Compositions and methods for preventing and treating skin radiation damage

Abstract

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

Description

[Technical Field]

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

[0002] Cutaneous radiation injury (CRI) is damage to the skin or underlying tissues in animals, including mammals and humans, induced by or resulting from radiation exposure from industrial or military sources, such as radioactive materials used in nuclear power plants or nuclear weapons. Minor skin damage, such as sunburn due to excessive exposure 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 proctitis, oral mucositis, or severe oral mucositis, each of which may be observed after medical radiation therapy administered to areas of the body to treat cancer or other conditions treatable with radiation.

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

[0004] After radiation therapy to treat head and neck cancer, patients with head and neck cancer may experience an inflammatory response in the oral cavity, leading to conditions such as oral mucositis, which is caused by damage to the epithelial cells lining the oral cavity. When radiation therapy causes ulcerative lesions to form in the oral cavity or makes it impossible for the patient to swallow solid food, the condition is considered "severe oral mucositis," or "SOM."

[0005] Radiation therapy administered to the pelvic region can cause damage to rectal tissue. Radiation therapy targeted to the pelvic region can result in a variety of injuries that can affect the anorectal region and may involve one or more of the following pathologies: inflammatory, ischemic, infectious, traumatic, or neoplastic. Symptoms of anorectal disease include anal or rectal pain, urgency to move a bowel, fecal incontinence, diarrhea, rectal bleeding, and difficulty emptying the rectum. These conditions are referred to as "radiation proctitis," and more recently and more accurately as "radiation proctopathy."

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

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

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

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

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

[0011] 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 they are not readily available and are difficult to administer.

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

[0013] Rectal suppositories are also used as an alternative form of drug delivery in patients who are unable to accept medications orally, allowing the medication to be absorbed by the mucous membranes and distributed systemically. Examples of this type of rectal suppository include those used to treat nausea and pain.

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

[0015] A class of ASMase inhibitors known as tricyclic antidepressants has not previously been known to be used to treat anorectal disorders such as radiation proctopathy or proctitis. Dosage forms containing tricyclic antidepressants, such as amitriptyline, have not been formulated for anal or rectal administration or for the in situ (or non-systemic) treatment of radiation proctopathy or proctitis. Amitriptyline has been formulated into a suppository dosage form. However, amitriptyline suppositories have only been prepared for systemic delivery and for the treatment of depression (a known indication for amitriptyline). Another indication for systemic delivery of amitriptyline suppositories is insomnia, taking advantage of the sleep-inducing side effect observed with amitriptyline. Amitriptyline suppositories have not previously been known to be administered to patients undergoing or who have undergone pelvic radiation therapy, or for the treatment of radiation proctopathy or proctitis, or for any other in situ treatment within the lower intestinal tract.

[0016] More specifically, amitriptyline has not previously been formulated into dosage forms such as suppositories or other anorectal delivery devices for the local treatment of radiation proctopathy or proctitis. Nor have tricyclic antidepressants such as amitriptyline been formulated as controlled-release formulations to avoid release in low pH environments (acidic pH less than 7), such as the stomach, for in situ delivery of drug to treat radiation proctopathy or proctitis, so that drug release occurs primarily in the intestine, preferably the lower intestine.

[0017] Another class of ASMase inhibitors, selective serotonin reuptake inhibitors (SSRIs), are not known to be available in suppository form, nor are SSRIs known to have been previously used to treat radiation proctopathy or proctitis.

[0018] There are many anorectal conditions that may benefit from the topical 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 present a variety of significant clinical problems for which limited treatment options are currently available.

[0019] It is also not known that ASMase inhibitors such as TCAs, e.g., amitriptyline, other 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, antihistamines, and SSRIs) are usually provided as oral solid dosage forms. However, it is not known that liquid oral dosage forms, such as oral solutions, suspensions, or emulsions containing tricyclic active ingredients or SSRIs (separately or collectively referred to herein as "oral rinses" or simply "gargles") have been formulated to treat oral mucositis.

[0020] Patients who have reduced saliva production due to radiation damage to the salivary glands and who have difficulty swallowing oral formulations or oral solid dosage forms that disintegrate quickly in the mouth may benefit from oral liquids, suspensions, or emulsions that can be used as gargles or mouthwashes to deliver active ingredients to damaged oral tissues.

[0021] The continued and increased use of radiation therapy in the treatment of cancer and the lack of available preventative or therapeutic medications for CRI, including radiation dermatitis or radiation proctopathy, is a long-standing unmet patient need that affects millions of patients. Summary of the Invention [Problem to be solved by the invention]

[0022] The present invention relates to methods for ameliorating or reducing the severity of, preventing, reducing the incidence or recurrence of, inhibiting, or reversing cutaneous radiation injury (CRI) resulting from environmental exposure to radiation from industrial or military radiation sources or from therapeutic radiation treatments in cancer therapy, including radiation dermatitis, radiation proctopathy, or oral mucositis (including severe oral mucositis or SOM). The term CRI generally includes radiation damage to the outer layer of the skin or dermis, but can also include damage to deeper skin layers, such as the subcutaneous layer, or the fat layer. Radiation dermatitis, radiation proctopathy, and oral mucositis are included in the definition of CRI but are generally considered to be conditions associated with damage to the dermis.

[0023] The method according to the present invention comprises topically administering or applying a composition comprising at least one acid sphingomyelinase (ASMase) inhibitor to the skin surface or mucosa of a patient suffering from a CRI, including radiation dermatitis, radiation proctopathy, or oral mucositis. Functional inhibitors of acid sphingomyelinase, known in the art by the acronym FIASMA, include certain selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), tricyclic antihistamines, antiarrhythmics, adrenoceptor blockers (ARBs), beta-blockers, and the like.

[0024] SSRIs useful in the methods of the present invention include one or more of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. A preferred SSRI is sertraline. According to a preferred embodiment, the dosage form of the present invention contains an ASMase inhibitor, such as an SSRI, in a dosage of 0.1 mg to 1000 mg, more preferably about 1 mg to 500 mg, and most preferably about 5 mg to 100 mg. A preferred dosage is contemplated to be about 10 to 100 mg of SSRI formulated in a 0.5 to 10% (w / w) composition. Topical compositions typically contain 0.5% to 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, and most preferably about 1.5% to about 2% of at least one FIASMA.

[0025] Dosages can vary, being lower for dosage forms that deliver the drug to the site more quickly and higher for dosage forms that release the drug slowly.

[0026] Tricyclic antidepressants (TCAs) useful in the methods or compositions of the present invention include one or more of amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin (alone or in combination), imipramine, iprindole, lofepramine, maprotiline, norclomipramine, nortiaden, nortriptyline, opipramol, protriptyline, tianeptine, or trimipramine. A preferred TCA is amitriptyline. According to a preferred embodiment, the dosage form of the present invention comprises amitriptyline in a dosage amount of 0.1 to 1000 mg, more preferably in a dosage amount of about 1 mg to 100 mg, and most preferably in a dosage amount of about 5 mg to 50 mg. A preferred dosage is about 10 to 50 mg of the TCA formulated in a 1 to 5% (w / w) composition. Dosages can vary, being lower for dosage forms that deliver the drug to the site more quickly and higher for dosage forms that release the drug slowly.

[0027] More specifically, the method of the present invention comprises: - providing a topical composition comprising as an active ingredient a pharmaceutically effective amount of at least one FIASMA or a combination of two or more FIASMA drugs; - topically administering or applying an effective amount of the composition to an appropriate patient before or after radiation therapy, or both. Includes.

[0028] In a method for preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or ameliorating radiation proctopathy, the method comprises: - anorectally administering to an appropriate patient, such as a patient undergoing radiation therapy of the pelvic region or a patient suffering from radiation proctopathy or proctitis, a dosage form comprising a pharmaceutically effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA.

[0029] In a method for preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or reversing oral mucositis or severe oral mucositis, the method comprises: - providing an oral solid dosage form comprising FIASMA as an active ingredient; administering to an appropriate patient, such as a patient undergoing radiation therapy for head and neck cancer, an oral solid 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 oral solid formulation is a modified release dosage form for sublingual administration comprising FIASMA as an active ingredient.

[0030] In another method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or reversing oral mucositis or severe oral mucositis, the method comprises: - providing a liquid oral formulation or "mouthwash" as a liquid, suspension or emulsion, containing one or more FIASMAs as active ingredients; - administering to an appropriate patient, such as a patient undergoing radiation therapy for head and neck cancer, a liquid oral formulation comprising a pharmaceutically effective amount of one or more FIASMAs as active ingredients in a liquid dosage form; may include:

[0031] Controlled-release dosage forms for sublingual administration are known in the art and can slow the dissolution of the dosage form so that the release of the drug is extended, maintained, or the residence time of the active agent in the oral cavity is increased. Such controlled-release dosage forms can be tablets, capsules, lozenges, pastilles, troches, thin film strips, etc., as recognized by those skilled in the pharmaceutical arts. Controlled-release dosage forms for sublingual administration are also known to dissolve or disintegrate rapidly in the oral cavity, providing immediate delivery of the active ingredient from the dosage form. Thus, "controlled release" is not limited to slowing dissolution, but can be "controlled" to disintegrate rapidly in the mouth and dissolve faster than the standard dissolution rate of an "immediate-release" solid dosage form. "Immediate release" generally refers to release in the stomach without significant delivery of the active agent before swallowing the dosage form.

[0032] One embodiment of the method of the present invention involves topically applying or administering a composition containing an effective amount of at least one FIASMA. It will be understood that applying or administering the composition before radiation therapy can include maintaining the composition in place during the radiation therapy session. The method can be repeated before, during, or after each radiation therapy session and can include administering or applying the composition at least once per week, several times per week, daily, or multiple times per day before, after, or during the radiation therapy session. The method can be continued after radiation therapy is completed, for example, 1 to 5 days after radiation therapy, 1 to 3 weeks after radiation therapy, or one or more months after radiation therapy. Typically, the method involves administering the composition about one week to about one month after radiation therapy sessions are discontinued.

[0033] Alternatively, the method 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. In conditions affecting the oral cavity, such as oral mucositis or severe oral mucositis, oral formulations that dissolve in the mouth and are not swallowed whole may be preferred.

[0034] In certain patients who suffer from damage to the salivary glands and are unable to produce enough saliva to dissolve solid dosage forms in the oral cavity, a liquid oral formulation containing FIASMA as an active ingredient may be a preferred dosage form. Such liquid oral formulations may be known as "gargles," "mouthwashes," "mouth rinses," or may be used as "sprays." The preferred term used in this disclosure for liquid oral formulations is "gargles." These liquid oral formulations will be understood to be in the form of liquid solutions, emulsions, or suspensions, but may contain thickeners or gelling agents to increase the viscosity of the solutions, emulsions, or suspensions.

[0035] For patients undergoing radiation therapy in the pelvic region, radiation proctopathy, a preferred method may involve providing a solid suppository or rectal plug dosage form containing a composition comprising FIASMA and placing the dosage form in the rectal cavity for the period required to deliver the active ingredient to the site.

[0036] The present invention also relates to topical pharmaceutical compositions comprising as an active drug or agent at least one functional inhibitor of acid sphingomyelinase (FIASMA), which are useful for preventing, reducing the incidence or recurrence of, treating, ameliorating, or reducing the severity of or reversing cutaneous radiation injury (CRI), including radiation dermatitis or radiation proctopathy.

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

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

[0039] In methods utilizing suppositories or rectal plug delivery devices for delivery of FIASMA to the anorectal cavity and in situ administration of the drug, the dosage form may comprise or be incorporated into the rectal plug delivery device as a controlled-release formulation having one or more excipients that can prevent release of the active drug incorporated into the dosage form or coated on the outer surface of the dosage form or particles, granules, or beads within the dosage form that contain the active ingredient. Controlled-release dosage forms can also be provided for oral administration in which the oral formulation is formulated as a delayed-release dosage form that avoids the acidic environment in the stomach and releases the active ingredient in the intestinal tract where the pH is above 7.0. Such controlled-release dosage forms can be formulated using an enteric coating on a tablet, provided in a delayed-release capsule or caplet, formulated in a slow-release matrix composition, or a combination of the above.

[0040] When the dosage form is a rectal plug delivery device, the device can be an insoluble plug forming a housing having an internal chamber for containing a composition containing a FIASMA, which can be a TCA or an SSRI, or various combinations thereof. For example, the chamber of the rectal plug can be filled with a viscous composition containing a TCA, or can contain a suppository dosage form containing a TCA active ingredient.

[0041] An alternative embodiment of a rectal plug delivery device useful in practicing the methods of the present invention comprises a porous compressible foam material soaked in or coated with a composition comprising a TCA, e.g., amitriptyline, an SSRI, e.g., sertraline, or a combination thereof. The devices described with respect to the methods of the present invention may contain an effective dose of FIASMA or a FIASMA combination from about 0.1 mg to about 1000 mg or more.

[0042] 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 one or more SSRIs in combination with one or more TCAs.

[0043] Compositions for use in the methods of the present invention may contain approximately 0.1 to 1000 milligrams (mg) of one or more FIASMAs. Topical compositions useful in the methods of the present invention may be provided as topical solutions, but are preferably provided as topical creams, gels, lotions, or ointments. A preferred FIASMA useful as an active ingredient in the compositions and methods of the present invention is the SSRI, sertraline. Another FIASMA useful as an active ingredient in the compositions and methods of the present invention is the TCA, amitriptyline. Another example of a FIASMA useful as an active ingredient in the compositions and methods of the present invention is the tricyclic antihistamine loratadine or its metabolite, desloratadine. Other FIASMA compounds may be substituted or provided in combination in the compositions or methods of the present invention.

[0044] The topical dosage forms may comprise conventional, commercially available pharmaceutical base compositions that are pharmaceutically compatible with one or more FIASMAs used as one or more active ingredients, and may further comprise other pharmaceutically acceptable excipients conventionally utilized in topical or oral formulations. These commercially available pharmaceutical bases may act as a vehicle or medium for the active drug substance and may include one or more emollients, penetration enhancers, solvents, gelling agents, thickening or viscosity-increasing agents, preservatives, or other suitable excipients commonly used in topical preparations.

[0045] Preferably, the FIASMA for topical administration is provided in an immediate-release topical formulation, which allows targeted dosing and immediate delivery of the drug from the composition to the skin simultaneously with application or administration of the composition. Retention of the FIASMA component at the site of administration or application may be preferable. Thus, the compositions of the present invention may omit a penetration enhancer to maintain the composition and active substance on the surface of the skin for a longer period of time, as opposed to compositions that include a penetration enhancer that allows or promotes penetration of the active substance into or under the skin, where the active substance can be absorbed systemically. Alternatively, in certain cases, a penetration enhancer may be preferred and used in the composition.

[0046] Oral formulations of the composition may be immediate-release or may be formulated with excipients such as polymers, gels, gums, waxes, or may be incorporated into a matrix or contain 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 treating oral mucositis may be formulated for dissolution in the oral cavity and may contain excipients that control, delay, slow, sustain, or extend the release of the drug from the dosage form. Alternatively, the oral solid dosage form may be formulated to rapidly dissolve or disintegrate in the oral cavity, for example, when treating oral mucositis. One preferred dosage form for treating oral mucositis is a liquid oral solution, emulsion, or suspension containing FIASMA, preferably formulated as a mouthwash containing an SSRI such as sertraline.

[0047] According to a further aspect of the present invention, the dosage form may contain a second active substance, such as a TCA or SSRI component, or may contain a second active substance that is neither a TCA nor an SSRI, for example, an active substance belonging to a different drug class, i.e., an active substance other than a tricyclic or SSRI. In a preferred embodiment, the composition contains a first active substance that is a TCA and a second active substance that is a different TCA or a compound of another class that is not an SSRI or TCA. For example, the second active substance may 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 nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic, such as a local anesthetic, e.g., lidocaine.

[0048] 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 compound from another class that is not a TCA or an SSRI. For example, the second active ingredient can be an antioxidant such as vitamin A, vitamin C, vitamin D, or vitamin E. Preferably, the second active substance in the composition is not an anti-inflammatory agent such as a nonsteroidal anti-inflammatory drug (NSAID) or an anesthetic agent such as a local anesthetic, e.g., lidocaine.

[0049] Preferably, the method is carried out using a FIASMA formulated into an external composition capable of delivering an effective dosage to a target area of ​​skin that is directly or secondarily exposed to radiation during radiation therapy or treatment. For example, the active ingredient can be formulated as a liquid composition and administered as drops to the target area of ​​skin. Alternatively, the FIASMA can be formulated into a composition containing a thickening or viscosity-increasing agent as a lotion, cream, ointment, or gel for application and topical delivery of the FIASMA to the patient's target skin area. The external formulation can be applied to or rubbed into the target area of ​​skin before or after radiation therapy.

[0050] In the method using an oral solid formulation, the active ingredient is provided in the form of particles, granules, beads, or other conventionally known forms, and is manufactured into tablets, capsules, capsulelets, or similar formulations. This is easily understood by those skilled in the art. The oral formulation may be provided, for example, as a sustained-release formulation in which the active ingredient is formulated to delay release from the final formulation. Examples include enteric-coated tablets, delayed-release capsules, or capsulelets. Alternatively, the active ingredient or components may be formulated to sustain the release of the active ingredient from the formulation after administration. Examples include matrix compositions.

[0051] In methods using liquid oral formulations, the active ingredient may be dissolved, emulsified, or suspended in a compatible, pharmaceutically acceptable carrier. Excipients or other inactive ingredients may be included to provide color, flavor, viscosity, and a pleasant mouthfeel to the patient to promote compliance. Combinations of these dosage forms may also be used. A second active ingredient that is not FIASMA may also be included. For example, a local anesthetic may be included, which is useful for reducing pain during or after treatment, and antiseptics, other anti-inflammatory agents, or antimicrobial agents may also be included.

[0052] Therefore, according to the present invention, a method for preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or ameliorating cutaneous radiation injury (CRI) comprises topically administering to a target area of ​​the skin of an appropriate patient at least once per day before, during, and after radiation treatment, 0.5 to 50 ml or more, depending on the size of the area to be treated, of a composition comprising an effective amount, e.g., about 0.1% to about 10% w / w, of a TCA (e.g., amitriptyline), a tricyclic antihistamine (e.g., loratadine), an SSRI (e.g., sertraline), or a combination of two or more FIASMAs.

[0053] Methods for preventing, treating, or ameliorating radiation dermatitis also include topically administering to a target area of ​​a patient's skin at least once per day before, during, and after radiation treatment, 0.5 to 50 ml or more, depending on the size of the area to be treated, of a composition comprising an effective amount, for example, about 0.5% to about 10% w / w, of a TCA (e.g., amitriptyline), a tricyclic antihistamine (e.g., loratadine), or an SSRI (e.g., sertraline), or a combination of two or more FIASMAs.

[0054] The method also includes preventing, treating, or ameliorating radiation proctopathy by topically administering or delivering to the target area of ​​an applicable patient at least once per day before, during, and after radiation treatment, 0.5 to 50 ml or more depending on the size of the area to be treated, of a composition comprising an effective amount, for example, about 0.5% to about 5% w / w, of a FIASMA, such as a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline).

[0055] Methods for preventing, treating, or ameliorating oral mucositis can include orally administering to a target area of ​​the skin or oral mucosa of an appropriate patient at least once daily before, during, and after radiation therapy, 0.5 to 50 ml or more, depending on the size of the area to be treated, of a composition containing an effective amount, for example, about 0.5% to about 10% w / w, of a FIASMA, such as a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline). It will be understood that the term "oral mucositis" includes "severe oral mucositis."

[0056] A preferred treatment for oral mucositis utilizes a dosage form comprising a mucoadhesive tablet, oral rinse, or a slow-dissolving adhesive tablet, such as an oral thin wafer or film, which is placed in the mouth, e.g., sublingually or bucally, and which is formulated to release an active ASMase inhibitor, preferably about 1 to 50 mg of sertraline, over a period of about 15 minutes up to 1 hour for release and delivery of the active agent to protect against oral mucositis, including severe oral mucositis (SOM).

[0057] One embodiment of an oral formulation used to treat oral mucositis or SOM comprises a lozenge or troche that is held in the mouth and slowly dissolves to release the active ingredient from the formulation, providing local or in situ protection against CRI that may occur during radiation therapy in head and neck cancer patients. It is understood that the lozenge or troche is formed to include a rod or stem that serves as a handle for convenient insertion and removal of the dosage form, similar in structure to a lollipop or other long-lasting confectionery.

[0058] Such "lollipop"-style systems for delivering pharmaceutical ingredients to the oral mucosa have been described. For example, U.S. Patent No. 6,103,257 describes a hard candy matrix attached to a handle to form a lollipop, a method for manufacturing the hard candy, a method for forming lollipop embodiments, and a method for using hard candy or lollipop embodiments to deliver local anesthetic to the oral mucosa. The disclosure of U.S. Patent No. 6,103,257 is incorporated herein by reference in its entirety.

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

[0060] The topical compositions may also contain antioxidants such as vitamin A, vitamin C, vitamin D, and vitamin E.

[0061] Preferably, the compositions used in the methods of the present invention are formulated as topical dosage forms that deliver an effective dose of the active ingredient to the target area of ​​the patient in situ. This can be achieved by using compositions formulated with a pharmaceutically acceptable base to form a lotion, cream, ointment, or gel for topical delivery of the active ingredient to the target area of ​​the patient's skin. To treat oral mucositis, the compositions can be formulated as oral solutions, emulsions, or suspensions, referred to herein as "mouthwashes."

[0062] Alternatively, the composition may include amitriptyline and a second tricyclic antidepressant that is not amitriptyline, such as amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin (alone but in combination), imipramine, iprindole, lofepramine, maprotiline, norclomipramine, nortiaden, nortriptyline, opipramol, protriptyline, tianeptine, or trimipramine.

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

[0064] The pharmaceutical compositions of the present invention may be provided as topical pharmaceutical compositions or may be oral formulations—either solid or liquid—comprising an effective amount of one or more active ingredients, such as amitriptyline, sertraline, or a combination thereof, for delivery of the one or more active ingredients to a patient. In preferred embodiments, the topical compositions of the present invention are free of, do not include, or exclude anti-inflammatory agents and anesthetic agents.

[0065] Preferred topical pharmaceutical compositions contain 10-20 mg of amitriptyline per ml of composition, or 1-100 mg of sertraline per ml of composition, or 15-20 mg of amitriptyline per ml of composition and 1-10 mg of sertraline per ml of composition, any of which may further contain an effective amount of an antioxidant, such as vitamin A, vitamin C, vitamin D, or vitamin E.

[0066] The oral formulations of the present invention can be formulated as controlled release oral formulations, which are either fast dissolving oral formulations or sustained or delayed release dosage forms.

[0067] It will be appreciated that the methods and compositions and dosage forms of the present invention may be useful in preventing, treating or ameliorating other skin conditions such as atopic dermatitis, burns, sunburn, dermatomyofibrilloma, sun-induced wrinkles, and the like. [Brief explanation of the drawings]

[0068] [Figure 1] Figure 1 shows the results of examining skin wounds after 30 Gy focal irradiation. Panel A of Figure 1 is a summary of skin wound scores for individual mice up to 4 weeks after 30 Gy. Panel B is a graphical representation of the observed changes in radiation skin wound scores over time. Data are presented as mean ± SEM. N = 5 mice per treatment group. [Figure 2] The results of an examination of skin wounds after 30 Gy focal irradiation are shown. Panel A of Figure 2 summarizes the skin wound scores of mice treated with 4% sertraline three times before irradiation, 4% sertraline twice after irradiation, or placebo five times before and after irradiation. Skin wound scores were examined weekly for up to 6 weeks after irradiation. Panels B-D of Figure 2 represent a comparison of skin wound scores over time between cohorts of mice receiving different treatments. Data are presented as mean ± SEM. N = 5 mice per treatment group. *P < 0.05 by two-way ANOVA with Bonferroni post-hoc test. [Figure 3] The percentage of patients who achieved an RTOG score of 2 or greater who were treated with either RAD-100 or the same vehicle during and after radiation therapy is shown. [Figure 4] 1 shows the effect of 1% sertraline on radiation-induced oral mucositis in mice. DETAILED DESCRIPTION OF THE INVENTION

[0069] Detailed Description of the Invention The present invention provides innovative methods for preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or reversing skin conditions in mammals, including humans, and methods of treatment can be carried out using novel compositions or dosage forms. The methods and compositions of the present invention are useful for treating cutaneous radiation injury or CRI.

[0070] Hereinafter, the terms "treat," "treating," or "treatment" in connection with cutaneous radiation injury or "CRI," or a specific condition considered to be a type of CRI, may mean, refer to, or be replaced by any one of "preventing," "reducing the incidence," "reducing the recurrence," "inhibiting," "improving," "reducing the severity," "ameliorating," or "treating" CRI. The specific terms "preventing," "reducing the incidence," "reducing the recurrence," "inhibiting," "improving," "reducing the severity," or "ameliorating" CRI may be used when intended to refer only to treatment, or a term may be expressly excluded from "treatment" when not intended to refer to that term. For example, a method of "reducing the incidence" may be used to mean only reducing the incidence of CRI, rather than "inhibiting" CRI. Alternatively, a "method of treating CRI, excluding reducing the occurrence of CRI," may mean a method of preventing, reducing the incidence, inhibiting, ameliorating, reducing the severity, or ameliorating CRI.

[0071] The term "cutaneous radiation injury" or "CRI" is recognized in the medical field as being defined as damage to the skin or underlying tissue in animals, including mammals and humans, caused by or resulting from exposure to radiation from industrial or military-related sources, such as nuclear power plants or nuclear weapons, or radioactive materials used in medical radiation therapy. Thus, the term CRI can include skin conditions such as radiation dermatitis or radiation proctopathy observed after medical radiation therapy. Minor skin damage, such as sunburn due to excessive exposure to sunlight, is generally not considered to be within the definition of CRI.

[0072] "Radiation dermatitis" refers to a skin disorder resulting from radiation therapy of a body part. For example, radiation therapy is a known and accepted treatment for cancerous breast tissue in women and men. Inflammation of the skin overlying the targeted cancerous tissue and exposed to radiation can result in damage to the skin. These signs and symptoms are known as radiation dermatitis. The term is used herein as it is clinically understood by dermatologists and other physicians who treat such disorders.

[0073] "Radiation proctopathy," or its alternative name "radiation proctitis," refers to a disorder of the rectum resulting from radiation therapy to the pelvic region, which causes changes in rectal function, including inflammation of the lining of the rectum. Radiation therapy to the pelvic region is a known and accepted therapeutic treatment for cancers of the genitourinary tissues, such as the treatment of prostate cancer in men or cervical cancer in women. The term is used herein as clinically understood by physicians treating such disorders.

[0074] "Oral mucositis" refers to a condition resulting from radiation therapy used to treat head and neck cancer. A more severe condition, appropriately referred to as "severe oral mucositis" or "SOM," can often be associated with ulcerated tissue in the mouth or when the patient is unable to swallow food or drink. Oral mucositis is a common and debilitating complication of cancer treatment, particularly radiation. It can lead to several problems, including pain, nutritional problems as a result of the inability to eat or drink, and an increased risk of infection due to sores in the oral mucosa. The use of the term "oral mucositis" herein includes "severe oral mucositis," and these terms can be used interchangeably.

[0075] "Emulsion" is a general term that includes macroemulsions, microemulsions, or nanoemulsions. Macroemulsions are kinetically stable dispersions of immiscible liquids. Microemulsions are kinetically and thermodynamically stable dispersions of immiscible liquids with droplet sizes in the micrometer size range. Nanoemulsions are kinetically and thermodynamically stable dispersions of immiscible liquids with droplet sizes in the range of about 20 nm to about 200 nm.

[0076] One embodiment of the present invention relates to a method of treating cutaneous radiation injury (CRI) by administering an effective amount or dosage of a functional inhibitor of acid sphingomyelinase (FIASMA), examples of which include certain selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines (particularly the tricyclic antihistamine loratadine or its metabolite desloratadine), antiarrhythmics, antipsychotics, antidiarrheals, adrenoceptor blocking agents (ARBs), beta-blockers, and estrogen receptor modulators.

[0077] Examples of SSRIs useful according to the present invention are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Preferred SSRIs useful according to the present invention include fluoxetine, fluvoxamine, paroxetine and sertraline.

[0078] Examples of TCAs useful according to the present invention are amitriptyline, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin (alone but in combination), imipramine, iprindole, lofepramine, maprotiline, norclomipramine, nortiaden, nortriptyline, opipramol, protriptyline, tianeptine and trimipramine. Preferred TCAs useful according to the present invention are amitriptyline, desipramine and imipramine.

[0079] Examples of tricyclic antihistamines useful according to the present invention include promethazine, cyproheptadine, latrepiridine, rupatadine, loratadine, and desloratadine. A particularly preferred tricyclic antihistamine according to the present invention is loratadine.

[0080] 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 FIASMAs from the same class of drug or at least two different FIASMAs from different classes of drugs. For example, the present invention may include the treatment of CRI using at least two TCAs, at least one TCA, at least one SSRI, or a tricyclic antihistamine, or at least one TCA, a tricyclic antihistamine, or a SSRI, and at least one additional active ingredient that is not a TCA, a tricyclic antihistamine, or a SSRI.

[0081] A preferred TCA for use in accordance with the present invention is amitriptyline. Amitriptyline is sold in the United States under the trade name ELAVIL® (AstraZeneca PLC, Cambridge, England) and is primarily used to treat several psychiatric disorders, including major depressive disorder, anxiety disorders, and less commonly, attention deficit hyperactivity disorder (ADHD) and bipolar disorder. Other uses include the prophylaxis of migraines, the treatment of neuropathic pain, such as fibromyalgia and postherpetic neuralgia, and less commonly, insomnia.

[0082] A preferred SSRI for use in accordance with the present invention is sertraline, which is sold in the United States under the trade name Zoloft® (Pfizer, New York, NY USA) and is primarily used to treat depression, panic attacks, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder (social phobia), and severe forms of premenstrual syndrome (premenstrual dysphoric disorder).

[0083] A preferred tricyclic antihistamine useful according to the present invention is loratadine (the active ingredient in the antihistamine product "Clarinex") or the loratadine metabolite desloratadine (the active ingredient in the antihistamine product "Clarinex").

[0084] Amitriptyline, loratadine, and sertraline have not previously been known to be effective in preventing or treating cutaneous radiation injury (CRI), including radiation dermatitis.

[0085] In a preferred embodiment, at least one FIASMA can be incorporated into a topical pharmaceutical composition for administration by placement or application to the surface of the skin or mucosa for the prevention, amelioration, or treatment of skin conditions or disorders such as radiation dermatitis, oral mucositis, etc. The composition can be administered once daily or more or less frequently as prescribed by the patient's physician or healthcare provider.

[0086] Dosage forms of topical compositions or preparations are well known in the art and are conventionally used in medicine. A preferred embodiment of the present invention involves incorporating a FIASMA into a pharmaceutically compatible base composition to produce a topical lotion, cream, gel, or ointment containing at least one FIASMA as the active pharmaceutical ingredient (API) or drug. Another embodiment of the present invention involves incorporating at least two different FIASMAs, e.g., a combination of at least one TCA and at least one SSRI, as active agents into a pharmaceutically compatible base composition to produce a topical lotion, cream, gel, or ointment. A preferred embodiment includes one or more active ingredients that are thoroughly mixed into a pharmaceutically acceptable cream or lotion base to provide a homogeneous mixture. While suspensions may be formed with active ingredients that are incompletely solubilized in the base, suspensions contain active ingredients that are thoroughly mixed to uniformly distribute the active agent throughout the base. The compositions of the present invention may include other pharmaceutically acceptable excipients conventionally used in topical dosage forms. For example, stabilizers, emulsifiers, penetration enhancers, etc. can be added as needed according to conventional methods for preparing topical preparations.

[0087] In another embodiment of the present invention, the active ingredient, such as one or more TCAs, tricyclic antihistamines, or SSRIs, can be formulated for oral administration. In one embodiment, the oral dosage is a solid oral formulation provided as an immediate-release dosage form. In one embodiment, the solid oral formulation is provided as a controlled-release dosage form. Yet another oral formulation is a liquid oral formulation containing an effective amount of a FIASM, such as an SSRI, sertraline. Tricyclic antihistamines have been found to provide a favorable taste profile or mouthfeel in oral formulations used for in situ oral or intraoral treatment. These liquid oral formulations are known as "gargles," "washes," "mouthwashes," or "sprays." The preferred term used in this disclosure for liquid oral formulations is "gargle." These liquid oral formulations, which will be understood to be in the form of a liquid solution, emulsion, or suspension, can contain thickeners or gelling agents to increase the viscosity of the solution, emulsion, or suspension, thereby extending the retention or residence time of the composition at the target site.

[0088] In one embodiment, the oral solid formulations provided for sublingual or buccal administration of the present invention comprise a pharmaceutical composition in unit dosage form (e.g., lozenge or troche, pill, tablet, film, or strip) containing at least one FIASMA, and in preferred embodiments are prepared as controlled-release formulations. Regarding the size of the unit dosage form, e.g., a lozenge, considerations are given to simplicity and manufacturing costs as well as consumer preference. The size of the sublingual or buccal dosage form can vary from approximately 5 mm to 20 mm, or from approximately 5 mm to 18 mm, or from approximately 7 mm to 18 mm, or from approximately 10 mm to 15 mm. When the sublingual or buccal dosage form has a circular or approximately circular shape, the size ranges are preferred diameter values. In most cases, the thickness of the lozenge will be 1 mm to 10 mm, more commonly 3 mm to 5 mm.

[0089] Sublingual or buccal dosage forms can be monolayered, bilayered, or multilayered. Sublingual or buccal dosage forms with soluble mucoadhesive properties can be prepared by compressing a powder containing a mucoadhesive hydrocolloid. For example, adhesive pastilles can be prepared by blending a dry powder containing gum arabic for adhesion with at least one FIASMA as an active ingredient. The oral residence time of a sublingual or buccal dosage form can be optimized according to the product's dissolution rate and total dissolution time. For example, sublingual or buccal controlled-release lozenges, mucoadhesive tablets, or films can be formulated to have an oral residence time of at least 1 minute, preferably 1 to 30 minutes, and more preferably 5 to 15 minutes, after administration.

[0090] In one embodiment of the present invention, the sublingual or buccal dosage form is a mucoadhesive tablet. Mucoadhesive tablets for sublingual or buccal administration can be prepared by compressing at least one mucoadhesive polymer to provide mucoadhesion and at least one FIASMA as an active ingredient. The mucoadhesive polymer can be one or more selected from the group consisting of cellulosic polymers, gum-type polymers, nonionic polymers, anionic polymers, derivatives thereof, mixtures thereof, etc. The cellulosic polymer can be hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, carboxymethyl cellulose, carboxypropyl cellulose, mixtures thereof, etc. The gum-type polymer can be xanthan gum, carrageenan gum, karayan gum, etc. The nonionic polymer can be polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide, etc. The anionic polymers may be polyacrylic acid, Carbopol® polymers and their neutralized polymers, other polyalkyl vinyl ether-maleic acid copolymers (trade name Gantrez), polyalginic acid and its salts, chitosan, hyaluronic acid and their derivatives, etc.

[0091] Mucoadhesive tablets may have a backing layer that slows the rate of saliva penetration and thereby slows the disappearance rate of the formulation in the oral cavity. The backing layer may be composed 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, methacryloyl ethyl betaine / methacrylate copolymer, methacrylic copolymers (methacrylic acid copolymers; Eudragit L 100, Eudragit L 12.5, Eudragit L 100-55, Eudragit L 30D-55), methacrylic acid copolymers such as aminoalkyl methacrylate copolymers, Eudragit E 100, Eudragit E 12.5, Eudragit RL 100, Eudragit RL 30D), cellulose acetate phthalate, and mixtures thereof. Waxes may include carnauba wax, yellow wax, white wax, etc. Additionally, any polymer that does not melt at the mouth conditions of pH 6-8 may be useful as a backing layer.

[0092] In another aspect, the invention features a pharmaceutical composition in a unit dosage form formulated for oral administration, such as sublingual or buccal administration, wherein the unit dosage form contains 5 to 100 mg of FIASMA (e.g., the dosage form contains 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg or more of sertraline).

[0093] In another aspect, the invention features a pharmaceutical composition in a unit dosage form formulated for oral administration, such as sublingual or buccal administration, where the unit dosage form contains 5-100 mg of FIASMA (e.g., the dosage form contains 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg or more of loratadine, or its metabolite, desloratadine). In a preferred embodiment, a dosage form for oral administration (either buccal or sublingual) can be provided as a lollipop, formed into the desired shape and equipped with a paper or plastic stick or stem as a handle to facilitate insertion into and removal from the oral cavity.

[0094] Alternatively, the oral formulation can be a liquid dosage form such as an oral solution, emulsion, or suspension containing about 1% to about 10% (w / w) of a FIASMA, e.g., an SSRI such as sertraline, in a pharmaceutically acceptable, compatible carrier. A preferred oral solution contains 10% sertraline. Controlled-release oral formulations include delayed-release formulations made by coating a solid dosage form with a polymeric film that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

[0095] The compositions of the present invention may contain conventional additives such as plasticizers, pigments, colorants, stabilizers, glidants, or other excipients.

[0096] In one embodiment, the FIASMA is provided in an oral formulation as a controlled release formulation, which allows for delivery of the drug over an extended period of time, as compared to immediate release formulations, which provide for complete delivery 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, formulated with the active agent and a suitable vehicle, ion exchange resins, waxes, alginates, gelling agents such as cellulose hydrogels (e.g., hydroxypropylmethylcellulose or HPMC) or polymeric acrylamides (e.g., CARBOPOL®).

[0097] 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 about 0.001 to 100 grams of an active ingredient and delivering the drug to an appropriate patient either directly to the skin as a topical composition such as a cream, lotion, or ointment, or formulated in an oral formulation.

[0098] According to one preferred embodiment, the FIASMA contained in the topical dosage form is amitriptyline provided in a dose of 1-1000 mg, more preferably about 5 mg-150 mg, and most preferably about 10-100 mg, administered as an about 0.5% to about 10% w / w topical composition. For example, a composition containing 1%-10% active ingredient (10-100 mg active ingredient per ml of composition) can be administered in a volume of about 0.5 ml to about 5 ml or more per topical application, depending on the size of the area to be treated. Preferably, the composition is administered topically in a volume of about 1 ml to about 2 ml, delivering 10-100 mg of active ingredient to the skin to prevent or treat CRI.

[0099] In another preferred embodiment, the FIASMA contained in the topical dosage form is sertraline provided in a dose of 1-1000 mg, more preferably about 5 mg-150 mg, and most preferably about 10-100 mg, administered as an about 0.1% to about 10% w / w topical composition. For example, a composition containing 0.1% to 10% active ingredient (1-100 mg active ingredient per ml of composition) can be administered in a volume of about 0.5 ml to about 5 ml or more per topical application, depending on the size of the area to be treated. Preferably, the composition is administered topically in a volume of about 1 ml to about 2 ml, delivering 1-200 mg of active ingredient to the skin to prevent or treat CRI.

[0100] One preferred dosage is administering at least 1 ml of a composition containing 1% FIASMA as an active ingredient according to the present invention. Another preferred dosage is administering at least 1 ml of a 2% w / w composition containing a FIASMA active ingredient according to the present invention. Yet another preferred dosage is administering at least 1 ml of a 3% w / w composition containing a FIASMA active ingredient according to the present invention. Yet another preferred dosage is administering at least 1 ml of a 4% w / w composition containing a FIASMA active ingredient according to the present invention. A further preferred dosage is administering at least 1 ml of a 5% w / w composition containing a FIASMA active ingredient according to the present invention. Preferred dosages may include administering at least 1 ml of a 6%, 7%, 8%, 9%, 10% or more than 10% w / w composition containing a FIASMA active ingredient according to the present invention.

[0101] It will be appreciated that concentrations of the drug may be provided in incremental increments of about 0.05%. By way of non-limiting illustration, FIASMA may be provided in 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%, as desired, to achieve the intended effect without negative side effects.

[0102] The dosage contained within a dosage form can vary, being lower for dosage forms that deliver the drug to the site more rapidly and higher for dosage forms that release the drug to the site over time. Dosage variations can also depend on the active ingredient or ingredients contained within the composition. For example, a composition containing two or more FIASMAs may contain less than 10% of each active ingredient, such as 0.1% to 9.9%, preferably about 0.5% to about 5%, of each active ingredient, such that the final composition contains less than about 1% to 10% of the total active ingredients in the composition. This can advantageously reduce the dosage of each active ingredient administered to a patient while providing equal or substantially equal prophylactic or therapeutic efficacy. It is also contemplated that a fixed-dose combination containing at least one TCA and at least one SSRI can provide a synergistic effect, with efficacy greater than the additive effect expected from each active ingredient used alone.

[0103] Preferably, FIASMA for topical administration is provided in an immediate-release topical formulation, which allows targeted dosing and immediate delivery of the drug from the composition to the skin simultaneously with application or administration of the composition. Retention of the FIASMA component at the site of administration or application may be preferable. Thus, the compositions of the present invention may omit a penetration enhancer to maintain the composition and active substance on the surface of the skin for a longer period of time, as opposed to compositions that include a penetration enhancer that allows or promotes penetration of the active substance into or under the skin, where the active substance can be systemically absorbed. Alternatively, in certain cases, a penetration enhancer may be preferred and used in the composition.

[0104] In a further aspect of the present invention, the dosage form may include a second active agent, such as a TCA, tricyclic antihistamine, or SSRI, or may include a second active agent that is not a TCA, tricyclic antihistamine, or SSRI, e.g., the second active agent is an active agent in a different class of drug. In a preferred embodiment, the composition includes a first active agent that is a TCA and a second active agent that is a different TCA, tricyclic antihistamine, or SSRI, or a compound in another class that is not a TCA. For example, the second active agent may be an antioxidant, such as vitamin A, vitamin C, vitamin D, or vitamin E. Preferably, the second active agent in the composition is not an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), or an anesthetic, such as a local anesthetic, e.g., lidocaine.

[0105] 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 class of compound that is not an SSRI. For example, the second active ingredient can be an antioxidant such as vitamin A, vitamin C, vitamin D, or vitamin E. Preferably, the second active substance in the composition is not an anti-inflammatory agent such as a nonsteroidal anti-inflammatory drug (NSAID) or an anesthetic agent such as a local anesthetic, e.g., lidocaine.

[0106] The topical dosage form may comprise a conventional, 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 utilized in topical or oral formulations. These commercially available pharmaceutical bases may act as a vehicle or medium for the active drug substance and may include one or more emollients, penetration enhancers, solvents, gelling agents, thickening or viscosity-increasing agents, preservatives, or other suitable excipients commonly used in topical preparations. In one embodiment, the commercially available pharmaceutical base is PEN Cream, an oil-in-water vanishing base available from Humco™.

[0107] Topical compositions containing FIASMA useful according to the present invention may be formulated as conventionally known in the pharmaceutical arts and may include 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 stiffening agent, at least one emulsifier, at least one anti-adherent, mixtures thereof, etc.

[0108] Preservatives for topical compositions may include phenoxy-2 ethanol, benzyl alcohol Emprove, etc. Solvents for topical compositions may include glycerin, propanediol-1,2, etc. Thickeners for topical compositions may include Carpool ETD 2020, xanthan gum, etc. Surfactants for topical compositions may include Brij S721, SP-Bri jS2-MBAL, etc. Stiffeners for topical compositions may include hydrogenated oils such as Kolliwax HCO, etc. Emulsifiers for topical compositions may include Miglyol 812 N, etc. Anti-sticking agents for topical compositions may include Q7-9120 Silicone Fluid, etc.

[0109] 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 a TCA (e.g., amitriptyline), a tricyclic antihistamine (e.g., loratadine), an SSRI (e.g., sertraline), or a combination thereof. The method includes providing a composition containing about 0.001 to 100 grams of the active ingredient and delivering the drug directly to the anorectal area either as a topical composition such as a cream or ointment, or formulated into 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 a dosage amount of 1 to 1000 milligrams (mg), more preferably about 5 mg to 150 mg, and most preferably about 10 to 100 mg, with a preferred dosage being 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 a dosage amount of 1 to 1000 milligrams (mg), more preferably in a dosage amount of about 5 mg to 150 mg, and most preferably in a dosage amount of about 10 to 100 mg, with a preferred dosage amount being a suppository or other dosage form containing about 100 mg. The dosage amount contained within the suppository or rectal plug can vary, being lower for dosage forms that deliver the drug to the site more rapidly and higher for dosage forms that provide a sustained release of the drug to the site. Furthermore, when two or more active pharmaceutical ingredients are provided in a fixed-dose suppository combination, the dosage of each active ingredient can be reduced in the dosage form, thereby advantageously reducing the risk or incidence of side effects.

[0110] Preferably, the method comprises providing a solid suppository or rectal plug dosage form containing a composition having a TCA or SSRI as an active ingredient and placing the dosage form in the rectal cavity for a period of time required to deliver the active ingredient to the site. The composition provided in the rectal plug delivery device can be a suppository.

[0111] Alternatively, the drug may be delivered using a rectal delivery device, such as a rectal plug, containing an effective dose of an active ingredient, such as a FIASMA or a combination of two or more FIASMAs. In one embodiment of the rectal plug device according to the present invention, the plug device includes an insoluble porous housing that forms a chamber for containing the active ingredient. The active ingredient may be provided as a soluble suppository disposed within the chamber portion formed within the porous rectal plug housing. Upon administration, the suppository is exposed to bodily fluids, causing 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 to fill the chamber within the rectal plug housing.

[0112] Other types of rectal plugs are known and may be adapted for use in accordance with the present invention. For example, rectal plugs formed of porous, sponge-like polymeric materials, such as polyurethane foam, are known for use in fecal incontinence. Such rectal plugs are sold under the name PERISTEEN™ Anal Plug (Coloplast Corp., North Minneapolis, MN, USA). The polyurethane foam can be soaked in a solution containing an effective amount of FIASMA that can be adsorbed onto the material for delivery upon insertion into the rectal cavity. These commercially available rectal plugs are generally provided in a compressed form for ease of insertion and are wrapped in a water-soluble film that dissolves after insertion, allowing them to expand into an expanded shape. Such compression and expansion are not required for in situ drug delivery according to the present invention.

[0113] The rectal plug delivery device may include a distal flange 102 that prevents the entire rectal plug delivery device from being drawn into the rectal cavity, thereby maintaining the rectal plug device in place during administration of the active ingredient. The active ingredient, such as a TCA or SSRI, may be provided as a pharmaceutical composition contained within a cavity (not shown) formed within the elongate member. The proximal end of the elongate member 101 includes a pore 103 that allows bodily fluids to enter the cavity formed within the elongate member, allowing the active ingredient to escape from the composition contained within the elongate member. The rectal plug delivery device may have an extension piece connected to the distal flange, such as a strap or string, that facilitates removal of the rectal plug delivery device, functioning similarly to the removal of a tampon.

[0114] Compositions for rectal administration can be formed as suppositories that dissolve or melt when administered into the rectal cavity. Alternatively, the compositions can be amorphous or amorphous compositions, including gels, creams, or ointments. Preferably, the compositions are provided as controlled-release compositions, preferably extended-release compositions, that gradually release the active ingredient from the composition.

[0115] In another embodiment, the dosage form comprises an anal plug comprising a soft, compressible, porous material (e.g., foam rubber or a polymeric sponge-like material), with the active ingredient permeated, impregnated, or coated onto the porous, compressible plug material.

[0116] The rectal plug delivery device comprises a soft, compressible, porous material in an expanded configuration. In this embodiment, the rectal plug delivery device includes a drug delivery element at its proximal end that expands and conforms to the shape of the rectal cavity upon insertion into the rectal cavity. An extension member, such as a strap or string, is connected to the drug delivery element and functions similarly to the removal of a tampon to facilitate removal of the rectal plug delivery device.

[0117] The composition containing the active ingredient according to the present invention can be soaked or impregnated into the porous material forming the delivery element as a liquid or gel, cream or ointment. The composition containing the active ingredient can be provided as a controlled release composition, preferably an extended release composition, which gradually releases the active ingredient.

[0118] A rectal plug delivery device comprising a porous material can be provided in a compressed form for easy insertion into the rectal cavity. The compressed drug delivery element can include a water-soluble wrapper surrounding the drug delivery element. After insertion of the rectal plug delivery device embodiment into the rectal cavity, bodily fluids dissolve the wrapper, allowing the drug delivery element to expand to its expanded shape. An extension, such as a strap or string, can be provided to facilitate removal of the rectal plug delivery device.

[0119] In a preferred embodiment, the active ingredient is provided in a controlled-release formulation that allows for delivery of the drug over a period of time, as compared to immediate-release formulations, which provide for delivery of all of the drug from the dosage form immediately upon administration. Controlled-release formulations known in the art include the use of coatings such as enteric-coated tablets, beads, or pellets formulated with the active agent and a suitable vehicle that melts or dissolves in rectal fluid, ion-exchange resins, waxes, alginates, gelling agents such as cellulose hydrogels (e.g., hydroxypropylmethylcellulose or HPMC), or polymeric acrylamides (e.g., CARBOPOL®). Such formulations and compositions, as well as methods for making suppositories or other controlled-release compositions, are well known in the art.

[0120] In the methods of the present invention, treating a CRI such as radiation dermatitis utilizes a composition comprising at least one FIASMA, such as a 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 compositions utilized in the methods of the present invention can be provided in topical dosage forms. Additionally, the present invention includes methods for treating, ameliorating, or preventing skin disorders or conditions, such as radiation dermatitis, using an oral formulation comprising at least one TCA, e.g., amitriptyline, and / or at least one SSRI, e.g., sertraline.

[0121] Preferably, the method comprises providing a topical dosage form comprising a composition having at least one FIASMA as an active ingredient therein, and placing an effective amount of the composition on the target area of ​​skin to be treated for a period of time required to deliver the active ingredient to the site. In a preferred embodiment, the active ingredient or ingredients may be formulated as a viscous, controlled-release gel, ointment, or cream for administration to the skin. The topical compositions of the present invention preferably contain from about a 0.1% concentration (1 mg / ml of composition) up to about a 10% concentration (100 mg / ml of composition) of each active ingredient, provided in 0.05% increments, e.g., 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%, 1.05%, and 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, etc., up to about 10.0%. A typical dose is about 0.5 ml to about 5 ml, preferably about 1 ml to about 2 ml, but is not limited to this, and doses of 3 ml, 4 ml, 5 ml or more can be applied only to the area of ​​the skin requiring treatment. Topical formulations can be applied to or rubbed into the target area of ​​the skin before or after radiation therapy.

[0122] In another preferred embodiment, the FIASMA for topical administration is provided in an immediate-release topical formulation, which allows for targeted dosing and immediate delivery of the drug from the composition to the skin upon application or administration of the composition. Retention of the FIASMA component at the site of administration or application may be preferred. Thus, the compositions of the present invention may exclude penetration enhancers to maintain the composition and active substance on the surface of the skin for a longer period of time, as opposed to compositions that include penetration enhancers that allow or promote penetration of the active substance into or under the skin, where the active substance can be systemically absorbed.

[0123] Alternatively, in certain cases, penetration enhancers may be preferred and utilized within the composition.

[0124] It will be understood that applying or administering the composition before radiation therapy can include maintaining the composition in place during the radiation therapy session.The method can be repeated during each radiation therapy session and can include administering or applying the composition at least once per week, several times per week, daily, or multiple times per day before, after, or during the radiation therapy session.The method can be continued for up to one month or up to one week after the radiation therapy session is stopped.In an alternative embodiment, the method can be continued for one week after the radiation therapy session is stopped.

[0125] According to one embodiment of the present invention, the method of the present invention comprises topically administering an effective dosage of one or more active ingredients, i.e., a drug that is a FIASMA, to the skin of an appropriate patient, such as a patient suffering from CRI after exposure to environmental radiation or a patient who is undergoing or has undergone medical radiation therapy and is suffering from radiation dermatitis or radiation proctopathy.

[0126] In a method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or reversing oral mucositis or severe oral mucositis, the method comprises: - Providing an oral solid dosage form containing FIASMA as an active ingredient; - administering to an appropriate patient, such as a patient undergoing radiation therapy 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; may include:

[0127] In one embodiment, the oral solid dosage form is a modified release dosage form for sublingual administration comprising FIASMA as an active ingredient.

[0128] In another method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or reversing oral mucositis or severe oral mucositis, the method comprises: - Providing an oral solid dosage form containing FIASMA as an active ingredient; - administering to an appropriate patient, such as a patient undergoing radiation therapy for head and neck cancer, a controlled release buccal dosage form comprising a pharmaceutically effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA; In one embodiment, the oral solid formulation is a modified release dosage form for buccal administration comprising FIASMA as an active ingredient.

[0129] In yet another method of preventing, reducing the incidence or recurrence of, inhibiting, treating, ameliorating, or reducing the severity of or reversing oral mucositis or severe oral mucositis, the method comprises: providing a liquid oral formulation or "gargle" containing FIASMA as an active ingredient; administering to an appropriate patient, such as a patient undergoing radiation therapy for head and neck cancer, an oral rinse formulation comprising a pharmaceutically effective amount of one or more active ingredients, wherein at least one active ingredient is FIASMA; may include:

[0130] In a method for treating radiation proctopathy, the method of the present invention comprises the step of anorectally administering an effective dose of one or more FIASMA drugs as an active ingredient, preferably drugs from a class selected from TCAs, SSRIs or combinations thereof, to the rectal cavity or rectal tissue of an appropriate patient, such as a patient suffering from radiation proctopathy or proctitis resulting from medical radiation therapy.

[0131] A preferred method for treating radiation proctopathy involves anorectal administration of an effective dose of a FIASMA as the active ingredient, such as a TCA, amitriptyline, the tricyclic antihistamine loratadine, or the SSRI, sertraline. Compositions containing fixed-dose combinations of two or more different FIASMAs or one or more FIASMAs with a non-FIASMA active ingredient may also be used. In a preferred example, the method is carried out using amitriptyline provided as a composition and in a dosage form capable of delivering an effective dose in situ to the rectal cavity of a patient. For example, amitriptyline can be formulated as a liquid and administered as an enema, or can be formulated with a thickening or viscosity-enhancing agent to provide a lotion, cream, ointment, or gel for topical delivery of amitriptyline to the anorectal area and rectal cavity of a patient.

[0132] Alternatively, the method can utilize a semi-solid or solid dosage form such as a suppository or a rectal plug delivery device for delivery of an active pharmaceutical ingredient to the anorectal cavity and in situ administration of the drug. Preferably, the dosage form provided with or incorporated within the rectal plug delivery device is a controlled release formulation having excipients capable of delaying or preventing release of the active drug incorporated into the dosage form or coated on the outer surface of the dosage form.

[0133] When the dosage form is a rectal plug delivery device, the device may be an insoluble plug forming a housing having an internal chamber for containing therein a composition comprising an active pharmaceutical ingredient according to the present invention. For example, the chamber of the rectal plug may be filled with a viscous composition comprising a FIASMA active ingredient, or may contain a suppository dosage form comprising FIASMA as the active ingredient.

[0134] An alternative embodiment of a rectal plug delivery device useful in practicing the methods of the present invention comprises a porous compressible foam material soaked in or coated with a composition comprising an active pharmaceutical ingredient according to the present invention. The devices described with respect to the methods of the present invention can accommodate an effective dose of FIASMA provided in an amount from about 0.1 mg to about 1000 mg or more.

[0135] The methods of the present invention may further comprise administering to an appropriate patient at least one active ingredient and an additional or second active ingredient that is not a FIASMA. Preferably, the additional active agent is formulated with at least one TCA, at least one SSRI, or a combination of a TCA and an SSRI in a fixed-dose drug combination.

[0136] A preferred embodiment of the composition having a first and 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 nonsteroidal anti-inflammatory drug (NSAID). Alternatively, the second active substance in the composition is not an anti-inflammatory agent, and the composition excludes steroid compounds, or the composition excludes nonsteroidal anti-inflammatory drugs (NSAIDs). The anesthetic can be a local anesthetic, such as lidocaine, which is typically used for topical administration. The antioxidant can be, for example, vitamin A, vitamin C, vitamin D, and vitamin E.

[0137] The present invention includes a composition for treating radiation proctopathy, comprising providing an effective amount of a FIASMA formulated as a controlled-release formulation for in situ delivery of the active ingredient to the rectal cavity. In a preferred embodiment, the composition may be formulated as a controlled-release suppository containing at least one TCA or at least one SSRI, or at least one TCA and one SSRI, as the active ingredient or active ingredients. The composition may include an additional drug that is not a FIASMA as described herein.

[0138] The active pharmaceutical ingredient contained in the suppository or rectal delivery device can be administered before, during, or after pelvic radiation therapy. Preferred administration involves inserting the suppository or rectal delivery device into the rectal cavity and leaving it there until delivery of the entire dose is complete. Preferred suppositories according to the present invention dissolve slowly and can remain in the rectal cavity for up to about 24 hours, i.e., throughout the entire day of use. The rectal plug delivery device can be retained in the rectal cavity for up to about 48 hours, but preferably contains a drug formulation that delivers a dose of the active ingredient or active ingredients within about 24 hours. This provides for daily use after a bowel movement. Alternatively, the rectal plug can be temporarily removed for a bowel movement and then reinserted.

[0139] The suppository containing the active pharmaceutical ingredient is placed in the rectal cavity so that it remains in the rectum for the period required for dissolution. When the suppository completely dissolves, the release of the active ingredient from the suppository is achieved after the suppository remains in the rectum. The released active ingredient is present in high concentration at the site of delivery, thereby increasing the effectiveness of this therapy for anorectal disorders.

[0140] It will be understood that applying or administering the composition before radiation therapy can include maintaining the composition in place during the radiation therapy session.The method can be repeated during each radiation therapy session, and can include administering or applying the composition at least once per week, several times per week, daily, or multiple times per day before, after, or during the radiation therapy session.The method can be continued for up to one month or up to one week after the radiation therapy session is stopped.In an alternative embodiment, the method can be continued for one week after the radiation therapy session is stopped.

[0141] According to alternative embodiments, the suppositories may contain or consist of other drugs or supplements, such as antioxidants, including vitamin E and vitamin C, as well as natural antioxidants such as fish oil, green tea, cranberry, etc. These may be used either in separate suppository preparations or as additional components of the suppositories of the present invention.

[0142] In any of these uses and embodiments of the present invention, suppository forms of these agents are used as clinical treatments for chronic diseases of the anus and rectum.

[0143] Any form of active ingredient contemplated by the present invention that is placed in a suppository form for the treatment of anorectal disorders is within the scope of the present invention. Furthermore, the incorporation of the active pharmaceutical ingredients described herein in combination with other active or inactive ingredients into a suppository for treating anorectal disorders is also embodied within the present invention. Furthermore, the incorporation of any FIASMA into a suppository as a means for treating anorectal disorders is also embodied within the present invention. Finally, other agents, such as anti-inflammatory agents, anesthetics, herbs, or other vitamins, may be included in the suppository to enhance the efficacy of the active ingredient or ingredients. Materials used to prepare suppositories include any fatty (or oily) base and / or water-soluble (or miscible) base.

[0144] In a particularly preferred embodiment, the medication contained in the suppository is amitriptyline. In a preferred embodiment, the suppository is composed of a fatty (or oily) base and / or a water-soluble (or miscible) base. However, other bases may be utilized in the present invention to allow for the transfer of medication to the rectum. More generally, any form of suppository base may be used to construct the device. Furthermore, various TCAs may be incorporated into the suppository to allow for direct application of these substances to the rectum and anus. Other aforementioned substances may also be included in the suppository to enhance their efficacy in treating anorectal disorders. The contents of the suppository may also consist of various TCAs alone or in combination with amitriptyline, depending on the goal of treatment.

[0145] Various dosages of amitriptyline may be used depending on the condition being treated. For example, the rectal dose of amitriptyline used to treat radiation proctopathy is 25 to 100 mg per day. Both lower and higher doses may be used initially in the development of the device. The optimal dosage for treating these conditions will be determined through clinical trials.

[0146] However, after appropriate clinical evaluation of this treatment, higher or lower doses of amitriptyline may ultimately be used to treat radiation proctopathy and other anorectal disorders. The dosage of amitriptyline and other TCAs in suppositories is expected to be lower than the oral dosage for treating anorectal diseases because these drugs are applied directly to the affected area. However, because delivery by suppository or rectal device does not require ingestion and allows for larger dosage forms, higher dosages than those typically used in oral formulations may be utilized if determined to be safe and effective based on further clinical experience or testing.

[0147] Preferably, the method for treating CRI is carried out using a FIASMA, e.g., a TCA such as amitriptyline, a tricyclic antihistamine such as loratadine, or an SSRI such as sertraline, wherein the TCA, tricyclic antihistamine, or SSRI, or a combination of at least two of these active ingredients, is prepared as a composition and provided in a dosage form capable of delivering an effective dosage in situ to a patient's skin. For example, amitriptyline can be formulated as a solution and administered to a target area of ​​the skin 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 a target area of ​​the skin of an appropriate patient, such as a patient scheduled for radiation therapy or suffering from radiation dermatitis.

[0148] Alternatively, the method may utilize administration of an oral solid formulation.

[0149] The methods of the present invention may further comprise administering to an appropriate patient at least one FIASMA and an additional active ingredient that is not a FIASMA. Preferably, the additional active agent is formulated with the at least one FIASMA in a fixed-dose drug combination for topical administration to the skin.

[0150] A preferred embodiment of the composition of the present invention having a first and 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, or vitamin E. A further embodiment of the composition of the present invention can comprise a TCA, an SSRI, and an antioxidant. Examples of active ingredients are amitriptyline as the TCA, loratadine as the tricyclic antihistamine, sertraline as the SSRI, and vitamin D as the antioxidant.

[0151] Depending on the condition being treated, various dosages of one or more of the active ingredients described herein may be utilized. For example, the topical dosage of amitriptyline used to prevent or treat radiation dermatitis ranges from 1 mg to 100 mg per day.

[0152] The optimal dosage and treated area for preventing or treating these conditions will be determined based on clinical trials, but after appropriate clinical evaluation of this treatment, higher or lower doses of amitriptyline or sertraline may ultimately be used to prevent or treat radiation dermatitis as well as other dermatological inflammatory diseases. [Example]

[0153] Example Example 1 - Use of Compositions Containing TCA A patient undergoing or scheduled to undergo radiation therapy for the treatment of a 25 mm breast tumor is given a composition that is an ointment containing 1% to 2% amitriptyline in a pharmaceutically acceptable base. The area of ​​skin over the tumor that is or will be exposed to radiation during the radiation therapy treatment can be identified and marked.

[0154] A medical professional or patient administers the composition by applying approximately 1 ml of the composition to the area of ​​skin that is expected to be exposed to or affected by radiation at least once per day. Administration of the composition is repeated at least daily or up to 5 times per day for a period of at least one week during the radiation therapy regimen. For example, a patient receiving a radiation therapy regimen 5 times a week (Monday to Friday) applies the cream to the treated area 90 minutes before radiation therapy each day, and then before going to bed for 7 days. Thus, before and after radiation therapy Monday through Friday, and then twice a day on weekends when radiation is not being received. This is repeated for 5 or 6 weeks.

[0155] Expected Results: Radiation dermatitis is prevented, improved, or ameliorated by administration of the composition.

[0156] Example 2 - Determining the efficacy of single active versus multiple actives Groups of five patients undergoing or scheduled to undergo radiation therapy for the treatment of 25 mm breast tumors are given a composition that is an ointment containing either: ■ 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 ■ Pharmaceutically acceptable base, alone (placebo).

[0157] The area of ​​the skin over the tumor that will be or is expected to be exposed to radiation during radiation therapy treatment can be identified and marked. A medical professional or patient administers the composition by applying approximately 1 ml of the composition to the area of ​​the skin that is or will be exposed to radiation at least once per day prior to radiation treatment. Administration of the composition is repeated at least daily or up to five times per day for a period of at least one week after radiation treatment.

[0158] Expected Results: The efficacy of each composition containing an active ingredient is determined by scoring the level of radiation dermatitis present in each group of patients. A determination of whether the efficacy of the combined use of amitriptyline and sertraline exhibits additive or synergistic effects can be determined by comparing whether the radiation dermatitis scores of compositions containing 1% amitriptyline and 1% sertraline are lower, equal, or higher than the effects of the 1% amitriptyline composition alone and the 1% sertraline composition alone. The radiation dermatitis score of a fixed-dose combination composition containing 0.5% amitriptyline and 0.5% sertraline in a pharmaceutically acceptable vehicle can provide information regarding the efficacy of lower doses of each active agent in the combination compared to higher doses of each active agent alone in the composition.

[0159] Example 3 - Treatment of radiation dermatitis in irradiated mice Objective: To determine the efficacy of topical reformulation of sertraline as a protective agent for radiation-induced skin wounds.

[0160] Materials and Methods: Radiation-induced dermatitis experiments were performed in 10-week-old female C57BL / 6J mice (The Jackson Laboratory). Approximately 3 × 3 cm of dorsal skin was shaved before drug treatment. Mice were randomly assigned to receive topical treatment with 4% sertraline or vehicle (n = 5 mice per cohort), and all investigators were blinded to the topical treatment.

[0161] The study compared an active drug-containing composition with a placebo (vehicle). Both the active drug-containing composition and the placebo were prepared by a third party and provided to the inventors for use in the study. The preparation of the compositions is summarized below. 4% sertraline cream4% (w / w) sertraline (as the hydrochloride salt) in an oil-in-water vanishing cream base containing hexylene glycol, purified water, isopropyl palmitate, caprylic / capric triglyceride, propylene glycol, ceteareth 20, cetearyl alcohol, glyceryl stearate, PEG 100 stearate, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin, and phenoxyethanol. Placebo cream -Oil-in-water vanishing cream base containing purified water, isopropyl palmitate, caprylic / capric triglyceride, propylene glycol, ceteareth 20, cetearyl alcohol, glyceryl stearate, PEG 100 stearate, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin and phenoxyethanol. Both products were packaged in white polypropylene jars marked for external use only, with white polypropylene closures with polyvinyl chloride disc liners, and stored at controlled room temperature (20°C-25°C) with instructions not to freeze.

[0162] The formulation is further described in Table A below. [Table 1]

[0163] A 4% sertraline composition is prepared as the free base as set forth in Composition Table A. The amount of sertraline HCl added to the formulation is adjusted to compensate for the HCl salt.

[0164] PEN Cream is a commercially available oil-in-water vanishing base purchased from Humco (https: / / www.humco.com / pharmaceuticals / pencream / ). The NDC code for the cream is 0395-6010-56.

[0165] Mice received topical treatment once daily for 12 days, starting 2 days before irradiation. Dermatitis was induced by delivering a single dose of 30 Gy X-rays to a 1 × 1 cm area of ​​shaved skin using an image-guided small animal irradiation system, X-Rad225Cx.

[0166] The occurrence of radiation-induced dermatitis was assessed by a single observer blinded to treatment group before and weekly for 4 weeks after irradiation. Skin reactions to radiation were assessed according to a semiquantitative scoring system previously established in preclinical studies—scoring ranges from 1.0 to 5.5 (in increments of 0.5) based on erythema, scaling (dry and moist), necrosis, and dermal loss (Table 1). [Table 2]

[0167] Results: During the first 2 weeks after 30 Gy irradiation, all mice treated with 4% sertraline cream had skin wound scores of 4.5, whereas vehicle-treated mice had less severe scores of 3.0 to 3.5 (Figure 1, Panels A and B). Scratching behavior and sequelae were observed in the 4% sertraline cohort.

[0168] At 21 days post-irradiation, both treatment cohorts had skin wound scores of 3.0-3.5. At the end of the experiment, 28 days post-irradiation, mice treated with 4% sertraline had less severe skin wound scores ranging from 1.5-2.0 with a mean score of 1.7.

[0169] In contrast, vehicle-treated mice maintained higher skin wound scores ranging from 1.5 to 3.5 with a mean score of 3.0 (Figure 1, panels A and B).

[0170] Discussion: Our preliminary results indicate that skin wounds in mice receiving 4% sertraline significantly improved 4 weeks after 30 Gy, whereas skin wounds in vehicle-treated mice remained severe. While the cause of the higher wound scores in mice treated with 4% sertraline during the first 2 weeks after irradiation remains under investigation, a literature review confirmed that topical sertraline induces significant pruritus-induced scratching in mice, as shown in a previously published animal study ( Neuron 87, 124-138, July 1, 2015). Repeating this experiment with cream removal after 30 minutes significantly reduced scratching behavior and initial skin wound scores, yet still demonstrated similar benefits after 2 weeks, consistent with the data presented above. Therefore, the early toxicity observed during the first week is likely related to sertraline-induced self-injury due to scratching.

[0171] Conclusion: The results surprisingly suggest that a 4% FIASMA composition, such as a 4% sertraline topical composition, has efficacy against radiation-induced skin wounds.

[0172] Compositions containing lower concentrations of active drug, e.g., less than 1% sertraline, preferably about 0.5%, can be formulated with one or more penetration enhancers, solubilizers, emollients, etc., to deliver substantially the same amount of drug to the target site as the compositions set forth in Table A above. These formulations containing 1% or less active drug may be advantageous in terms of dosage to the patient and therefore may be preferred.

[0173] A topical gel composition for delivering a therapeutically effective amount to a target site on a patient's skin may contain, for example, 0.5-1.0% active agent in admixture with one or more preservatives, one or more humectants / solvents, one or more rheology modifiers / thickeners, one or more anti-sticking agents / glidants, etc. An example of a topical gel formulation is provided below in Gel Composition Table B. [Table 3]

[0174] A topical cream formulation for delivering a therapeutically effective amount to a target site on a patient's skin may contain, for example, 0.5-1.0% active agent in admixture with one or more preservatives, one or more humectants / solvents, one or more rheology modifiers / thickeners, one or more anti-sticking agents / glidants, etc. An example of a topical gel formulation is provided below in Cream Composition Table C. [Table 4]

[0175] Example 4 - Comparison of pre-irradiation and post-irradiation treatments The experiment presented in Example 3 was repeated in mice to compare 4% sertraline administered as a pre-irradiation treatment and a post-irradiation treatment. 4% amitriptyline was also tested.

[0176] The same scoring chart shown in Example 3 was used to evaluate the irradiated sites of the mice.

[0177] Methods: Radiation-induced dermatitis experiments were performed using 10-week-old female C57BL / 6J mice (The Jackson Laboratory). An approximately 3 × 3 cm area of ​​dorsal skin was shaved before drug treatment. A single dose of 30 Gy X-rays was delivered to a 1 × 1 cm area of ​​skin using an image-guided small animal irradiator, X-Rad225Cx, to induce dermatitis. Mice were randomly assigned per cage to receive topical treatment with 4% sertraline cream once daily for 3 days before irradiation, and either 4% sertraline cream once daily for 2 days starting 24 hours after irradiation, or placebo once daily for 5 days (before and after irradiation).

[0178] The occurrence of radiation-induced dermatitis was examined weekly for 6 weeks after irradiation by two observers (SH and SS) blinded to the treatment cohort. Skin reactions to radiation were assessed according to a semiquantitative scoring system previously established in preclinical studies—scoring ranged from 1.0 to 5.5 (in increments of 0.5) based on erythema, scaling (dry and moist), necrosis, and dermal loss.

[0179] The score results at 1, 2, 3 and 4 weeks after irradiation treatment (IR) are shown in Table 2 below. [Table 5]

[0180] Results: Four weeks after irradiation, 9 of 10 sertraline-treated mice showed lower scores (greater improvement) than mice treated with vehicle alone. In general, 4% sertraline cream performed better when administered after irradiation than before. However, it showed some preventative effect before irradiation. 4% sertraline cream administered 24 and 48 hours after irradiation also showed an early response, showing lower scores within one week of irradiation and continuing to show improved scores up to four weeks after irradiation.

[0181] These results are illustrated in Figure 2, Panels A–D. Overall, mice receiving 4% sertraline twice post-irradiation showed accelerated recovery from acute radiation dermatitis starting from the first week after irradiation (Figure 2, Panels A, B, and D). Skin wound scores in the post-irradiation group were significantly lower than those in the placebo group from 3 to 6 weeks after 30 Gy (Figure 2, Panel B). On the other hand, skin wound scores in the pre-irradiation group were significantly lower than those in the placebo group only at 5 weeks after 30 Gy (Figure 2, Panel C). Notably, mice receiving 4% sertraline three times pre-irradiation showed significantly slower recovery from acute radiation dermatitis compared with mice receiving 4% sertraline twice post-irradiation (Figure 2, Panel D).

[0182] Of note, administration of 4% amitriptyline cream and 4% fluoxetine cream had adverse effects on mice, leading to the termination of this arm of the study, suggesting that the 4% cream formulations containing tricyclic antidepressants (TCAs) were excessively dosed and that lower doses were needed to determine their efficacy.

[0183] Example 5 - Oral solution or mouthwash containing an SSRI for treating oral mucositis associated with head and neck radiation therapy Objective: The goal of this planned study is to evaluate the effectiveness of an oral solution or mouthwash containing an SSRI (sertraline) for treating oral mucositis and xerostomia associated with head and neck radiotherapy. A. Optimal Radiation Dose to Induce Oral Mucositis in a Mouse Model A pilot study was conducted to determine the optimal dose of irradiation for testing radiation-induced oral mucositis and xerostomia in 8-week-old female C57BL / 6J mice. The head and neck regions of mice were treated with single doses of 0, 16, 18, 20, and 22 Gy X-rays (n=10 per radiation dose) using the Small Animal Radiation Research Platform (SARRP).

[0184] Two measurements are taken to determine the duration and severity of oral mucositis. (a) Mice were weighed daily from day 7 to day 16 after irradiation and then three times a week until day 21 after irradiation; and (b) Pathomorphological changes of the tongue will be evaluated using an otoscope on days 9, 12, and 16 after irradiation.

[0185] Pain control medications and supportive care may be provided as needed.

[0186] To assess the severity of xerostomia, saliva production per mouse was measured 30 and 60 days after irradiation according to previously described methods. See Ashcraft et al. (2015) "Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model." International Journal of Radiation Oncology, Biology, Physics 93 (4): 892-900; Saiki et al. (2018) "Aldehyde Dehydrogenase 3A1 Activation Prevents Radiation-Induced Xerostomia by Protecting Salivary Stem Cells from Toxic Aldehydes." Proceedings of the National Academy of Sciences of the United States of America 115 (24): 6279-84.

[0187] B. Determining the Effect of Sertraline Oral Solution on the Development of Radiation-Induced Oral Mucositis and Xerostomia Using the optimal radiation dose determined in A above, 8-week-old female C57BL / 6J mice were head and neck radiotherapy, plus vehicle only (control); head and neck radiation therapy plus 2% sertraline in vehicle; Head and neck radiation therapy plus 4% sertraline in vehicle, and Head and neck radiation therapy plus 6% sertraline in vehicle (n=20 mice / treatment cohort) will be randomly assigned to receive

[0188] Mice are treated with sertraline oral solution once daily for 5 consecutive days (2 days before irradiation, 2 days immediately before irradiation on the same day as irradiation, and 2 days after irradiation).

[0189] Two measurements are performed to assess the duration and severity of oral mucositis. (a) Mice are weighed daily from 7 to 16 days after irradiation and then three times a week until 21 days after irradiation. (b) Tongue pathomorphological changes are assessed using an otoscope at 9, 12, and 16 days after irradiation. Pain control medications and supportive care may be provided as needed. To assess the severity of xerostomia, saliva production per mouse is measured at 30 and 60 days after irradiation (Ashcraft et al. 2015; Saiki et al. 2018). Salivary gland fibrosis is assessed by histology at 60 days after irradiation (Ashcraft et al. 2015).

[0190] It is hypothesized that oral treatment with sertraline will reduce the severity and / or duration of radiation-induced oral mucositis and xerostomia by reducing acute inflammation. It is expected that results will be dose-dependent and that sertraline oral solution will be effective in treating oral mucositis and / or xerostomia.

[0191] Example 6 - Treatment of radiation dermatitis in patients undergoing and recovering from radiation therapy Place Objective: To determine the effectiveness of RAD-100 in preventing or reducing radiation-induced dermatitis in postoperative breast cancer patients receiving a standard course of radiotherapy.

[0192] Materials and Methods: A randomized, double-blind study was conducted using subjects aged 18 years or older who had recently undergone breast cancer surgery - either breast-conserving (lampectomy) or mastectomy - and who were scheduled to receive a standard course of radiotherapy at 1.8-2.0 GY per session in 25-30 sessions over a period of 5-6 weeks administered as daily treatments for 5 consecutive days per week.

[0193] Subjects were excluded from the study if they met any one of the following exclusion criteria: Ulcerated breast tissue or open breast wounds at the start of radiation therapy. · Skin lesions in the area to be irradiated before the start of radiation. Known allergy, hypersensitivity or reaction to any of the ingredients of the cream or to sertraline. Any neurological or psychiatric condition that, in the opinion of the treating physician, makes the subject unable to participate in the study. Any other significant comorbidity that, in the opinion of the investigator, may affect the outcome of the study (e.g., poorly controlled diabetes, renal failure, liver dysfunction, cardiovascular disease, etc.). BMI > 35.0 Subjects involved in an investigational drug trial within the past 30 days. Subjects taking monoamine oxidase inhibitors. Subjects receiving concomitant chemotherapy treatment. ·Pregnant or breastfeeding.

[0194] Subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study and were asked to read, understand, and sign an informed consent form, complete a medical questionnaire, undergo a complete physical examination, and provide a fasting blood sample for chemistry and hematology and a urine sample for urinalysis.

[0195] The study consisted of a cohort of 14 subjects 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 radiation treatment and for 14 days after the last radiation treatment.

[0196] Subjects were dispensed the cream on the Friday before the first week of radiation therapy and instructed to begin applying it the Sunday evening before their first radiation treatment. One day before starting the standard course of radiation therapy, all subjects were asked to begin applying the cream to a defined area where radiation would be administered, which included the entire breast for breast-conserving subjects and a defined area for mastectomy subjects.

[0197] Subjects were asked to apply the cream twice daily, once in the morning and once in the evening, and to continue this regimen daily during radiation treatment and for 14 days after the last radiation treatment. All subjects received medications blinded and coded according to a predetermined randomization code in a ratio of 2 active substances to 1 vehicle control, unknown to either the subject or the investigator / evaluator. All subjects were given a diary to record the time they applied the cream and to record any concomitant medications and adverse events. Photographs of the application sites were taken twice weekly on Tuesdays and Fridays before radiation treatment and on days 7 and 14 after radiation treatment.

[0198] After an initial one-day run-in period, all subjects attended the radiology department daily, five days a week, to receive their radiation dose. Just before each radiation treatment every Tuesday and Friday, the principal investigator (PI) or the PI's designated assistant assessed the skin at the radiation site using the revised Radiation Therapy Oncology Group (RTOG) scoring system and recorded a score. Subjects were questioned weekly about the radiation site and asked to report pain levels and any adverse or unusual events. Subjects were reminded to continue applying the cream during the two radiation-free days per week and to note any changes in the radiation treatment site in a diary. Upon completion of the radiation phase of the study, all subjects were asked 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 released from the study with a request to spontaneously report any subsequent changes in the radiation site.

[0199] Results: Dermatitis did not occur before day 26 except in a few subjects. Results showed P-values ​​favoring the treatment group throughout the treatment period and in the post-radiation period. Radiation-induced dermatitis, as recorded by RTOG scores, worsened during the 7-day post-radiation period in the placebo group, while mean scores stabilized in the treatment group. Table 3 shows the mean RTOG score data from day 26 onwards. [Table 6]

[0200] The distribution of RTOG scores within each group at different times was also evaluated. Dermatitis worsened faster 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 7]

[0201] Although the RTOG includes scores higher than 2, radiation therapy is designed to not exceed a score of 2. Data are presented as the percentage of patients in each group with a score of 2 or higher, although no patients actually had a score above 2.

[0202] The data in Table 5 (below) show the categorized 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, approaching statistical significance on day 33. The placebo group also showed poorer recovery. [Table 8]

[0203] The results of Table 5 are shown graphically in FIG.

[0204] Conclusion: The results of this study showed that treatment with RAD100 improved the course of dermatitis during both the radiation treatment and recovery phases, achieving several near-significant P-values. A larger number of subjects would necessarily improve the statistical data of this study, but current values ​​predict that a larger study would achieve high statistical significance. Overall, the delayed development of dermatitis and the faster rate of healing in the treatment groups support the data generated in mice in Examples 3 and 4. The mouse data, like the human data, show an improved rate of healing in the RAD100-treated group.

[0205] Example 7 - Treatment of tissue toxicity associated with head and neck radiation therapy Objective: To determine the effect of sertraline on the development of radiation-induced oral mucositis in mice by investigating the effect of sertraline oral solution on the development of radiation-induced oral mucositis in mice.

[0206] Experimental Procedure: Ten-week-old female C57BL / 6 mice were randomly assigned per cage to receive either 16 Gy intraoral irradiation plus placebo or 16 Gy intraoral irradiation plus 1% sertraline solution. Placebo or sertraline solution was applied to the oral cavity of the mice once daily for five consecutive days (two days before irradiation, 30 minutes to one hour before irradiation on the same day, and two days after irradiation). The development of radiation-induced severe oral mucositis was monitored for 21 days after irradiation.

[0207] Results: Results showed that in the placebo group, 16 Gy intraoral irradiation caused death from acute radiation toxicity of the oral mucosa in 66% of mice (4 of 6), whereas in the 1% sertraline group, only 33% of mice (2 of 6) died (Figure 4). These findings support the development of oral sertraline treatment as a novel approach to ameliorate radiation-induced severe oral mucositis.

[0208] The foregoing description is for illustrative purposes 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 specific embodiments, variations and modifications exist within the scope and spirit of the invention as set forth and defined in the following claims. The above disclosure and examples generally describe the invention and are provided for illustrative purposes, not to limit the scope of the invention.

[0209] The invention described herein may be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms. Terms and expressions are used as terms of description, not limitation, and there is no intention to use such terms and expressions to exclude any equivalents of the features shown and described, or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, while the invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be employed by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention as defined by the claims.

Claims

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

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

3. The method of claim 1 , wherein the CRI occurs as a result of medical radiation treatment for cancer.

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

5. 10. The method of claim 1, wherein the CRI is oral mucositis.

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

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

8. The method of claim 1 , wherein the composition is an oral solid formulation.

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

10. The method of claim 1 , wherein the composition is an oral liquid.

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

12. 2. The method of claim 1, wherein the FIASMA is selected from the group of selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenoceptor blockers (ARBs), and beta-blockers.

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

14. 14. The pharmaceutical composition of claim 13, wherein treating CRI includes preventing CRI, reducing the incidence or recurrence rate of CRI, inhibiting CRI, curing CRI, ameliorating or reducing the severity of CRI, or reversing CRI.

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

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

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

18. 14. The pharmaceutical composition of claim 13, wherein the FIASMA is selected from the group of selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), tricyclic antihistamines, antiarrhythmics, adrenoceptor blockers (ARBs), and beta-blockers.

19. 14. The composition of claim 13, which is an oral formulation containing 1 to 100 mg / ml of an SSRI.

20. 20. The composition of claim 19, wherein the oral formulation is a mucoadhesive tablet.

21. A solid dosage form in the form of a lozenge or troche containing an effective amount of loratadine for administration to a patient undergoing radiation therapy for head and neck cancer.

22. 27. The solid dosage form of claim 26, wherein the lozenge or troche is provided with a handle to form a lollipop.

23. 1. A method of preventing, treating, or reducing the incidence of oral mucositis or severe oral mucositis (SOM) in a patient undergoing radiation therapy for head and neck cancer, comprising: Providing a lozenge or troche containing loratadine according to claim 25; Optionally, administering the lozenge or troche to a patient; A method comprising:

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