotherapy periods. The method according to the invention may continue for up to one month or up to one week after the radiotherapy period has ceased. In an alternative embodiment, the method according to the invention may continue for one week after the radiotherapy period has ceased.

[0128] According to one embodiment of the invention, the method of the invention comprises the steps of: Topically administering an effective dose of one or more active ingredients (i.e., a drug as 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 who is about to undergo or is undergoing radiotherapy with a drug and is suffering from radiation dermatitis or radiation proctopathy.

[0129] In a method of preventing oral mucositis or severe oral mucositis, reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, improving the condition, or reducing the severity of the condition, or reversing the condition, the method may comprise the steps of: - providing a solid oral dosage form comprising FIASMA as an active ingredient, and - administering to a patient in need thereof, such as a patient undergoing radiotherapy for head and neck cancer, a controlled release sublingual dosage form comprising a pharmaceutically effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA.

[0130] In one embodiment, the solid oral dosage form is a modified release dosage form for sublingual administration comprising FIASMA as an active ingredient.

[0131] In another method of preventing oral mucositis or severe oral mucositis, reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, improving the condition, or reducing the severity of the condition, or reversing the condition, the method may comprise the steps of: - providing a solid oral dosage form comprising FIASMA as an active ingredient, and - administering to a patient in need thereof, such as a patient undergoing radiotherapy 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. In one embodiment, the solid oral dosage form is a modified release dosage form for buccal administration comprising FIASMA as an active ingredient.

[0132] In yet another method of preventing oral mucositis or severe oral mucositis, reducing the occurrence or recurrence of the condition, inhibiting the condition, treating the condition, ameliorating the condition, or reducing the severity of the condition, or reversing the condition, the method can comprise the steps of: - providing a liquid oral dosage form or "mouthwash" comprising FIASMA as an active ingredient, and - administering the mouthwash dosage form to a patient in need thereof, such as a patient undergoing radiotherapy for head and neck cancer, the mouthwash dosage form comprising a pharmaceutically effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA.

[0133] In a method for treating radiation proctopathy, the method of the invention comprises the steps of: administering an effective dose of one or more FIASMA drugs as active ingredients, preferably drugs selected from the class of TCA, SSRI or combinations thereof, to the rectal lumen or rectal tissue of a patient in need thereof (such as a patient suffering from radiation proctopathy or proctitis caused by medical radiotherapy).

[0134] A preferred method for treating radiation proctopathy comprises administering an effective dose of FIASMA as an active ingredient, such as amitriptyline (TCA), loratadine (a tricyclic antihistamine), or sertraline (SSRI), by an anorectal route. Combinations can also be used that contain two or more different FIASMA, or a fixed-dose combination of one or more FIASMA and non-FIASMA active ingredients. In a preferred example, the method is carried out using amitriptyline formulated into a composition and provided in a dosage form capable of delivering an effective dose in situ to the rectal lumen of the patient. For example, amitriptyline can be formulated as a liquid and administered as an enema, or can be formulated with a thickening or viscosity-increasing agent to provide a lotion, cream, ointment or gel for topical delivery of amitriptyline to the anorectal area and rectal lumen of the patient.

[0135] Alternatively, the method can employ a semi-solid or solid dosage form (such as a suppository or rectal plug delivery device) for delivering the active pharmaceutical ingredient to the anorectal cavity and administering the drug in situ. Preferably, the dosage form provided or incorporated into the rectal plug delivery device is a controlled-release formulation having excipients that can delay or retard the release of the active drug incorporated into or coated onto the outer surface of the dosage form.

[0136] In the case where the dosage form is a rectal suppository delivery device, the device can be an insoluble suppository forming a housing having an internal chamber for containing therein a composition comprising an active pharmaceutical ingredient according to the present invention. For example, the chamber of the rectal suppository can be filled with a viscous composition containing the FIASMA active ingredient, or can accommodate a suppository dosage form containing FIASMA as the active ingredient.

[0137] Alternative embodiments of the rectal suppository delivery device that can be used to carry out the method of the present invention include a porous compressible foam material that is infused with or coated with a composition comprising an active pharmaceutical ingredient according to the present invention. The device described for the method of the present invention can accommodate an effective dose of FIASMA, with the amount of FIASMA provided being between about 0.1 mg and about 1000 mg or greater.

[0138] The method of the present invention can further comprise administering to a patient in need at least one active ingredient and an additional or second active ingredient that is not FIASMA. Preferably, the additional active substance is formulated in a fixed-dose combination pharmaceutical product together with at least one TCA, at least one SSRI, or a combination of TCA and SSRI.

[0139] A preferred embodiment of the composition having a first active substance and a second active substance comprises a TCA or SSRI and an anti-inflammatory agent, an anesthetic, or an antioxidant. The anti-inflammatory agent can be a steroid or a non-steroidal anti-inflammatory drug (NSAID). Alternatively, the second active substance in the composition is not an anti-inflammatory agent, where the composition excludes steroid compounds, or the composition excludes non-steroidal anti-inflammatory drugs (NSAIDs). The anesthetic can be a local anesthetic commonly used for topical administration, such as lidocaine. The antioxidant can be, for example, vitamin A, vitamin C, vitamin D, and vitamin E.

[0140] The present invention includes a composition for treating radiation proctopathy, the composition comprising providing an effective amount of FIASMA, the FIASMA being formulated as a controlled-release formulation for in situ delivery of the active ingredient to the rectal lumen. In a preferred embodiment, the composition can 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 one or more active ingredients. The composition can contain additional drugs that are not FIASMA as described herein.

[0141] The active pharmaceutical ingredient contained in the suppository or rectal delivery device can be administered before, during, or after pelvic radiotherapy. Preferred administration includes 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 the entire dose has been delivered. The preferred suppository according to the invention can dissolve slowly and remain for a period of up to about 24 hours, i.e., for daily use. The rectal plug delivery device can remain in the rectal cavity for a period of up to about 48 hours, but preferably comprises a pharmaceutical formulation that delivers a dose of one or more active ingredients within about 24 hours. This provides for daily use after defecation. Alternatively, the rectal plug can be temporarily removed for defecation and reinserted.

[0142] The suppository containing the active pharmaceutical ingredient is placed to remain in the rectal cavity for the period required to dissolve. Since the suppository is completely soluble, after the suppository has remained in the rectum, release of the active ingredient from the suppository will occur. The released active ingredient will be present at a high concentration at the delivery site, thereby enhancing the effectiveness of this therapy for anorectal disorders.

[0143] It should be understood that applying or administering the composition before radiotherapy can include maintaining the composition in place during the radiotherapy session. The method can be repeated for each radiotherapy session and can include administering or applying the composition at least once a week, several times a week, daily, or several times a day, before, after, or during the radiotherapy session. The method according to the invention can continue for up to one month or up to one week after the radiotherapy session has stopped. In an alternative embodiment, the method according to the invention can continue for one week after the radiotherapy session has stopped.

[0144] According to an alternative embodiment, the suppository can comprise or consist of: other drugs or supplements, such as antioxidants, including vitamin E and vitamin C, and natural antioxidants such as fish oil, green tea, cranberries, etc. These can be used as different suppository formulations or as additional components of the suppository according to the invention.

[0145] These uses and in any embodiment of the invention, the suppository form of these agents is used for the clinical treatment of chronic anorectal diseases.

[0146] Any form of active ingredient contemplated by the present invention for placement in the form of a suppository for the treatment of anorectal diseases is within the scope of the present invention. Additionally, within the present invention is embodied the incorporation of the active pharmaceutical ingredients described herein in combination with other active or inactive ingredients into the suppository for the treatment of anorectal diseases. Additionally, within the present invention is embodied the incorporation of any FIASMA into the suppository as a means of treating anorectal disorders. Finally, other medicaments such as anti-inflammatory agents, anesthetics, herbs, or other vitamins may be included in the suppository to enhance the efficacy of one or more active ingredients. Substances for the production of suppositories include any fatty (or oily) base and / or water-soluble (or miscible) base.

[0147] In a particularly preferred embodiment, the drug 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 bases may be employed in the present invention to allow the drug to enter the rectum. More generally, any form of suppository base can be used for construction design. Additionally, various TCAs can be incorporated into the suppository to allow direct application of these substances to the rectum and anus. Other aforementioned substances may also be included in the suppository to enhance its efficacy in treating anorectal disorders. The contents of the suppository may also consist of various TCAs, either alone or in combination with amitriptyline, depending on the treatment objective.

[0148] Depending on the condition being treated, variable doses of amitriptyline may be utilized. For example, the rectal dose of amitriptyline for the treatment of radiation proctopathy is 25 - 100 mg per day. Both doses below and above these doses were initially used for the construction of the design. The optimal dose for treating these conditions will be determined based on clinical studies.

[0149] However, after appropriate clinical evaluation of this treatment, ultimately larger or smaller doses of amitriptyline may be used for the treatment of radiation proctopathy as well as other anorectal disorders. For the treatment of anorectal diseases, it is expected that the administration of amitriptyline and other TCAs in the suppository will be lower than the oral dose, since these medicaments will be applied directly to the affected area. However, since delivery by suppository or rectal device does not require ingestion and the size of the dosage form may be larger, higher doses than those typically employed in oral dosage forms may also be utilized if determined to be safe and effective based on further clinical experience or research.

[0150] Preferably, the method for treating CRI is carried out using FIASMA, such as TCA (such as amitriptyline), tricyclic antihistamines (such as loratadine), or SSRI (such as sertraline), wherein the TCA, tricyclic antihistamine, or SSRI or a combination of at least two active ingredients is prepared as a composition and provided in a dosage form capable of delivering an effective dose in situ to the skin of a patient. For example, amitriptyline can be formulated as a liquid and applied to the skin target area in liquid form, or it can be formulated with a thickening or viscosity-increasing agent to provide a lotion, cream, ointment, or gel for topical delivery of amitriptyline to the skin target area of a patient in need (such as a patient who will undergo radiotherapy or is suffering from radiation dermatitis).

[0151] Alternatively, the method can employ the administration of a solid oral dosage form.

[0152] The method of the present invention can further comprise administering to a patient in need at least one additional active ingredient of FIASMA and non-FIASMA. Preferably, the additional active substance is formulated together with at least one FIASMA in a fixed-dose combination pharmaceutical product for topical administration to the skin.

[0153] A preferred embodiment of the composition of the present invention having a first active substance and a second active substance comprises an SSRI as the first active ingredient and a TCA, tricyclic antihistamine, or antioxidant as the second active ingredient. The antioxidant can be, for example, vitamin A, vitamin C, vitamin D, and vitamin E. Further embodiments of the composition of the present invention can comprise a TCA, an SSRI, and an antioxidant. Examples of active ingredients are amitriptyline as a TCA, loratadine as a tricyclic antihistamine, sertraline as an SSRI, and vitamin D as an antioxidant.

[0154] Variable doses of one or more of the active ingredients described herein can be utilized, depending on the condition being treated. For example, the topical dose of amitriptyline for preventing or treating radiation dermatitis is 1 mg - 100 mg per day.

[0155] The optimal dose and the area to be treated for preventing or treating these conditions will be determined based on clinical studies. However, after appropriate clinical evaluation of this treatment, ultimately, larger or smaller doses of amitriptyline or sertraline can be used for preventing or treating radiation dermatitis and other dermatological inflammatory disorders. Examples Example 1 - Use of a composition containing TCA

[0156] A composition is provided to a patient who is undergoing or planning to undergo radiotherapy for the treatment of a 25 mm breast tumor. The composition is an ointment containing 1% - 2% amitriptyline in a pharmaceutically acceptable base. The skin area above the tumor that is exposed or will be exposed to radiation during the radiotherapy procedure will be identified and may be marked.

[0157] The composition will be administered by a healthcare worker or the patient by applying approximately 1 ml of the composition at least once a day to the skin area that is exposed or expected to be affected by radiation. During the radiotherapy regimen, the administration of the composition will be repeated at least daily or up to five times daily for a period of at least one week. For example, a patient undergoing a radiotherapy regimen five times a week (Monday to Friday) can apply the cream to the treatment area 90 minutes before each daily radiotherapy and then at bedtime for seven days. Thus, before and after radiotherapy on Monday to Friday, and then twice a day on weekends when no radiotherapy is received. This will be repeated for 5 or 6 weeks.

[0158] Expected outcome: Radiation dermatitis is prevented, improved, or reversed by the administration of the composition. Example 2 - Determination of the efficacy of a single active substance and multiple active substances

[0159] A composition is provided to a group of five patients who are undergoing or planning to undergo radiotherapy for the treatment of a 25 mm breast tumor. The composition is an ointment containing: ■ 1% amitriptyline in a pharmaceutically acceptable base; ■ 1% sertraline in a pharmaceutically acceptable base; ■ 1% amitriptyline and 1% sertraline in a pharmaceutically acceptable base; ■ 0.5% amitriptyline and 0.5% sertraline in a pharmaceutically acceptable base; and ■ A pharmaceutically acceptable base alone (placebo).

[0160] The skin area above the tumor that is exposed or will be exposed to radiation during the radiotherapy procedure will be identified and may be marked. The composition will be administered by a healthcare worker or the patient by applying approximately 1 ml of the composition at least once a day to the skin area that is exposed or to be exposed to radiation before radiotherapy. After radiotherapy, the administration of the composition will be repeated at least daily or up to five times daily for a period of one week.

[0161] Expected result: The efficacy of each composition containing the active ingredient will be determined by scoring the level of radiation dermatitis present in each group of patients. The determination of whether the combination of amitriptyline and sertraline exhibits an additive or synergistic effect can be made by comparing whether the radiation dermatitis score of the composition containing 1% amitriptyline and 1% sertraline is less than, equal to, or greater than the effects of the 1% amitriptyline composition alone and the 1% sertraline composition alone. The radiation dermatitis score of the fixed-dose combination composition containing 0.5% amitriptyline and 0.5% sertraline in a pharmaceutically acceptable base can provide information about the efficacy of each active substance at a lower dose compared to a higher dose of each active substance alone in the composition. Example 3 - Treatment of radiation dermatitis in irradiated mice

[0162] Objective: To determine the effect of a topically reformulated sertraline as a protector against radiation-induced skin damage.

[0163] Materials and methods: A radiation-induced dermatitis experiment was conducted in 10-week-old female C57BL / 6J mice (The Jackson Laboratory). Prior to drug treatment, an area of approximately 3 x 3 cm was shaved on the dorsal skin of the mice. The mice were randomly assigned to receive topical treatment with 4% sertraline or vehicle (n = 5 mice / group), and all investigators were blinded to the topical treatment.

[0164] This study compared the composition containing the active drug with a placebo (vehicle). The composition containing the active drug and the placebo were both prepared by a third party and provided to us for use in the study. The preparation of the compositions is summarized as follows: 4% Sertraline Cream - 4% (w / w) sertraline (as hydrochloride) in an oil-in-water vanishing cream base containing hexylene glycol, purified water, isopropyl palmitate, caprylic / capric triglyceride, propylene glycol, ceteth-20, cetearyl alcohol, glyceryl stearate, PEG 100 stearate, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin, and phenoxyethanol. Placebo Cream - An oil-in-water vanishing cream base containing: purified water, isopropyl palmitate, caprylic / capric triglyceride, propylene glycol, ceteth-20, cetearyl alcohol, glyceryl stearate, PEG 100 stearate, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin, and phenoxyethanol. Both products are packaged in white polypropylene jars with white polypropylene closures and polyvinyl chloride disc liners, labeled for external use only, stored at a controlled room temperature (20°C to 25°C), and accompanied by instructions not to freeze.

[0165] The formulation is further described in Composition Table A below: Composition Table A.

[0166] 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.

[0167] PENCream is a commercially available oil-in-water vanishing base (https: / / www.humco.com / pharmaceuticals / pencream / ) purchased from Humco. The NDC code for the cream is 0395 - 6010 - 56.

[0168] Mice received topical treatment once daily starting 2 days before irradiation for 12 days. 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 image-guided small animal irradiator X-Rad 225Cx.

[0169] Radiation-induced dermatitis development was examined before irradiation and weekly for 4 weeks after irradiation by a single observer blinded to the treatment groups. Skin response to radiation was evaluated according to a semi-quantitative scoring system previously created for preclinical studies - scores ranged from 1.0 to 5.5 (in 0.5 increments) based on erythema, desquamation (dry and wet), necrosis, and dermal loss (Table 1). Table I: Semi-Quantitative Skin Injury Score

[0170] Results: During the first two weeks after 30 Gy irradiation, all mice treated with 4% sertraline cream had a skin injury score of 4.5, while mice treated with vehicle had a less severe score of 3.0 - 3.5 (Figure 1, Panels A and B). Scratching behavior and sequelae were noted in the 4% sertraline group.

[0171] On day 21 after irradiation, both treatment groups had a skin injury score of 3.0 - 3.5. At the end of the experiment on day 28 after irradiation, mice treated with 4% sertraline had a less severe skin injury score ranging from 1.5 - 2.0, with an average score of 1.7.

[0172] In contrast, the mice treated with vehicle maintained a higher skin injury score, ranging from 1.5 - 3.5, with an average score of 3.0 (Figure 1, Panels A and B).

[0173] Discussion: Our preliminary results showed that the skin injury in mice receiving 4% sertraline improved significantly 4 weeks after 30 Gy, while the skin injury in vehicle-treated mice remained severe. The reason for the higher injury scores in mice treated with 4% sertraline during the first two weeks after irradiation is under investigation, but a literature search has confirmed that in mice, topical sertraline induces significant itch-induced scratching, as shown in previously published animal studies (Neuron 87, 124 - 138, July 1, 2015). Repeating this experiment with removal of the cream after 30 minutes significantly reduced scratching behavior and the initial skin injury score, while still showing benefits similar to the data presented above at 2 weeks. Therefore, it is believed that the early toxicity noticed in week 1 is related to self-injury due to sertraline-induced scratching.

[0174] Conclusion: The results surprisingly showed that a 4% FIASMA composition, such as a 4% sertraline topical composition, is effective against radiation-induced skin injury.

[0175] Compositions containing a lower concentration of the active drug, such as less than 1%, preferably about 0.5% sertraline (where these ingredients are formulated with one or more penetration enhancers, solubilizers, emollients, etc.), can deliver substantially the same amount of drug to the target site as the compositions described in Table A above. These formulations containing 1% or less of the active drug may be advantageous in terms of dosage for the patient and are therefore preferred.

[0176] A topical gel composition for delivering a therapeutically effective amount to a skin target site of a patient can comprise, for example, a mixture of 0.5% - 1.0% active agent with one or more preservatives, one or more humectants / solvents, one or more rheology modifiers / thickeners, one or more anti-adhesion agents / glidants, etc. Examples of the formulation of the topical gel are provided in Gel Composition Table B below. Gel Composition Table B

[0177] A topical cream formulation for delivering a therapeutically effective amount to a skin target site of a patient can comprise, for example, a mixture of 0.5% - 1.0% active agent with one or more preservatives, one or more humectants / solvents, one or more rheology modifiers / thickeners, one or more anti-adhesion agents / glidants, etc. Examples of the formulation of the topical gel are provided in Cream Composition Table C below. Cream Composition Table C Ingredient %(w / w) Phenoxyethanol 0,5 Benzyl Alcohol EMPROVE EXPERT PH 1 Glycerol 5 Propylene Glycol-1,2 10 CARBOPOL ETD 2020NF 0,2 Xanthan Gum FF 0,3 Purified Water QS 100% Micronized Sertraline Hydrochloride 0,5595 SP BRIJ S721MBAL-PA-(SG) 1 SP BRIJ S2 MBAL-SO 4 KOLLIWAX HCO 2 KOLLIWAX SA 2 MIGLYOL 812N 10 Q7-9120 Silicone Fluid 350 CST 1 Sodium Hydroxide 10% (w / w) Solution QS pH 5±0.5 Example 4 - Comparison of pre-irradiation treatment and post-irradiation treatment

[0178] The experiment presented in Example 3 was repeated in mice to compare 4% sertraline administered before and after irradiation treatment. 4% amitriptyline was also tested.

[0179] The same scoring chart shown in Example 3 was used to evaluate the irradiated sites on the mice.

[0180] Method: A radiation-induced dermatitis experiment was conducted using 10-week-old female C57BL / 6J mice (Jackson Laboratory). Before drug treatment, an area of approximately 3 x 3 cm was shaved on the dorsal skin of the mice. A single dose of 30 Gy of X-rays was delivered to a 1 x 1 cm area of the skin using an image-guided small animal irradiator X-Rad 225Cx to induce dermatitis. The mice were randomized by cage to receive the following topical treatments: 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 (before and after irradiation) once daily for 5 days.

[0181] Two observers (S.H. and S.S.) blinded to the treatment groups examined the development of radiation-induced dermatitis weekly for 6 weeks after irradiation. The skin response to radiation was evaluated according to a semi-quantitative scoring system previously created for preclinical studies - the score ranged from 1.0 to 5.5 (0.5 increment) based on erythema, desquamation (dry and wet), necrosis, and dermal loss.

[0182] The scoring results at 1 week, 2 weeks, 3 weeks, and 4 weeks after irradiation treatment (IR) are shown in Table 2 below: Table 2 - Semi-quantitative skin injury score A. Apply 4% Sertraline Cream 48 h, 24 h and 30 min before irradiation treatment B. Apply only vehicle 48 h, 24 h, and 30 min before irradiation treatment and 24 h and 48 h after irradiation treatment Substance Cream C. Apply 4% Sertraline Cream 24 h and 48 h after irradiation treatment

[0183] Results. Four weeks after irradiation treatment, 9 out of 10 sertraline-treated mice showed lower scores (better improvement) than mice treated with vehicle only. Generally, 4% sertraline cream performed better when applied after irradiation treatment than before; however, pre-irradiation treatment showed some preventive effects. 4% sertraline cream applied at 24 h and 48 h after irradiation treatment also showed earlier responses, with lower scores within one week of irradiation treatment and continued improvement in scores up to the fourth week after irradiation treatment.

[0184] These results are graphically presented in Figure 2, subpanels A - D. Overall, mice receiving 2 doses of 4% sertraline after irradiation started to show accelerated recovery from acute radiation dermatitis starting from the 1st week after irradiation (Figure 2, subpanels A, B, and D). From the 3rd to 6th week after 30 Gy, the skin injury scores of the latter 2-dose group were significantly lower than those of the placebo group (Figure 2, subpanel B). On the other hand, at the 5th week after 30 Gy, the skin injury scores of the former 3-dose group were significantly lower than those of the placebo group (Figure 2, subpanel C). Apparently, mice receiving 3 doses of 4% sertraline before irradiation showed significantly slower recovery from acute radiation dermatitis compared to mice receiving 2 doses of 4% sertraline after irradiation (Figure 2, subpanel D).

[0185] Notably, the application of 4% amitriptyline cream and 4% fluoxetine cream had a harmful effect on the mice, and this group was discontinued from the experiment. This indicates that the 4% cream formulations containing tricyclic antidepressants (TCA) are overdose doses, and lower doses are needed to determine their efficacy. Example 5 - Oral solution or mouthwash containing SSRI for the treatment of oral mucositis associated with head and neck radiotherapy or mouthwash

[0186] Objective: The goal of this planned study was to evaluate the effectiveness of an oral solution or mouthwash containing SSRI (sertraline) for the treatment of oral mucositis and xerostomia associated with head and neck radiotherapy. A. Optimal radiation dose for inducing oral mucositis in a mouse model Preliminary experiments will be conducted to determine the optimal irradiation dose for studying radiation-induced oral mucositis and xerostomia in 8-week-old female C57BL / 6J mice. The head and neck regions of the mice were treated with single doses of 0, 16, 18, 20, and 22 Gy X-rays using a small animal radiation research platform (SARRP) (n = 10 / radiation dose).

[0187] Two measurements will be made to evaluate the duration and severity of oral mucositis: (a) The body weight of the mice will be measured daily from the 7th day to the 16th day after irradiation and then three times a week until 21 days after irradiation, and (b) The tongue will be assessed for pathological morphological changes using otoscopy on days 9, 12, and 16 after irradiation.

[0188] Pain control medications and supportive care can be provided if needed.

[0189] To assess the severity of xerostomia, saliva production of each mouse will be measured 30 and 60 days after irradiation according to previously described methods. See Ashcraft et al. (2015) “Novel Manganese-PorphyrinSuperoxide Dismutase-Mimetic Widens the Therapeutic Margin in a PreclinicalHead and Neck Cancer Model.” International Journal of Radiation Oncology,Biology,Physics 93(4):892–900; Saiki et al. (2018) “AldehydeDehydrogenase 3A1 Activation Prevents Radiation-Induced Xerostomia byProtecting Salivary Stem Cells from Toxic Aldehydes.” Proceedings of the NationalAcademy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America 115(24):6279–84. B. Determine the effect of sertraline oral solution on the development of radiation-induced oral mucositis and xerostomia

[0190] Using the optimal radiation dose determined in A. above, 8-week-old female C57BL / 6J mice were randomly assigned to receive Head and neck radiation therapy, plus vehicle only (control), Head and neck radiation therapy + 2% sertraline in vehicle, Head and neck radiation therapy + 4% sertraline in vehicle, and Head and neck radiation therapy + 6% sertraline in vehicle (n=20 mice / treatment group).

[0191] Mice will be treated with sertraline oral solution once daily for 5 days (2 days before irradiation, immediately before irradiation on the same day, and 2 days after irradiation).

[0192] Two measurements will be made to evaluate the duration and severity of oral mucositis: (a) The body weight of the mice will be measured daily from day 7 to day 16 after irradiation and then three times a week until day 21 after irradiation. (b) The pathological morphological changes of the tongue will be evaluated using an otoscope on days 9, 12, and 16 after irradiation. If necessary, pain control medications and supportive care can be provided. To evaluate the severity of xerostomia, the saliva production of each mouse will be measured on days 30 and 60 after irradiation (Ashcraft et al. 2015; Saiki et al. 2018). The fibrosis of the salivary glands will be evaluated histologically on day 60 after irradiation (Ashcraft et al. 2015).

[0193] 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. The expected outcome will be dose-dependent and sertraline oral solution will be effective in treating oral mucositis and / or xerostomia. Example 6 - Treatment of radiation dermatitis in patients undergoing radiotherapy and recovering from radiotherapy

[0194] Objective: To determine the efficacy of RAD-100 in preventing or reducing radiation-induced dermatitis in post-operative breast cancer patients undergoing a standard course of radiotherapy.

[0195] Materials and Methods: A randomized, double-blind study was conducted using subjects 18 years of age or older who had recently undergone breast cancer surgery (breast-conserving (lumpectomy) or mastectomy) and were scheduled to undergo a standard course of radiotherapy, which was 1.8 to 2.0 GY per session and was administered 25 to 30 times over a five- to six-week period, in 5 consecutive daily treatments per week.

[0196] If a subject met any of the following exclusion criteria, they were excluded from the study: · Breast tissue ulceration or an open breast wound at the start of radiotherapy. · Skin lesions in the area planned for radiotherapy before the start of radiotherapy. · Known allergies, hypersensitivity reactions, or reactions to any component of the cream or sertraline. · Any neurological or psychiatric condition that the attending physician considered precluded the subject's participation in the study. · Any other major comorbidities that the investigator considered likely to affect the study outcome (e.g., uncontrolled diabetes, renal failure, liver dysfunction, cardiovascular disease, etc.). ·BMI > 35.0 · Subjects who have participated in an investigational drug trial within the past thirty (30) days. · Subjects taking monoamine oxidase inhibitors. · Subjects undergoing concurrent treatment with chemotherapeutic agents. · Pregnant or lactating

[0197] Subjects who meet all inclusion criteria and do not meet any of the exclusion criteria are enrolled in the study and are required to read, understand, and sign an informed consent form, complete a medical questionnaire, undergo a comprehensive physical examination, provide fasting blood samples for chemistry and hematology, and urine samples for urine analysis.

[0198] This 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 required to apply the cream twice daily (once in the morning and once in the evening) and to continue the regimen daily during radiotherapy and for 14 days after the last radiotherapy.

[0199] The cream was dispensed to subjects on the Friday before the first week of radiotherapy and they were instructed to start applying the cream on the Sunday evening before their first radiotherapy. On the day before starting the standard radiotherapy course, all subjects were required to start applying the cream to the defined area to be irradiated. This included the entire breast in breast-conserving subjects and the defined area in mastectomy subjects.

[0200] Subjects were required to apply the cream twice daily (once in the morning and once in the evening) and to continue this regimen daily during radiotherapy and for 14 days after the last radiotherapy. All subjects received blinded coded drugs according to a pre-determined randomization code of two active substances to one vehicle control, which was unknown to the subjects and the investigator / assessor. A diary was provided to all subjects to record the times they applied the cream and to record any concomitant medications and adverse events. Photographs of the application site were taken twice weekly on Tuesdays and Fridays before radiotherapy and on days 7 and 14 after radiotherapy.

[0201] After an initial one-day run-in period, all subjects reported to the radiology department five days a week for their radiation dose. Prior to radiation therapy treatment on Tuesdays and Fridays, the principal investigator (PI) or the PI's designated assistant evaluated the skin at the radiation site and recorded the score using the revised Radiation Therapy Oncology Group (RTOG) scoring system. Subjects were asked weekly about the radiation site and were required to report pain levels and any adverse or abnormal events. Subjects were reminded to continue applying the cream during the two days of the week when they did not receive radiation and to record any changes at the radiation treatment site in a diary. At the end of the radiation phase of the study, all subjects were required to continue the treatment regimen daily for the next 14 days. Subjects returned for evaluation on days 7 and 14. At the end of this 14-day post-radiation period, subjects were discharged from the study and asked to voluntarily report any subsequent changes at the radiation site.

[0202] Results: The onset of dermatitis was not earlier than day 26, with the exception of a few subjects. The results showed that the P values were in favor of the treatment group throughout the treatment period and continued into the post-radiation phase. Although radiation-induced dermatitis, as recorded by the RTOG score, worsened in the placebo group during the 7-day period after radiation, the mean score in the treatment group remained stable. Table 3 shows the mean RTOG score data starting from day 26. Table 3. Mean RTOG Score day RTOG (treatment group) N RTOG placebo group N P 26 0.7 10 1.0 4 0.28 29 1.0 10 1.0 4 1.00 33 1.0 10 1.5 4 0.13 36 1.2 10 1.5 4 0.46 7 days later 1.2 10 2.0 4 0.27 14 days later 0.9 10 1.0 4 0.81

[0203] The distribution of RTOG scores within each group at different times was also evaluated. 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-radiation phase, the treatment group appeared to heal faster. Table 4 shows the distribution of RTOG scores by category. Table 4. Categorical RTOG Scores (% of Subjects with a Specific Score)

[0204] Although the RTOG does include scores higher than 2, the radiation treatment was designed not to exceed a score of 2. Although the data are presented as the percentage of patients in each group with a score of 2 or higher, in reality, no score exceeded 2.

[0205] The data in Table 5 (below) show the categorical data for this study. During the radiation treatment phase, the placebo group had a higher percentage of 2.0 scores on days 33 and 36, with borderline statistical significance on day 33. The placebo group also showed poorer recovery. Table 5. Classified RTOG Data (% of subjects scored 2 or >2) day Treatment group % N Placebo group % N P 26 0 10 0 4 -- 29 10 10 0 4 0.52 33 10 10 50 4 0.10 36 30 10 50 4 0.48 7 days later 44 9 75 4 0.31 14 days postoperatively 12 8 33 3 0.43

[0206] The results of Table 5 are Figure 3 presented graphically in

[0207] Conclusion: The results of this study have shown that treatment with RAD100 improves the course of dermatitis during both the radiotherapy phase and the recovery phase, achieving some nearly significant P-values. Although a larger number of subjects will inevitably improve the statistics of this study, the current values predict that a larger study will achieve high statistical significance. Overall, the delayed onset of dermatitis and the rapid healing rate in the treatment group are consistent with the data generated in mice in Examples 3 and 4. The mouse data, like the human data, show an improvement in the healing rate in the RAD100 treatment group. Example 7 - Treatment of tissue toxicity associated with head and neck radiotherapy

[0208] Objective: To determine the effect of sertraline on the development of radiation-induced oral mucositis in mice by examining the effect of sertraline oral solution on the development of radiation-induced oral mucositis in mice.

[0209] Experimental procedures: Ten-week-old female C57BL / 6 mice were randomly assigned by cage to receive 16 Gy oral irradiation + placebo or 16 Gy oral irradiation + 1% sertraline solution. The placebo or sertraline solution was applied to the oral cavity of the mice once a day for 5 days (2 days before irradiation, 30 minutes to 1 hour before irradiation on the same day, and 2 days after irradiation). The development of radiation-induced severe oral mucositis was followed up within 21 days after radiation.

[0210] Results: The results showed that in the placebo group, 16 Gy oral irradiation led to the death of 66% (4 out of 6 mice) of the mice due to acute radiation toxicity of the oral mucosa, while only 33% (2 out of 6) of the mice died in the 1% sertraline group( Figure 4 ). These findings support oral sertraline treatment as a novel approach for improving radiation-induced severe oral mucositis. _________________________

[0211] The foregoing description is illustrative only and is not intended to limit the scope of the invention to the precise terms set forth. Although the invention has been described in detail with reference to certain embodiments, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims. The above disclosure and examples generally describe the invention and are provided for illustrative purposes and are not intended to limit the scope of the invention.

[0212] The invention described herein can be practiced without the presence of any element or elements, or limitation or limitations, not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with any of the other two terms. The terms and expressions are used as terms of description and not of limitation, and are not intended to exclude any equivalents or portions thereof of the features shown or described by the invention using such terms and expressions, but it will be recognized that various modifications within the scope of the invention as claimed are possible. Accordingly, it should be understood that although the invention has been specifically disclosed by way of preferred embodiments and optional features, modifications and variations of the concepts disclosed herein may be made by those of ordinary skill in the art, and such modifications or variations are considered to be within the scope of the invention as defined by the claims.

Claims

1. A method for treating cutaneous radiation injury (CRI), the method comprising: administering to a skin target area of a patient in need thereof at least once daily, before, during, or after radiotherapy, 0.5 - 10 ml of a composition comprising an effective amount of one or more functional inhibitors of acid sphingomyelinase (FIASMA).

2. The method according to claim 1, wherein treating CRI comprises preventing CRI, reducing the occurrence or recurrence of CRI, inhibiting CRI, treating CRI, improving CRI, or reducing the severity of CRI, or reversing CRI.

3. The method according to claim 1, wherein the CRI is caused by medical radiotherapy for cancer.

4. The method according to claim 1, wherein the CRI is radiation dermatitis.

5. The method according to claim 1, wherein the CRI is oral mucositis.

6. The method according to claim 1, wherein the CRI is radiation proctopathy.

7. The method according to claim 1, wherein the composition is a topical cream, gel, or ointment.

8. The method according to claim 1, wherein the composition is a solid oral dosage form.

9. The method according to claim 8, wherein the solid oral dosage form is a mucoadhesive tablet.

10. The method according to claim 1, wherein the composition is an oral solution.

11. The method according to claim 10, wherein the oral solution is a mouthwash comprising 1 - 100 mg / ml of SSRI.

12. The method according to claim 1, wherein the FIASMA is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), antihistamines, antiarrhythmic agents, adrenergic receptor blockers (ARB), and beta blockers.

13. A pharmaceutical composition for treating cutaneous radiation injury (CRI), the composition comprising an effective amount of at least one functional inhibitor of acid sphingomyelinase (FIASMA).

14. The pharmaceutical composition according to claim 13, wherein treating CRI comprises preventing CRI, reducing the occurrence or recurrence of CRI, inhibiting CRI, treating CRI, improving CRI, or reducing the severity of CRI, or reversing CRI.

15. The pharmaceutical composition according to claim 13, wherein the CRI is radiation dermatitis.

16. The pharmaceutical composition according to claim 13, wherein the CRI is oral mucositis.

17. The pharmaceutical composition according to claim 13, wherein the CRI is radiation proctopathy.

18. The pharmaceutical composition according to claim 13, wherein the FIASMA is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), tricyclic antihistamines, antiarrhythmic agents, adrenergic receptor blockers (ARB), and beta blockers.

19. The composition according to claim 13, wherein the composition is an oral dosage form comprising 1 - 100 mg / ml of SSRI.

20. The composition according to claim 19, wherein the oral dosage form is a mucoadhesive tablet.

21. A solid dosage form in the form of a lozenge or troche, containing an effective dose of loratadine for delivery to a patient undergoing radiotherapy for head and neck cancer.

22. The solid dosage form according to claim 26, wherein the lozenge or troche comprises a handle fixed thereto to form a lollipop.

23. A method for preventing, treating or reducing the incidence of oral mucositis or severe oral mucositis (SOM) in a patient undergoing radiotherapy for head and neck cancer, the method comprising the steps of: - providing a lozenge or troche containing loratadine as described in claim 25; and - administering the lozenge or troche to the patient as needed.

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