JP2023544448A - Compositions and methods for the prevention and treatment of cutaneous radiation injury - Google Patents

Abstract

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

Description

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

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

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

Patients with head and neck cancer can suffer from oral mucositis, which is caused by damage to the epithelial cells lining the oral cavity, after radiation therapy to treat head and neck cancer. When ulcerative lesions form in the oral cavity due to radiation therapy, or when the patient is unable to swallow solid food, this condition is considered "severe oral mucositis," or "SOM." It will be done.

Radiation therapy administered to the pelvic area can cause damage to rectal tissue. The diverse range of lesions produced by radiotherapy targeting the pelvic region can affect the anorectal region and involve one or more of the following: inflammatory, ischemic, infectious, traumatic, or neoplastic pathologies. obtain. Symptoms of anorectal disease include anal or rectal pain, urgency to move the bowels, fecal incontinence, diarrhea, rectal bleeding, and difficulty in rectal emptying. These conditions have been referred to as "radiation proctitis," and more recently, and more accurately, "radiation proctopathy."

In view of the prevalence of these conditions in cancer patients undergoing radiation therapy, several strategies and treatments have been proposed for patients suffering from radiation dermatitis, without great success. Aloe vera and topical vitamin C were tried but did not improve the outcome of the irradiated breast tissue.

Other reports have shown that prophylactic and continued use of topical corticosteroids or dexpanthenol-containing emollients can reverse 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 to no effect on pigmentary changes.

Biafine and Lipiderm were shown to have no radioprotective effect, while a retrospective analysis showed a significant skin cell protective effect from the use of amifostine.

Misoprostol, a prostaglandin E(l) analog, has been found to be an effective radioprotective agent in animal studies, preventing oncogenic transformation in Syrian hamster embryos exposed to radiation in utero. did. However, no successful results were obtained in humans.

Attempts to prevent or treat radiation rectal injury or proctitis have also been largely unsuccessful. Many topical treatments used for anorectal or lower intestinal conditions appear ineffective. For example, the use of the anti-inflammatory drug 5-aminosalicylic acid (5-ASA), previously used to treat inflammatory bowel disease (IBD), with or without steroids such as hydrocortisone, may lead to radiation proctopathy or proctitis. Treatment was unsuccessful. Sucralfate was recommended for radiation rectal injury but proved ineffective.

Topical therapies such as nitroglycerin and calcium channel blockers have also not been found to be effective in treating radiation rectal damage. Short-chain fatty acid enemas have also been used to treat radiation rectal damage, but they are not readily available and difficult to administer.

Recently, antioxidants such as vitamin A, vitamin C, and vitamin E formulated in suppositories have been described for the treatment of radiation rectal injury or proctitis. Suppositories are solid dosage forms containing medicament that are placed in the anus or vagina for the treatment of certain systemic conditions, but can 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.

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

It has been proposed that damage to healthy tissue from radiotherapy may involve an endothelial response associated with signaling from the plasma membrane via the acid sphingomyelinase/ceramide pathway (Corre, I., et al. 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 within normal tissues. Corre, supra, at 22685. Although inhibitors of ASMase 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 or radiation rectal damage in particular.

Amitriptyline is formulated in suppository form. However, amitriptyline suppositories have only been prepared for systemic delivery and for the treatment of depression (a known indication for amitriptyline). Another indication for amitriptyline suppositories for systemic delivery is insomnia, taking advantage of the sleep-inducing side effects observed with amitriptyline. Amitriptyline suppositories have not previously been administered to patients who are undergoing or have undergone pelvic radiotherapy, or for the treatment of radiation rectal lesions or proctitis, or for any other in situ treatment in the lower intestinal tract. was unknown to.

Tricyclic antidepressants have generally not been previously known for the treatment of anorectal disorders such as radiation rectal disorders or proctitis. Dosage forms containing tricyclic antidepressants such as amitriptyline have also not been formulated for anal or rectal administration or for in situ (or non-systemic) treatment of radiation rectal lesions or proctitis. More specifically, amitriptyline has not previously been formulated into a dosage form, such as a suppository or other anorectal delivery device, for the topical treatment of radiation rectal injury or proctitis. Tricyclic antidepressants, such as amitriptyline, also have low drug release, such that drug release occurs primarily in the intestine, preferably in the lower intestine, for in situ delivery of the drug for the treatment of radiation rectal injury or proctitis. It was not formulated as a controlled release formulation to bypass release in a pH environment (acidic pH below 7), for example in the stomach.

Selective serotonin uptake inhibitors (SSRIs) are not known to be available in suppository form; SSRIs are also not previously known to have been used in the treatment of radiation proctopathy or proctitis. .

There are a number of anorectal diseases that may benefit from topical administration of TCAs such as amitriptyline, or SSRIs such as sertraline. These conditions include inflammatory bowel disease (IBD), including ulcerative proctitis and Crohn's disease, anal fissures, internal hemorrhoids, radiation rectal lesions, anal and rectal tumors, anal warts, anal dysplasia, and isolated rectal ulcer syndrome. , perianal pruritus, and anorectal ischemia. These conditions represent a diverse and substantial clinical problem with limited treatment options currently available.

The continued and increasing use of radiotherapy in the treatment of cancer, and the lack of available prophylactic or therapeutic medicines for CRI, including radiation dermatitis or radiation rectal injury, is a long-standing problem affecting millions of patients. is an unmet patient need.

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

The method according to the invention comprises the topical administration or application of a composition comprising at least one acid sphingomyelinase (ASMase) inhibitor to the skin surface of a patient suffering from CRI, including radiation dermatitis or radiation rectal injury. including. Functional inhibitors of acid sphingomyelinase, known in the art by the acronym FIASMA, include certain selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, Includes adrenergic receptor blockers (ARBs), beta-blockers, etc.

SSRIs useful in the methods of the invention include one or more of: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. A preferred SSRI is sertraline. According to a preferred embodiment, the dosage form of the invention comprises amitriptyline in a dose of 0.1 mg to 1000 mg; more preferably a dose of about 1 mg to 100 mg, most preferably a dose of about 5 mg to 50 mg. It is contemplated that a preferred dose is about 10-50 mg of the SSRI formulated in a 1-5% (w/w) composition. The dose may be varied, with a lower dose in the dosage form delivering the drug to the site more rapidly, or a higher dose in the dosage form releasing the drug more slowly.

Tricyclic antidepressants (TCAs) useful in the methods or compositions of the invention are: amineptine, amitriptyline, amoxapine, butryptyline, clomipramine, desipramine, dibenzepine, dosulepine, doxepin (in combination and not alone), imipramine, iprindol. , lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, opipramol, protriptyline, tianeptine, or trimipramine. A preferred TCA is amitriptyline. According to one preferred embodiment, the dosage form of the invention comprises amitriptyline in a dose of 0.1 to 1000 mg; more preferably a dose of about 1 mg to 100 mg, most preferably a dose of about 5 mg to 50 mg. A preferred dose is about 10-50 mg TCA formulated in a 1-5% (w/w) composition. The dose may be varied, with a lower dose in the dosage form delivering the drug to the site more rapidly, or a higher dose in the dosage form releasing the drug more slowly.

More specifically, the method of the invention:
- 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;
- locally administering or applying an effective amount of the composition to a patient in need thereof before radiotherapy, or after radiotherapy, or both;
including.

A method for preventing, reducing the incidence or recurrence rate, inhibiting, treating, ameliorating or reducing the severity of, or reversing radiation rectal injury, the method comprising:
- administering a pharmaceutically effective amount of one or more active ingredients to a patient in need thereof, such as a patient undergoing radiotherapy to the pelvic region or suffering from radiation rectal damage or proctitis; or rectally administering a dosage form comprising the method, wherein at least one active ingredient is FIASMA.

A method of preventing, reducing the incidence or recurrence rate, inhibiting, treating, ameliorating or reducing the severity of, or reversing oral mucositis or severe oral mucositis, the method comprising:
- providing a sublingual controlled release dosage form comprising FIASMA as an active ingredient;
- administering to a patient in need thereof, such as a patient undergoing radiotherapy for head and neck cancer, a controlled release sublingual dosage form containing a pharmaceutically effective amount of one or more active ingredients, comprising: , at least one active ingredient is FIASMA;
can include.

Controlled release dosage forms for sublingual administration are known in the art and can delay the dissolution of the dosage form, thereby prolonging the release of the drug over a period of time and reducing the presence of the active drug in the oral cavity. or increase residence time. Such controlled release dosage forms can be tablets, capsules, lozenges, pastilles, troches, thin film strips, and the like, as recognized by those skilled in the pharmaceutical arts.

It will be appreciated that applying or administering the composition prior to radiation therapy may include keeping the composition in place during the radiation therapy session. The method can be repeated for each radiotherapy session, administering or administering the composition at least once/week, several times/week, daily, or multiple times per day before, after, or between radiotherapy sessions. may include applying.

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

In patients with radiation rectal damage who are undergoing radiation therapy in the pelvic region, a preferred method is to provide a solid suppository or rectal plug dosage form containing a composition comprising FIASMA and to apply the dosage form to the active site. and placement within the rectal cavity for a period of time necessary to deliver the component.

The subject invention also provides methods 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 rectal injury. The present invention relates to topical pharmaceutical compositions comprising as an active drug or substance at least one functional inhibitor of acid sphingomyelinase (FIASMA) useful for.

The invention may also include suppository forms for use in preventing, reducing the incidence or recurrence of, treating, ameliorating or reducing the severity of, or reversing radiation rectal damage. Suppository forms can include a soluble carrier and a TCA, such as amitriptyline, an SSRI, such as sertraline, or a combination of one or more TCAs or SSRIs, as well as other agents conventionally used in suppository forms. Pharmaceutically acceptable excipients may be included.

In methods that use suppositories or rectal plug delivery devices for delivery of FIASMA to the anorectal cavity and in situ administration of the drug, the dosage form is provided with or incorporated into the rectal plug delivery device as a controlled release formulation. one or more excipients capable of retarding the release of the active drug incorporated into the dosage form or coated on the external surface of the dosage form, or particles, granules or beads in the dosage form containing the active ingredient; . Controlled release dosage forms may also be provided for oral administration, where the oral dosage form is a delayed release agent that bypasses the acidic environment of the stomach and releases the active ingredient in the intestinal tract where the pH is above 7.0. It is formulated as a form. Such controlled release dosage forms may be formulated with enteric coatings on tablets, provided in delayed release capsules or caplets, formulated in delayed release matrix compositions, or combinations of the above. .

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

An alternative embodiment of a rectal plug delivery device useful in carrying out the methods of the invention is a porous compressible plug injected with or coated with a composition comprising a TCA, e.g., amitriptyline, an SSRI, e.g., sertraline, or a combination thereof. Contains foam material. Devices described for the methods of the invention can include an effective dose of FIASMA or FIASMA combinations from about 0.1 mg to about 1000 mg or more.

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

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

Topical dosage forms can include conventional and commercially available pharmaceutical base compositions that are pharmaceutically compatible with one or more FIASMAs used as one or more active ingredients, and further include topical or oral dosage forms. Other pharmaceutically acceptable excipients conventionally used therein may be included. These commercially available pharmaceutical bases can function as vehicles or vehicles for the active drug substance and include emollients, penetration enhancers, solvents, gelling agents, thickeners or viscosity enhancers, preservatives, or one or more other suitable excipients commonly used in topical formulations.

Preferably, the FIASMA is provided in an immediate release topical formulation that allows targeted administration and immediate delivery of drug from the composition to the skin after application or administration of the composition. It may be preferable for the FIASMA component to be retained at the site of administration or application. Accordingly, the compositions of the present invention can exclude penetration enhancers in order to maintain the composition and active on the surface of the skin for a longer period of time than compositions containing penetration enhancers, which Enables or facilitates the penetration of active substances into or under the skin where they can be absorbed systemically. Alternatively, in certain cases, penetration enhancers may be preferred and used in the composition.

Oral dosage forms of the compositions may be immediate release or may be formulated with excipients such as polymers, gels, gums, waxes, etc., or incorporated into matrices, or after oral administration. may include coatings for slow, delayed, sustained, or extended release of the active ingredient from the composition. For example, solid dosage forms for sublingual administration of FIASMA in the treatment of oral mucositis may be formulated to dissolve in the oral cavity, controlling, delaying, sustaining or prolonging the release of the drug from the dosage form. It may also contain excipients.

According to a further aspect of the invention, the dosage form may include a second active substance, such as a TCA or SSRI component, or a second active substance that is not a TCA or SSRI, e.g. an active ingredient of a different drug class. can be included. In a preferred embodiment, the composition comprises a first active ingredient that is a TCA and a second active ingredient that is a different TCA or is an SSRI or is another class of compound that is not a TCA. For example, the second active ingredient can be an antioxidant, such as vitamin A, vitamin C, vitamin D, or vitamin E. Preferably, the second active agent in the composition is neither an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), nor an anesthetic, such as a local anesthetic, such as lidocaine.

In another preferred embodiment, the composition of the invention comprises a first active ingredient that is an SSRI and a second active ingredient that is a different SSRI or is a TCA or is another class of compound that is not an SSRI. including. For example, the second active ingredient can be an antioxidant, such as vitamin A, vitamin C, vitamin D, or vitamin E. Preferably, the second active in the composition is neither an anti-inflammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), nor an anesthetic, such as a local anesthetic, such as lidocaine.

Preferably, the method is carried out using FIASMA formulated in a topical composition capable of delivering an effective dose to a target area of skin exposed directly or concomitantly to radiation during radiotherapy or treatment. be exposed. For example, the active ingredient can be formulated as a liquid composition and administered as droplets to the target area of the skin. Alternatively, FIASMA may be formulated in a composition containing a thickening agent or viscosity enhancer as a lotion, cream, ointment or gel for topical delivery of FIASMA to targeted skin areas of a patient. Topical formulations may be rubbed onto or into the target area of the skin before or after radiation therapy.

In methods using solid oral dosage forms, the active ingredient is provided as particles, granules or beads, which can be manufactured in the form of tablets, capsules, caplets, etc., as is readily understood in the art. Oral dosage forms can be provided, for example, as controlled release dosage forms, in which the active ingredient is formulated into delayed release dosage forms, such as enteric-coated tablets, delayed release capsules or caplets, or in a delayed release matrix composition. It can be formulated into products. Combinations of these controlled release dosage forms can also be used.

Therefore, according to the present invention, a method for preventing, reducing the incidence or recurrence rate, inhibiting, treating, reversing or reducing the severity of cutaneous radiation injury (CRI) is disclosed. An effective amount, e.g., about 0.5% to about 5% w/w of FIASMA, e.g., TCA (e.g., amitriptyline) or an SSRI (eg, sertraline), topically administering 0.5 to 50 ml or more depending on the size of the area to be treated.

The method for preventing, treating, or ameliorating radiation dermatitis also includes applying to a target area of the skin of a patient in need thereof at least once per day before, during, and after radiation therapy, e.g. A composition comprising 0.5% to about 5% w/w of FIASMA, such as a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline), in 0.5 to 50 ml or more depending on the size of the range to be treated; Including topical administration.

The method also includes administering an effective amount, e.g., about 0.5% to about 5% w/w, of FIASMA to the target area of a patient in need thereof at least once per day before, during, and after radiation therapy. , for example, by topical administration or delivery of a composition containing a TCA (e.g., amitriptyline) or an SSRI (e.g., sertraline) in 0.5 to 50 ml or more, depending on the size of the area to be treated, to prevent radiation rectal damage. including treating, treating, or rehabilitating.

The topical composition used in the method can contain 5 to 50 mg of amitriptyline per ml of composition, or 5 to 50 mg of sertraline per ml of composition, or 10 to 40 mg of sertraline per ml of composition. of amitriptyline, and 10 to 40 mg of sertraline per ml of the composition.

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

Preferably, the compositions used in the methods of the invention are formulated as topical dosage forms that deliver an effective dose of the active ingredient in situ to the target area of the patient. It uses compositions formulated with pharmaceutically acceptable carriers to form lotions, creams, ointments, or gels for topical delivery of active ingredients to targeted areas of a patient's skin. may be performed.

Alternatively, the composition comprises amitriptyline and a second tricyclic antidepressant that is not amitriptyline, such as amineptine, amitriptyline, amoxapine, butryptyline, clomipramine, desipramine, dibenzepine, dosulepine, doxepin (in combination rather than alone), imipramine, ip Can include lindole, lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, opipramol, protriptyline, tianeptine, or trimipramine.

Compositions comprising sertraline can include a second selective serotonin uptake inhibitor that is not sertraline, such as citalopram, escitalopram, fluoxetine, fluvoxamine, or paroxetine.

Pharmaceutical compositions of the invention are provided as topical pharmaceutical compositions containing an effective amount of one or more active ingredients, such as amitriptyline, sertraline, or combinations thereof, for delivery of one or more active ingredients to a patient. or may be in oral dosage form. In preferred embodiments, the topical compositions of the invention are free of, free from, or exclude anti-inflammatory agents and anesthetic agents.

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

Oral dosage forms of the invention can be formulated as controlled release oral dosage forms.

The methods and compositions and dosage forms of the invention are useful for preventing, treating, or ameliorating other skin conditions such as atopic dermatitis, burns, sunburn, dermatomyofibroma, and exposure-induced wrinkles. It will be appreciated that this may be useful.

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

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. The use of novel compositions or dosage forms can be employed to provide and carry out methods of treatment.

Hereinafter, the terms "treat," "treating," or "treatment of" in relation to cutaneous radiation injury, or "CRI," or a specific condition considered a type of CRI, will be used to mean "preventing" CRI. ”, “reducing the incidence”, “reducing the recurrence rate”, “inhibiting”, “reversing”, “reducing the severity”, “reversing” or can mean or refer to, or be substituted with, any one of "treating"; Specific terms include ``preventing'', ``reducing the incidence'', ``reducing the recurrence rate'', ``inhibiting'', ``reversing'', and ``reducing the severity of CRI. "that" or "reversing" are used when the term is intended to designate only that treatment, or these terms are expressly removed from "treatment" when the term is not intended to mean that treatment. may be excluded. For example, a method to "reduce the incidence" of CRI can only mean reducing the incidence of CRI, not "inhibiting" CRI. Alternatively, "a method for treating CRI other than reducing the incidence of CRI" includes methods for preventing, reducing the incidence of, inhibiting, ameliorating, or reducing the severity of CRI. can refer to a method for reducing or reversing the degree of

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

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

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

"Oral mucositis" refers to a condition resulting from radiation therapy used to treat head and neck cancer; a more severe condition, aptly referred to as "severe oral mucositis" or "SOM", is often , associated with ulcerated tissue in the oral cavity, or when the patient is unable to swallow food or drink. Oral mucositis is a common and debilitating complication of cancer treatment, especially radiation. This can lead to several problems including pain, nutritional problems as a result of not being able to eat, and increased risk of infection due to open wounds in the mucous membranes.

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

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

Examples of useful TCAs according to the subject invention are amineptine, amitriptyline, amoxapine, butryptyline, clomipramine, desipramine, dibenzepine, dosulepine, doxepin (in combination and not alone), imipramine, iprindol, lofepramine, maprotiline, norclomipramine, northiaden, These are nortriptyline, opipramol, protriptyline, tianeptine, and trimipramine. Preferred TCAs useful according to the subject invention are amitriptyline, desipramine, and imipramine.

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

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

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

Amitriptyline and sertraline were not previously known to be useful in preventing or treating radiation dermatitis.

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

Topical compositions or formulations as dosage forms are well known in the art and conventionally used in medical therapy. Preferred embodiments according to the subject invention incorporate FIASMA into a pharmaceutically compatible base composition to form topical lotions, creams, gels, or ointments that include at least one FIASMA as an active pharmaceutical ingredient (API) or drug. It is to create. Another embodiment of the invention incorporates a combination of at least two different FIASMAs as active agents, such as at least one TCA and at least one SSRI, into a pharmaceutically compatible base composition to create a topical lotion. Including making creams, gels, or ointments. Preferred embodiments include thoroughly mixing one or more active ingredients into a pharmaceutically acceptable matrix to provide a homogeneous mixture. In the case of incompletely dissolved active ingredients in the substrate, a suspension can form, which is a mixture of the active ingredients thoroughly mixed so that the active substances are evenly distributed throughout the substrate. including. Compositions of the invention may include other pharmaceutically acceptable excipients conventionally used in topical dosage forms.

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

In one embodiment, the oral dosage form for sublingual administration of the invention comprises a pharmaceutical composition in unit dosage form (e.g., lozenge, pill, tablet, film, or strip) comprising at least one FIASMA; In a preferred embodiment, it is prepared as a controlled release formulation. Ease of manufacture and cost as well as consumer preference will be considered with regard to the size of the unit dosage form, eg, lozenge. The size of sublingual dosage forms can vary from about 5 mm to 20 mm, or about 5 mm to 18 mm, or about 7 mm to 18 mm, or about 10 mm to 15 mm. If the sublingual dosage form is circular or nearly circular, the size range is the appropriate diameter value. In most cases, the thickness of the lozenge will be between 1 mm and 10 mm, more commonly between 3 mm and 5 mm.

Sublingual dosage forms may be in monolayer or bilayer form. Sublingual dosage forms with soluble mucoadhesive properties can be made by pressing powders containing mucoadhesive hydrocolloids. As an example, adhesive pastils may be made by mixing dry powders containing gum arabic for adhesive properties and at least one FIASMA as the active ingredient. The residence time of a sublingual dosage form in the oral cavity can be optimized according to the dissolution rate and total dissolution time of the product. For example, a sublingual controlled release lozenge or film can be prepared to have a residence time in the oral cavity of at least 1 minute, preferably 1 to 30 minutes, more preferably 5 to 15 minutes after administration.

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

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

The compositions of the invention may include conventional additives or other excipients such as plasticizers, pigments, colorants, stabilizers, glidants, and the like.

The present invention provides methods of 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 active ingredient and administering the drug to a patient in need thereof directly to the skin as a topical composition, such as a cream or lotion or ointment; formulating and delivering the oral dosage form.

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

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

The dosage contained in a dosage form may vary, with a lower dosage in the dosage form delivering the drug to the site more rapidly, or a higher dosage in the dosage form releasing the drug more slowly. Variations in dosage may also depend on the active ingredient contained in the composition. For example, a composition comprising more than one FIASMA may contain less than 1% of each active agent, such as 0.1% to 0.9%, preferably about 0.5% of each active agent; The final composition thus contains less than 1% to 2% total active ingredients in the composition. This may advantageously reduce the dose of each active ingredient administered to the patient while providing an equivalent or substantially equivalent prophylactic or therapeutic effect. It is also contemplated that fixed-dose combination products containing at least one TCA and at least one SSRI may provide synergistic effects, where efficacy is defined as the expected additive effect when each active ingredient is used alone. Greater than action.

In one embodiment, the FIASMA is provided in an oral dosage form as a controlled release formulation, as compared to an immediate release formulation that provides delivery of all of the drug from the dosage form upon administration. Allows delivery of drugs over a period of time. Controlled release formulations known in the art include coatings, such as enteric-coated tablets, beads, or pellets, ion exchange resins, waxes, alginates, gelling agents, such as cellulose hydrogels (e.g., Hydroxypropyl methylcellulose (HPMC) or polymeric acrylamides (eg Carbopol®) and a suitable vehicle.

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

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

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 FIASMA, or a combination of more than one FIASMA. In one embodiment of a rectal plug device according to the invention, the plug device includes an insoluble porous housing forming a chamber for containing the active ingredient. The active ingredient may be provided as a soluble suppository placed within a chamber portion formed within the porous rectal plug housing. Suppositories are exposed to body fluids when administered to dissolve the active ingredient from the suppository and deliver it in situ. In preferred embodiments, suppositories are formulated as controlled release formulations. Alternatively, the active ingredient may be formulated as a viscous controlled release gel, ointment, or cream that fills a chamber within the rectal plug housing.

Other types of rectal plugs are known and may be adapted for use with the subject invention. For example, rectal plugs formed from porous sponge-like polymeric materials, such as polyurethane 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 injected with a solution containing an effective amount of FIASMA and can be adsorbed onto the material for delivery upon insertion into the rectal cavity. These commercially available rectal plugs generally come in a compressed configuration for ease of insertion and are wrapped in a water-soluble film that dissolves after insertion and can be expanded to an enlarged configuration. Such compression and expansion are not necessary for in situ delivery of drugs according to the subject invention.

1 and 2 illustrate an example of a rectal plug delivery device for use with the present invention. FIG. 1 shows a rectal plug delivery device 100 that includes an elongate member 101 forming the proximal end of the device that is inserted into the rectal cavity and resides there during delivery of the active ingredient. The rectal plug delivery device includes a distal flange 102 to prevent the entire rectal plug delivery device from being incorporated into the rectal cavity, thereby allowing the rectal plug device to remain in place during administration of the active ingredient. The active ingredient, such as TCA or SSRI, may be provided as a pharmaceutical composition contained in a cavity (not shown) formed within the elongate member. The proximal end of the elongate member 101 has a pore 103 for allowing the entry of body fluids into a cavity formed within the elongate member and for allowing the exit of the active ingredient from the composition contained within the elongate member. include. The rectal plug delivery device can have an extension component, such as a strap or string, connected to the distal flange that facilitates removal of the rectal plug delivery device, functioning similarly to tampon removal.

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

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

FIG. 3 shows a rectal plug delivery device 200 comprising a soft compressible porous material in an expanded configuration. Rectal plug delivery device 200 includes a drug delivery component 201 at its proximal end that expands and conforms to the shape of the rectal cavity when inserted into the rectal cavity. An extension component 202, such as a strap or string, is connected to the drug delivery component to facilitate removal of the rectal plug delivery device, functioning similarly to removal of a tampon.

Compositions containing active ingredients according to the invention may be injected or infiltrated into the porous material forming delivery component 201 as a liquid or gel, cream, or ointment. Compositions containing the active ingredient may be provided as controlled release compositions, preferably extended release compositions that release the active ingredient over time.

FIG. 4 shows the rectal plug delivery device 200 of FIG. 3 in which the drug delivery component 201 is provided in a compressed form to facilitate insertion into the rectal cavity. Compressed drug delivery component 201 can include a water-soluble wrapper surrounding drug delivery component 201. After inserting rectal plug delivery device embodiment 200 into the rectal cavity, bodily fluids dissolve the wrapper and allow drug delivery component 201 to expand to its expanded configuration shown in FIG. 3. FIG. 4 further shows an extension component 202, which may be a strap or string, to facilitate removal of the rectal plug delivery device.

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

In a method according to the invention, treating CRI, such as radiation dermatitis, comprises using a composition comprising at least one FIASMA, e.g. a TCA, e.g. amitriptyline, and/or at least one second FIASMA, e.g. an SSRI, e.g. sertraline. use. Compositions used in the methods of the invention can be provided in topical dosage forms. Additionally, the subject invention uses an oral dosage form comprising at least one TCA, such as amitriptyline, and/or at least one SSRI, such as sertraline, to treat or ameliorate skin disorders or conditions, such as radiation dermatitis. , or methods for prevention.

Preferably, the method includes providing a topical dosage form comprising a composition having at least one FIASMA as an active ingredient in the composition and applying an effective amount of the composition to the target area of the skin to be treated. and disposing the component for a period of time necessary to deliver the component to the site. In one preferred embodiment, the active ingredient can be formulated as a viscous, controlled release gel, ointment, or cream for administration to the skin. The topical compositions of the present invention preferably contain from about 0.1% concentration (1 mg per ml of composition) to about 5% concentration (50 mg per ml of composition) of each active ingredient provided; for example, 0.1% to about 5% concentration (50 mg per ml of composition); 1%. 0.2%, 0.3%, 0.4%, . 0.1% increments such as 0.05%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% and 1.1%, 1.2%, 1.3%, etc. Contains up to about 5.0%. Typical doses are from about 0.5 ml to about 2 ml, preferably about 1 ml, but are not limited as such and are only limited by the area of skin that requires treatment, thus applying doses of 5 ml or more. be able to.

According to one embodiment of the invention, the method of the invention:
Patients who are suffering from CRI after exposure to environmental radiation or who are receiving or are undergoing medical radiation therapy and are in need thereof, such as those suffering from radiation dermatitis or radiation rectal damage. The method comprises topically administering an effective dose of one or more active ingredients, namely a drug, to the skin of the skin.

In a method of preventing, reducing the incidence or recurrence rate, inhibiting, treating, ameliorating or reducing the severity of, or reversing oral mucositis or severe oral mucositis, the method comprises:
- providing a sublingual controlled release dosage form comprising FIASMA as an active ingredient;
- administering a controlled release sublingual dosage form containing a pharmaceutically effective amount of one or more active ingredients to a patient in need thereof, such as a patient undergoing radiotherapy for head and neck cancer. is possible,
At least one active ingredient is FIASMA.

In the method of treating radiation rectal damage, the method of the present invention comprises:
An effective dose of one or more FIASMA drugs, preferably a class of drugs selected from TCAs, SSRIs, or combinations thereof, as an active ingredient for patients in need thereof, such as radiation rectal disorders resulting from medical radiotherapy. or anorectal administration into the rectal cavity or rectal tissue of a patient suffering from proctitis.

A preferred method of treating radiation rectal injury involves anorectal administration of an effective dose of FIASMA, such as TCA, amitriptyline or the SSRI, sertraline, as the active ingredient. Compositions containing fixed dose combinations of two or more different FIASMAs, or one or more FIASMAs and an active ingredient that is not a FIASMA, can also be used. In one preferred example, the method is performed using amitriptyline formulated as a composition and provided in a dosage form capable of delivering an effective dose in situ to the rectal cavity of the patient. For example, amitriptyline may be formulated as a liquid and administered as an enema, or formulated with thickeners or viscosity enhancers as a lotion for topical delivery of amitriptyline to the anorectal area and rectal cavity of a patient. , creams, ointments or gels may be provided.

Alternatively, the method can use semi-solid or solid dosage forms, such as suppositories or rectal plug delivery devices, to deliver the active pharmaceutical ingredient to the anorectal cavity and for in situ administration of the drug. Preferably, the dosage form provided with or incorporated into the rectal plug delivery device is capable of slowing or delaying the release of the active drug incorporated into or coated on the outer surface of the dosage form. It is a controlled release formulation with excipients that can be used.

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

Alternative embodiments of rectal plug delivery devices useful in carrying out the methods of the present invention include porous compressible foam materials infused or coated with compositions containing active pharmaceutical ingredients according to the subject invention. The devices described in the methods of the invention can include an effective dose of FIASMA provided in an amount from about 0.1 mg to about 1000 mg or more.

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

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

The subject invention includes a composition for treating radiation rectal injury comprising providing an effective amount of FIASMA formulated as a controlled release formulation for in situ delivery of an active ingredient to the rectal cavity. In one 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 active ingredients. The composition can include additional drugs that are not FIASMA as described herein.

The active pharmaceutical ingredient contained in the suppository or rectal delivery device can be administered before, during, or after pelvic radiotherapy. Preferred administration involves inserting the suppository or rectal delivery device into the rectal cavity and allowing the suppository or rectal delivery device to remain within the rectal cavity until delivery of the entire dose is completed. Preferred suppositories according to the invention dissolve slowly and can remain for periods of up to about 24 hours, ie, can be used daily. The rectal plug delivery device can remain within the rectal cavity for a period of up to about 48 hours, but preferably includes a drug formulation that delivers a dose of active ingredient within about 24 hours. It provides for daily use after defecation. Alternatively, the rectal plug may be temporarily removed for defecation and reinserted.

The suppository containing the active pharmaceutical ingredient is placed so that it remains in the rectal cavity for the period necessary for dissolution. Since suppositories are completely soluble, release of the active ingredient from the suppository is achieved after retention of the suppository in the rectum. The released active ingredient occurs in high concentrations at the site of delivery, thereby enhancing the effectiveness of this treatment for anorectal disorders.

According to an alternative embodiment, the suppository 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, lingonberry, etc. . These may be used as separate suppository formulations or as additional components of the suppositories of the invention.

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

Any form of active ingredient contemplated by this invention that is placed in suppository form for the treatment of anorectal disorders is within the scope of this invention. Additionally, the incorporation of the active pharmaceutical ingredients described herein in combination with other active or inactive ingredients into suppositories for treating anorectal diseases is embodied within the scope of this invention. Additionally, the incorporation of any FIASMA into suppositories as a means of treating anorectal disorders is embodied within the scope of this invention. Finally, other agents can be included in the suppository to enhance the effectiveness of the active ingredient, such as anti-inflammatory drugs, anesthetics, herbs, or other vitamins. The materials used to make suppositories include any fatty (or oily) and/or water-soluble (or miscible) bases.

In particularly preferred embodiments, the medicament contained in the suppository is amitriptyline. In preferred embodiments, suppositories are comprised of fatty (or oily) bases and/or water-soluble (or miscible) bases. However, other substrates can be used in the present invention to allow passage of the medicament into the rectum. More generally, any form of suppository substrate can be used to construct the device. Additionally, various TCAs can be incorporated into suppositories to allow these materials to be applied directly to the rectum and anus. Other previously mentioned substances can also be included in suppositories to enhance their effectiveness in treating anorectal disorders. The contents of the suppository can also consist of various TCAs, alone or in combination with amitriptyline, depending on the therapeutic goal.

Various doses of amitriptyline can be used depending on the condition being treated. For example, the rectal dose of amitriptyline used to treat radiation rectal damage is 25-100 mg per day. Both lower and higher doses will be used initially in device construction. Optimal dosages for treating these conditions will be determined based on clinical trials.

However, after clinical evaluation of this treatment, higher or lower doses of amitriptyline may ultimately be used to treat radiation rectal disorders and other anorectal disorders. Dosages of amitriptyline and other TCAs in suppositories are expected to be lower than oral doses for the treatment of anorectal disease because these agents are applied directly to the affected area. However, because delivery by suppository or rectal device does not need to be ingested and the dosage form can be larger in size, oral dosage forms may be used if determined to be safe and effective based on further clinical experience or testing. Higher doses than typically used in

Preferably, the method for treating CRI is carried out using a FIASMA, e.g., a TCA, such as amitriptyline, or an SSRI, e.g., sertraline, wherein the TCA or SSRI, or both, are prepared as a composition and administered to the patient in an effective dose. The drug is provided in a dosage form that can be delivered in situ to the skin of the patient. For example, amitriptyline can be formulated as a liquid and administered in liquid form to areas of skin, or it can be formulated with thickeners or viscosity enhancers to treat patients in need of it, such as radiation therapy. A lotion, cream, ointment or gel can be provided for topical delivery of amitriptyline to targeted areas of the skin of a patient suffering from or suffering from radiation dermatitis.

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

The methods of the invention can further include administering at least one FIASMA and an additional non-FIASMA active ingredient to a patient in need thereof. Preferably, the additional active substance is formulated together with at least one FIASMA in a fixed-dose combination formulation for topical administration to the skin.

A preferred embodiment of the composition of the invention having first and second active ingredients comprises an SSRI as the first active ingredient and a TCA or an antioxidant as the second active ingredient. Antioxidants can be, for example, vitamin A, vitamin C, vitamin D, and vitamin E. Further embodiments of compositions of the invention may include a TCA, an SSRI, and an antioxidant. Examples of active ingredients are amitriptyline as a TCA, sertraline as an SSRI, and vitamin D as an antioxidant.

Depending on the condition being treated, various doses of one or more of the active ingredients described herein can be used. For example, topical doses of amitriptyline used to prevent or treat radiation dermatitis are 1 mg to 100 mg per day.

Optimal dosages and therapeutic ranges for preventing or treating these conditions will be determined based on clinical trials. However, after appropriate clinical evaluation of this treatment, higher or lower doses of amitriptyline or sertraline may ultimately be used for the prevention or treatment of radiation dermatitis and other skin inflammatory disorders.

Example 1 - Use of a composition comprising a TCA A composition is provided to a patient undergoing or scheduled to undergo radiation therapy for the treatment of a 25 mm breast tumor, the composition comprising a pharmaceutically acceptable base. It is an ointment containing 1% to 2% amitriptyline. Areas of skin on the tumor that are or will be exposed to radiation during radiotherapy treatment may be identified and marked.

A health care professional or patient administers the composition by applying about 1 ml of the composition at least once per day to areas of skin expected to be exposed to or affected by radiation. Administration of the composition is repeated at least once a day, or up to five times a day, for at least one week during the radiation treatment regimen. For example, a patient receiving a radiation therapy regimen five times a week (Monday through Friday) may apply the cream daily to the treated area 90 minutes before radiation therapy, then at bedtime for 7 days. Twice a day, Monday through Friday, before and after radiation treatment, then on weekends when the patient is not receiving radiation. Repeat this for 5 or 6 weeks.

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

Example 2 - Determination of the Efficacy of a Single Active Agent vs. Multiple Active Agents Five patient groups undergoing or scheduled to undergo radiotherapy for the treatment of 25 mm breast tumors were:
■ 1% amitriptyline in a pharmaceutically acceptable matrix;
■ 1% sertraline in a pharmaceutically acceptable matrix;
■ 1% amitriptyline and 1% sertraline in a pharmaceutically acceptable matrix;
■ 0.5% amitriptyline and 0.5% sertraline in a pharmaceutically acceptable carrier; and ■ Pharmaceutically acceptable carrier alone (placebo).
A composition is provided that is an ointment comprising any of the following.

Areas of skin on the tumor that are or will be exposed to radiation during radiotherapy treatment may be identified and marked. The health care worker or patient administers the composition by applying about 1 ml of the composition at least once per day to areas of skin expected to be exposed to or affected by radiation prior to radiation therapy. do. Administration of the composition is repeated at least once a day, or up to five times a day, for one week after radiation therapy.

Expected Results: The effectiveness of each composition containing the active ingredient will be determined by scoring the level of radiation dermatitis present in each group of patients. Determination of whether the effectiveness of the use of a combination of amitriptyline and sertraline is additive or synergistic is that the radiation dermatitis score of the composition containing 1% amitriptyline and 1% sertraline is higher than that of the 1% amitriptyline composition alone, and It can be determined by comparing whether the effect is lower than, equal to, or higher than that of the 1% sertraline composition alone. Radiation dermatitis scores of fixed dose combination compositions containing 0.5% amitriptyline and 0.5% sertraline in a pharmaceutically acceptable matrix compared to higher doses of each active alone in the composition can provide information regarding the effectiveness of lower doses of each active substance combination.

Example 3 - Treatment of Radiation Dermatitis in Irradiated Mice Objective: Determination of the efficacy of topical reformulation of sertraline as a protective agent for radiation-induced skin injury.

Materials and Methods: Radiation-induced dermatitis experiments were performed in 10 week old female C57BL/6J mice (The Jackson Laboratory). An approximately 3x3 cm area on the dorsal skin of the mice was shaved before drug treatment. Mice were randomly assigned to receive topical treatment with 4% sertraline or vehicle (n=5 mice per cohort), and all investigators were blinded to topical treatment.

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

4% Sertraline Cream - 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 4% (w/w) sertraline (as the hydrochloride salt) in an oil-in-water vanishing cream base containing phenoxyethanol.

Placebo Cream - In water containing purified water, isopropyl palmitate, caprylic/capric triglycerides, propylene glycol, ceteareth 20, cetearyl alcohol, glyceryl stearate, PEG 100 stearate, dimethicone, octyldodecanol, lecithin, ethylhexylglycerin, and phenoxyethanol. Oil vanishing cream base.

Both products were packaged in white polypropylene bottles with white polypropylene closures with polyvinyl chloride disc liners, labeled for external use only, stored at controlled room temperature (20°C to 25°C), and protected from freezing. instructed.

The formulation is further described in the composition table below:

A 4% sertraline composition is prepared as a free substrate as shown in the composition table. The amount of sertraline HCl added to the formulation is adjusted to compensate for the HCl salt.

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

Mice received topical treatment once daily for 12 days starting 2 days before irradiation. Image-guided small animal irradiation An X-Rad 225 Cx was used to induce dermatitis by delivering a single dose of 30 Gy of X-rays to a 1 x 1 cm area of shaved skin.

The development of radiation-induced dermatitis was examined before irradiation and weekly for 4 weeks after irradiation by one observer blinded to treatment group. Skin response to radiation was evaluated according to a semi-quantitative scoring system previously established for preclinical studies - scoring from 1.0 to 5 based on erythema, desquamation (dry and moist), necrosis and dermal loss. .5 (0.5 increments) (Table 1).

Results: During the first two weeks after 30 Gy irradiation, all mice treated with 4% sertraline cream had a skin injury score of 4.5, whereas mice treated with vehicle had a milder score of 3.5. 0 to 3.5 (Figure 1, panels A and B). Scratching behavior and sequelae were observed in the 4% sertraline cohort.

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

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

Discussion: Our preliminary results show that skin injury in mice receiving 4% sertraline substantially improved after 4 weeks of 30 Gy, while skin injury in vehicle-treated mice remained severe. Show that. Although the cause of the higher injury scores in mice treated with 4% sertraline during the first two weeks after irradiation is under investigation, a literature search reveals that topical sertraline has not been shown to be effective in mice in previously established animal studies. (Neuron 87, 124-138, July 1, 2015) was confirmed to induce significant itch-induced scratching in mice. Removing the cream after 30 minutes and repeating this experiment substantially reduced scratching behavior and initial skin injury scores, but still showed similar benefits after 2 weeks, as data shown above. Therefore, the early toxicity observed at week 1 is likely related to self-injury due to sertraline-induced scratching.

Conclusion: The results surprisingly suggest that 4% FIASMA compositions, such as 4% sertraline topical compositions, are effective against radiation-induced skin injury.

Example 4 - Comparison before and after radiation therapy The experiment set forth in Example 3 was repeated in mice to compare 4% sertraline administered before and after radiation therapy. 4% amitriptyline was also tested.

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

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

The incidence of radiation-induced dermatitis was examined weekly for 6 weeks after irradiation by two observers (S.H. and S.S.) blinded to the treatment cohort. Skin response to radiation was evaluated according to a semi-quantitative scoring system previously established for preclinical studies - scoring from 1.0 to 5 based on erythema, desquamation (dry and moist), necrosis and dermal loss. .5 (0.5 increments).

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

result. Four weeks after radiation treatment, 9 out of 10 sertraline-treated mice showed lower scores (better improvement) than mice treated with vehicle alone. In general, 4% sertraline cream performed better when administered after radiation therapy compared to before radiation therapy; however, it did show some protective effects before radiation therapy. 4% sertraline cream administered 24 and 48 hours after radiation therapy also showed earlier responses, lower scores within one week of radiation therapy, and improved scores by the fourth week after radiation therapy. continued to show.

These results are shown graphically in FIG. 6, panels AD. Overall, mice that received two doses of 4% sertraline after irradiation showed accelerated recovery from acute radiation dermatitis starting 1 week after irradiation (FIGS. 6, A and 2). Post-treatment skin injury scores in the 2x group were significantly lower than in the placebo group from 3 to 6 weeks after 30 Gy (Figure 6, Panel B). On the other hand, the skin injury score of the pre-treatment 3x group was significantly lower than the placebo group only 5 weeks after 30 Gy (Figure 6, Panel C). Of note, mice that received three doses of 4% sertraline before irradiation showed significantly slower recovery from acute radiation dermatitis compared to mice that received two doses of 4% sertraline after irradiation ( Figure 6, panel D).

In particular, administration of 4% amitriptyline cream and 4% fluoxetine cream had deleterious effects on the mice and this experimental arm was discontinued. This suggests that 4% cream formulations containing tricyclic antidepressants (TCAs) are overdosing and lower doses are needed to determine their effectiveness.

The foregoing description of the invention is illustrative only and is not intended to limit the scope of the invention to the precise terms presented. Furthermore, although the invention has been described in detail with reference to particular exemplary embodiments, variations and modifications lie within the scope and spirit of the invention as described and defined in the following claims. .

The above disclosure and examples are generally descriptive of the invention and are provided for illustrative purposes and are not intended to limit the scope of the invention. The invention described herein can be practiced in the absence of any element, limitation, or limitation not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprising,""consisting essentially of," and "consisting of" can be replaced with either of the other two terms. The terms and expressions are used as terms of description and not as limitations, and in their use there is no intention to exclude equivalents of the features shown and described or any part thereof, but the claims It will be appreciated that various modifications are possible within the scope of the invention. Therefore, while the present invention has been specifically disclosed in terms of preferred embodiments and optional features, modifications and variations of the concepts disclosed herein may be utilized by those skilled in the art, and such modifications and variations may be incorporated herein by reference to patents. It is to be understood that the invention is considered within the scope of the invention as defined by the claims.

Claims (46)

A method for treating cutaneous radiation injury (CRI), the method comprising:
A topical composition comprising an effective amount of one or more functional inhibitors of acid sphingomyelinase (FIASMA) applied to a targeted area of the skin of a patient in need thereof at least once per day before, during or after radiation therapy. A method comprising administering 0.5-5 ml. Claim 1, wherein treating CRI includes preventing CRI, reducing the incidence or recurrence rate of CRI, inhibiting, treating, ameliorating or reducing the severity of CRI, or reversing CRI. Method described. 2. The method of claim 1, wherein the CRI results from exposure to environmental radiation. 2. The method of claim 1, wherein the CRI results from exposure to radiation from military weapons. 2. The method of claim 1, wherein the CRI results from medical radiotherapy for cancer. 2. The method of claim 1, wherein the CRI is radiation dermatitis. 2. The method of claim 1, wherein the CRI is oral mucositis. 2. The method of claim 1, wherein the CRI is radiation rectal injury. The FIASMA is selected from the group of selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenergic receptor blockers (ARBs), and beta blockers. 2. The method according to claim 1. 2. The method of claim 1, wherein the FIASMA is SSRI. 2. The method of claim 1, wherein the FIASMA is TCA. 2. The method of claim 1, wherein the FIASMA is a TCA excluding doxepin. 2. The method of claim 1, wherein the FIASMA is sertraline. 2. The method of claim 1, wherein the FIASMA is amitriptyline. 2. The method of claim 1, wherein the composition comprises from 5 to 50 mg of FIASMA. 2. The method of claim 1, wherein the composition comprises up to 20 mg amitriptyline per ml of the composition. 2. The method of claim 1, wherein the composition comprises up to 40 mg sertraline per ml of the composition. 2. The method of claim 1, wherein the composition comprises 10-20 mg amitriptyline per ml of the composition and further comprises 5-50 mg sertraline per ml of the composition. 2. The method of claim 1, wherein the composition further comprises an antioxidant selected from vitamin A, vitamin C, vitamin D, and vitamin E. 2. The method of claim 1, wherein the composition is formulated as a topical dosage form that delivers an effective dose of the active ingredient in situ to the target area of the patient. Claim 1, wherein the composition is formulated with a pharmaceutically acceptable carrier to form a lotion, cream, ointment, or gel for topical delivery of the active ingredient to a targeted area of the patient's skin. The method described in. 2. The method of claim 1, wherein the composition is formulated as a sublingual dosage form. 2. The method of claim 1, wherein the composition is provided in suppository form. 2. The method of claim 1, wherein the composition is administered by a rectal plug device for delivering the FIASMA to the anorectal cavity. 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). Claim 25, wherein treating CRI includes preventing CRI, reducing the incidence or recurrence rate of CRI, inhibiting, treating, reversing or reducing the severity of CRI, or reversing CRI. Pharmaceutical compositions as described. 26. The pharmaceutical composition of claim 25, wherein the CRI is radiation dermatitis. 26. The pharmaceutical composition of claim 25, wherein the CRI is oral mucositis. 26. The pharmaceutical composition according to claim 25, wherein the CRI is radiation rectal injury. The FIASMA is selected from the group of selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antihistamines, antiarrhythmics, adrenergic receptor blockers (ARBs), and beta blockers. 26. The pharmaceutical composition according to claim 25. 26. The pharmaceutical composition of claim 25, wherein the FIASMA is an SSRI. 26. The pharmaceutical composition of claim 25, wherein the FIASMA is TCA. 26. The pharmaceutical composition of claim 25, wherein the FIASMA is a TCA excluding doxepin. 26. The pharmaceutical composition of claim 25, wherein the FIASMA is sertraline. 26. The pharmaceutical composition of claim 25, wherein the FIASMA is amitriptyline. 26. The pharmaceutical composition of claim 25, wherein the composition comprises 5 to 50 mg of at least one FIASMA. 26. The pharmaceutical composition of claim 25, wherein the composition comprises up to 20 mg amitriptyline per ml of the composition. 26. The pharmaceutical composition of claim 25, wherein the composition comprises up to 40 mg sertraline per ml of the composition. 26. The pharmaceutical composition of claim 25, wherein the composition comprises 10-20 mg amitriptyline per ml of the composition and further comprises 5-50 mg sertraline per ml of the composition. 26. The pharmaceutical composition of claim 25, wherein the composition further comprises an antioxidant selected from vitamin A, vitamin C, vitamin D, and vitamin E. 26. The pharmaceutical composition of claim 25, wherein the composition is formulated as a topical dosage form that delivers an effective dose of the active ingredient in situ to the target area of the patient. 25. The composition is formulated with a pharmaceutically acceptable carrier to form a lotion, cream, ointment, or gel for topical delivery of the active ingredient to a targeted area of the patient's skin. The pharmaceutical composition described in . 26. A pharmaceutical composition according to claim 25, wherein said composition is administered in a sublingual dosage form. 26. A pharmaceutical composition according to claim 25, wherein said composition is provided in suppository form. 26. The pharmaceutical composition of claim 25, wherein the composition is administered by a rectal plug device for delivering the FIASMA to the anorectal cavity. 26. The pharmaceutical composition of claim 25, comprising an effective amount of FIASMA and free of anti-inflammatory agents and anesthetics.

Images