Topical benzimidazole formulations and methods for use in the treatment of inflammatory skin diseases

Abstract

【Solution】A composition and method for treating and preventing inflammatory and autoimmune skin conditions, particularly rosacea, using one or more topically applied benzimidazole compounds in a pharmaceutically acceptable carrier for use on the skin. Preferred benzimidazole compounds include mebendazole. The therapeutic composition preferably contains 0.05 to 0.20% by weight of mebendazole in an aqueous or non-aqueous carrier or vehicle including creams, gels, lotions, liquids, emulsions, microemulsions, aerosol sprays, non-aerosol sprays, serums, solutions, suspensions, or ointments, may contain up to 20.0% of mebendazole, and is applied at least once a day over a treatment period of at least two weeks, resulting in a reduction in the appearance of skin cytotoxic CD+8 T cells, papules, pustules, swelling, redness or inflammation, and / or itching at the affected site compared to pre-treatment levels.

Description

Technical Field

[0001] <Cross - Reference to Related Applications> This application claims the benefit of U.S. Provisional Application No. 63 / 353,907, filed on June 21, 2023.

[0002] <Technical Field> The present invention relates to topical formulations of benzimidazoles, particularly mebendazole, and their use in the treatment and prevention of inflammatory and other skin diseases and conditions, such as rosacea.

Background Art

[0003] The use of benzimidazoles, including mebendazole, for the treatment of various health - related conditions in humans and non - human animals is known in the art. Mebendazole is an approved anthelmintic drug with a favorable toxicity profile. It is generally administered orally for intestinal parasitosis. The dosing regimens vary from short - term low - dose treatments to long - term high - dose treatments over several months. For example, U.S. Pat. Nos. 9,877,950 and 5,169,846 disclose the use of mebendazole as an anthelmintic drug for the treatment of parasites and helminths in animals.

[0004] Interestingly, mebendazole has also been found to have significant anti - proliferative activity across various cancer models. These include cell lines of glioblastoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer, osteosarcoma, melanoma, etc. Currently, in clinical trials, the usefulness of mebendazole for high - grade glioblastoma, medulloblastoma, and metastatic gastrointestinal cancer is being evaluated. For example, WO2002058697 discloses the use of mebendazole for the treatment of cancer, including topical application. Similarly, U.S. Patent Application Publication No. 20210369679 discloses the use of mebendazole in combination with non - steroidal anti - inflammatory drugs (NSAIDs) for the treatment of cancers, including skin cancer.

[0005] The anti-parasitic effect of mebendazole is due to the inhibition of tubulin, which disrupts the cytoskeletal network of organisms and leads to the death of parasites. Mebendazole also inhibits mammalian tubulin, but with low binding affinity. The inhibition of tubulin is also thought to be one of the mechanisms by which mebendazole exerts a cytotoxic effect on tumor cells. In addition to its ability to bind and inhibit tubulin polymerization, mebendazole also binds to and inhibits a number of cytoplasmic kinases that are important for cancer initiation, progression, and metastasis. Examples of these kinases include ABL1, BRAF, DYRK1B, JAK3, and PDGFR.

[0006] The immunomodulatory effects of mebendazole have been roughly studied in in vitro models. For example, mebendazole has been found to cause a phenotypic switch from M2 to M1 in the monocyte / macrophage model. This may explain the advantages of mebendazole in solid malignancies beyond its direct anti-proliferative effect on tumor cells, since M1 macrophages induce direct and indirect anti-tumor effects. Furthermore, mebendazole has been shown to uniquely upregulate ERK signaling in THP-1 monocyte-like cells and human CD4+ T cells isolated from patients with systemic lupus erythematosus, which is known to have defects in ERK signaling. This is an effect specific to mebendazole and not seen in other benzimidazoles. Therefore, it is speculated that mebendazole may be effective in autoimmune diseases characterized by defects in ERK signaling. The treatment of scleroderma with mebendazole is disclosed, for example, in WO2019112031. However, the use of benzimidazoles for the topical treatment of other inflammatory or autoimmune diseases and conditions of the skin, such as eczema, is not known.

[0007] Rosacea is one of the most common inflammatory skin diseases in humans. Rosacea is a chronic inflammatory skin disorder characterized by facial flushing, telangiectasia, irritation, pain, papules, pustules, and neoplastic / granulomatous changes. There are four main subtypes: erythematotelangiectatic rosacea (ETR), papulopustular rosacea (PPR), phymatous rosacea (PR), and ocular rosacea (OR). Rosacea was initially thought to be a disease caused by blood vessels, but it is now known that immunological factors play a major role in the progression of the disease. This immunological factor is driven by a number of processes, particularly the release of inflammatory neuropeptides by cutaneous nerve endings, changes in the inflammatory environment by the local microbiota, and elements of innate immunity that alter the cytokine environment. With respect to adaptive immunity, the presence and proliferation of CD4+ and CD8+ T cells have been found to be increased in ETR and PPR compared to healthy skin.

[0008] A reduction in skin inflammation is thought to lead to an improvement in rosacea. This has been actually demonstrated by the use of topical and systemic antibacterial agents, corticosteroids, and other non-steroidal immunomodulatory agents. Examples of such treatments include, but are not limited to, ivermectin, metronidazole, tetracycline, and prednisone. Since CD8+ T cells are upregulated in rosacea, reducing / suppressing the activity, proliferation, or viability of CD8+ T cells is also considered a viable treatment strategy.

[0009] The immunomodulatory effect of mebendazole has been studied in monocytes / macrophages and CD4+ T cells, but its effect on CD8+ T cells has not been studied so far. There is a need in the art for improved immunomodulatory treatments for inflammatory or autoimmune diseases and conditions of the human skin, particularly for the treatment of rosacea. According to a preferred embodiment of the present invention, the use of mebendazole provides such an improvement, particularly in the immunomodulatory effect on CD8+ T cells.

[0010] In addition, in the art, there is also a need for mebendazole therapeutic compositions with improved solubility and skin penetration ability that can be used to treat such skin conditions. Mebendazole has a water solubility of about 0.035 mg / mL at 25 °C in mebendazole polymorph C and is poorly soluble in water. In addition to its extremely low solubility in water, mebendazole also has extremely low solubility in most solvents other than DMSO (about 2% by weight). Mebendazole also freely dissolves in formic acid. However, due to safety considerations, DMSO and formic acid are not suitable as pharmaceutical vehicle components for skin treatment products, especially for facial skin treatment compositions (since rosacea mainly affects the face). Therefore, there is a need for methods and composition components for increasing the solubility of mebendazole in a pharmaceutical vehicle suitable for use on human and animal skin, especially human facial skin.

SUMMARY OF THE INVENTION

[0011] In certain preferred embodiments of the present invention, a therapeutic composition comprising one or more benzimidazoles in a pharmaceutically acceptable vehicle for topical application is used for the treatment of inflammatory or autoimmune diseases and / or conditions of the skin. In preferred embodiments, the diseases or conditions treated by the compositions according to the present invention affect only animals (non-human), only humans, or both animals and humans. Most preferably, the compositions according to the preferred embodiments are used for the treatment of rosacea in humans.

[0012] According to a preferred embodiment, the therapeutic composition comprises mebendazole, a salt of mebendazole, or methyl 5-benzoylbenzimidazole-2-carbamate (each of which is generally referred to herein as MBZ). In other embodiments, the therapeutic composition comprises albendazole, thiabendazole, fenbendazole, MBZ, or one or more of their salts. Except as recited in the claims, any other benzimidazole may be used instead of, or in addition to, mebendazole or MBZ referred to herein in connection with the description of the invention and the preferred embodiments of the invention. Mebendazole exists in several polymorphic crystalline states, including polymorphs A, B, and C. Polymorph C is the preferred form for the compositions of the present invention. However, others may be used and may also be excluded. Salts of mebendazole may include mebendazolium lactate, mebendazolium glycolate, mebendazolium mesylate, and the like.

[0013] In a preferred embodiment, the MBZ therapeutic composition, regardless of the presence or absence of other active ingredients, contains about 0.01 to 1.0% by weight, more preferably about 0.05 to 0.25% by weight, and most preferably about 0.05 to 0.15% by weight of mebendazole in an MBZ gel composition, an MBZ cream base vehicle, or another pharmaceutically acceptable vehicle for topical use on human and / or animal skin. Such amounts of MBZ are particularly preferred when the vehicle for the MBZ therapeutic composition is a clear aqueous solution, non-aqueous solution, or gel. According to another preferred embodiment, the composition comprises (1) about 0.01 to 0.50% by weight, more preferably about 0.05 to 0.25%, and most preferably about 0.05 to 0.15% of mebendazole, (2) in total about 10 to 60% by weight, more preferably about 25 to 60%, and most preferably about 40 to 55% of one or more solvents, penetration enhancers, and / or emulsifying components, and (3) water. One or more other active ingredients may also be included in these embodiments. In these embodiments where smaller amounts of MBZ are used, the solvent and / or other components preferably increase the solubility of MBZ to at least 5 times, more preferably at least 10 times or more, the solubility of MBZ in water, enabling the achievement of preferred skin penetration performance using less MBZ.

[0014] In other preferred embodiments, the MBZ therapeutic composition comprises a vehicle that does not increase the solubility of MBZ as much as other preferred embodiments, and thus more MBZ is required to increase the skin penetration performance of such an MBZ therapeutic composition. One such vehicle is Vanicream® described herein. In these embodiments, the MBZ therapeutic composition comprises 1.0 to 20.0% by weight, more preferably about 1.0 to 10.0% by weight, and most preferably about 1.0 to 5.0% by weight of mebendazole. Such amounts of MBZ are particularly preferred when the vehicle for the MBZ therapeutic composition is an aqueous lotion, cream, emulsion or anhydrous suspension of mebendazole and mebendazole is in a mostly insoluble crystalline form. In these embodiments where larger amounts of MBZ are used, the solvent and / or other components preferably increase the solubility of MBZ to no more than 10 times, more preferably no more than 5 times, the solubility of MBZ in water.

[0015] In some preferred embodiments, mebendazole (or other benzimidazoles) is physically nano-sized in the composition. According to other preferred embodiments, mebendazole (or other benzimidazoles) is also preferably undissolved and / or suspended mebendazole, encapsulated in the composition. In still other preferred embodiments, mebendazole (or other benzimidazoles) is solubilized as much as possible by a non-DMSO solvent and / or surfactant. According to other preferred embodiments, mebendazole (or other benzimidazoles) and at least one solvent are processed through a microfluidizer to form an MBZ (or other benzimidazoles) enriched composition and / or an MBZ (or other benzimidazoles) therapeutic composition. In another preferred embodiment, mebendazole (or other benzimidazoles) and at least one solvent are not processed through a microfluidizer to form an MBZ (or other benzimidazoles) enriched composition and / or an MBZ (or other benzimidazoles) therapeutic composition. These variations regarding mebendazole (or other benzimidazoles) may be used with any composition containing mebendazole (or other benzimidazoles) according to the preferred embodiments of the compositions herein.

[0016] In another preferred embodiment, the vehicle in the composition comprises an aqueous lotion, cream, gel, solution, suspension, or ointment. In yet another preferred embodiment, the vehicle in the composition comprises a non-aqueous lotion, cream, solution, suspension, gel or ointment. Preferred embodiments for the vehicle preferably include one or more of the following, preferably all of the following: (1) water (preferably purified water or deionized water), (2) petrolatum, (3) sorbitol, (4) cetearyl alcohol, (5) propylene glycol, (6) ceteth-20 (a polyethylene glycol ether of cetearyl alcohol), (7) simethicone, (8) glyceryl stearate, (9) PEG-30 stearate (a polyethylene glycol ester of stearic acid), (10) sorbic acid, and (11) BHT (butylated hydroxytoluene). Other preferred embodiments for the vehicle preferably include one or more of the following, preferably all of the following: (1) water (preferably purified water or deionized water), (2) glycerin, (3) polyacrylic acid (preferably carbomer), (4) disodium ethylenediaminetetraacetate (EDTA), (5) cetyl alcohol, (6) stearyl alcohol, (7) glyceryl stearate and / or PEG100 stearate, (8) polysorbate 80, (9) triethanolamine, and (10) phenoxyethanol. It should be noted that any component listed as being able to be included in a particular preferred embodiment may be excluded in another preferred embodiment.

[0017] According to one preferred embodiment, the MBZ concentrated composition comprises (1) mebendazole (or other benzimidazoles) and (2) one or more compounds or components acting as a solvent, a skin penetration enhancer, and / or an emulsifier. In another preferred embodiment, there are at least two, more preferably at least three components in category (2). Preferably, at least one component of category (2) acts as a solvent and an emulsifier. In another preferred embodiment, the MBZ concentrated composition comprises (1) mebendazole (or other benzimidazoles), (2) a sorbitol-based solvent, (3) an ethylene and / or propylene glycol-based solvent, and (4) a solubilizer and / or an emulsifier. These preferred MBZ concentrated compositions contain about 1.0 to 10.0% by weight, more preferably about 3.0 to 6.0% by weight, and most preferably about 3.0 to 4.0% by weight of mebendazole. In yet another preferred embodiment, the amount of mebendazole in the MBZ concentrated composition is reduced to about 0.05 to 1.0% by weight, more preferably 0.05 to 0.2%, and most preferably 0.05 to 0.15%.

[0018] A preferred ethylene glycol-based solvent is diethylene glycol monoethyl ether (Transcutol P®), although others may also be used. A preferred propylene glycol-based solvent is propylene glycol monolaurate (Lauryl Glycol®), although others may also be used. According to another preferred embodiment, the MBZ concentrated composition contains a total of about 15.00 to 25.00% by weight, more preferably about 18.00 to 21.00% by weight of an ethylene glycol-based solvent and / or a propylene glycol-based solvent. In some preferred embodiments, both the ethylene glycol-based solvent and the propylene glycol-based solvent are used together in the MBZ concentrated composition at a weight ratio of about 80:20 to 70:30, more preferably about 75:25 to 65:35, and most preferably about 60:40.

[0019] A preferred sorbitol-based solvent is dimethyl isosorbide (DMI). In another preferred embodiment, the MBZ concentrate composition comprises from about 32.00 to 45.00% by weight, more preferably from about 36.00 to 40.00% by weight, of a sorbitol-based solvent.

[0020] A preferred solubilizer and / or emulsifier is polyoxyl 40 hydrogenated castor oil (Cremophor RH 40). According to another preferred embodiment, the MBZ concentrate composition comprises from about 32.00 to 45.00% by weight, more preferably from about 36.00 to 40.00% by weight, of a solubilizer and / or emulsifier.

[0021] The solvents used in the compositions according to the preferred embodiments are (1) preferably suitable for dissolving MBZ at more than 10 times the solubility of MBZ in water (which is approximately 35 μg / mL), and (2) suitable for use in an amount necessary to dissolve MBZ according to the preferred embodiments on human or animal skin. In yet another preferred embodiment, other solvents / skin penetration enhancers that can be used in addition to or instead of dimethyl isosorbide, diethylene glycol monoethyl ether, and Cremophor RH 40 include caprylocaproyl macrogol-8 glyceride, propylene glycol monocaprylate, polyglyceryl-3 dioleate, diisopropyl adipate, diethylhexyl adipate, poly(glyceryl) adipate, and the like.

[0022] In a preferred embodiment, the MBZ-concentrated composition according to the preferred embodiments of the present specification comprises: (1) a step of mixing one or more solvents and mebendazole to form a first mixture; (2) a step of heating the first mixture at a temperature within a first temperature range for a first period; and (3) a step of mixing or stirring during the heating step, for example, using a magnetic stirrer. According to a preferred embodiment, the first period is about 5 to 20 minutes, more preferably about 5 to 15 minutes. Most preferably, the heating temperature and the first period do not result in more than 10% decomposition of MBZ, more preferably 8% or less, and most preferably 5% or less decomposition. The first temperature range is most preferably at least 60 °C and less than the temperature at which MBZ experiences more than 5% decomposition. More preferably, the first temperature range is 60 to 90 °C, and most preferably 70 to 90 °C. Preferably, steps 1 to 3 are carried out before mixing MBZ or the first mixture with any water or aqueous application vehicle.

[0023] According to a preferred embodiment, the MBZ gel composition comprises: (1) mebendazole (or other benzimidazoles), (2) water, and (3) a gelling agent or thickening agent. According to another preferred embodiment, the MBZ gel composition comprises: (1) the MBZ-concentrated composition, (2) water, and (3) a gelling agent or thickening agent. In other preferred embodiments, the MBZ gel composition further comprises (4) a cyclodextrin compound for assisting the solubility of MBZ / reducing the precipitation of MBZ. A preferred cyclodextrin compound is hydroxypropyl-β-cyclodextrin (Cavasol® W7 HP). Other cyclodextrin compounds can also be used, including α-cyclodextrin and γ-cyclodextrin, as well as alternative chemical modifications of α, β, and γ cyclodextrins, including hydroxyalkylation, methylation, ethylization, phosphorylation, and sulfonation.

[0024] According to another preferred embodiment, the composition for MBZ treatment comprises an MBZ gel composition, which may be mixed with a vehicle or applied to the skin for treatment without being mixed with an additional vehicle component. According to another preferred embodiment, the composition for MBZ treatment comprises an MBZ concentrated composition, which is mixed with a vehicle before being applied to the skin for treatment.

[0025] In another preferred embodiment, a method for treating inflammatory or autoimmune diseases and conditions of the skin comprises topically applying a composition comprising one or more benzimidazoles in a pharmaceutically acceptable vehicle to the affected area of the skin at least once a day for a treatment period of at least two weeks, more preferably at least twelve weeks, and continuing to apply the composition to the affected facial area daily or every other day to prevent recurrence of rosacea. Most preferably, the composition used in the preferred method is according to a preferred embodiment of the present invention. According to a preferred method, the composition comprising mebendazole is applied to the affected area of the skin at a dosage of about 100 - 500 milligrams, more preferably 50 - 250 milligrams, per side of the affected facial area.

[0026] The use of the therapeutic compositions and methods according to the preferred embodiments of the present invention has been found to be effective in reducing the survival rate of T cells and in treating patients with rosacea. The inventors have found that the use of mebendazole according to the preferred embodiments reduces the survival rate of T cells in an in vitro model. The use of preferred methods and composition components for preparing MBZ concentrated compositions, MBZ gel compositions, and / or compositions for MBZ treatment has also been found to result in increased skin penetration and / or increased solubility of MBZ in a pharmaceutical vehicle suitable for use on human and animal skin, particularly human facial skin. The methods and compositions of the preferred embodiments provide advantages as therapeutic agents for immunomodulation for the treatment of inflammatory and autoimmune diseases and conditions of the skin, particularly rosacea, through a suppressive effect especially on CD8+ T cells, with improved permeability and solubility of MBZ.

Brief Description of the Drawings

[0027] The compositions and methods of the present invention are further described and explained in connection with the following drawings.

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0028] The composition for topical treatment of mebendazole based on a preferred embodiment of the present invention is effective in reducing T lymphocytes (see FIGS. 1 to 3) and can be used as an effective immunomodulator alone or in combination with additional therapeutic agents such as oxymetazoline. Accordingly, a method for treating or preventing a disease or disorder in a subject (preferably a human) is disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a composition comprising one or more benzimidazoles in a vehicle or carrier for topical application. Most preferably, the benzimidazoles include mebendazole, which is in the topical cream vehicle described herein. Most preferably, the vehicle or carrier is a pharmaceutically acceptable carrier composition suitable for use on the skin of humans and / or animals (other than humans). Preferably, the disease or disorder is an autoimmune disease or an inflammatory skin disorder. Most preferably, the disease or disorder is rosacea.

[0029] As used herein, the terms "treat", "treating", "treatment", etc. refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Treating a disease or condition, although not precluding it, does not require that the disease, condition, or associated symptoms be completely eradicated.

[0030] As used herein, the terms "treat", "treating", "treatment", etc. may include "preventive treatment" which refers to reducing the recurrence of a disease or condition, or reducing the likelihood of recurrence of a previously controlled disease or condition, in a subject who does not have the disease or condition but is at risk of or prone to recurrence of that disease or condition. The terms "treat" and its synonyms are intended to administer a therapeutically effective amount of the compositions of the present disclosure to an individual in need of such treatment. Within the scope of the subject matter of the present disclosure, "treatment" includes prevention of recurrence or stage prevention and treatment of acute or chronic symptoms, signs and / or dysfunctions. Treatment can be carried out symptomatically, for example, by suppressing symptoms. It can be done over a short period, over a medium period, or, as part of maintenance therapy, over a long period. As used herein, the terms "prevent", "preventing", and "prevention" are as recognized in the art and, when used with respect to a condition such as alcoholism, are well understood in the art and include administration of a composition that reduces the frequency of symptoms of a medical condition in a subject or delays its onset as compared to a subject not receiving the composition. Thus, prevention of alcoholism includes, for example, reducing or restoring the level of T cell lymphocytes near the hair follicles in a treated population and an untreated control population by a statistically and / or clinically significant amount.

[0031] In some cases, the compositions and methods disclosed herein include those for treating or preventing alcoholism. In some cases, the compositions and methods disclosed herein include those for treating alcoholism. In some cases, the compositions and methods disclosed herein include those for preventing alcoholism.

[0032] A preferred composition for MBZ treatment contains about 0.01 to 1.0% by weight, more preferably about 0.05 to 0.5% by weight, and most preferably about 0.1 to 0.15% by weight of mebendazole. Depending on the other components used in the composition for MBZ treatment, especially depending on the solvent or penetrant used, the amount of mebendazole may increase up to about 20.0% by weight, more preferably up to about 10.0% by weight, and most preferably up to about 5.0% by weight in order to enable sufficient solubility and skin penetration of mebendazole. The remainder of the preferred composition for MBZ treatment contains a pharmaceutically acceptable carrier or vehicle component for topical administration and optionally one or more other pharmaceutically active components. The pharmaceutically active vehicle or carrier may include an aqueous or non-aqueous lotion, cream, solution, suspension, or ointment, or a clear aqueous or anhydrous solution or gel. One preferred vehicle is a moisturizing cream or lotion containing an emulsion or microemulsion for the facial treatment and prevention of erythematotelangiectatic rosacea, papulopustular rosacea, and phymatous rosacea, or a sterile ophthalmic solution, suspension, emulsion, or ointment for the treatment or prevention of ocular rosacea.

[0033] In some cases, the methods disclosed herein include administering one or more additional pharmaceutically active agents to a subject, and / or such one or more additional pharmaceutically active agents may be included in the compositions according to the preferred embodiments. In some cases, the additional pharmaceutically active agents are immunosuppressants, anti-infective agents, calcineurin inhibitors, Janus kinase (JAK) inhibitors, retinoids, or vasoconstrictors. In some cases, the immunosuppressant is a corticosteroid. In some cases, the corticosteroid is hydrocortisone, triamcinolone, clobetasol, fluocinonide, etc. In some cases, the anti-infective agent is tetracycline, doxycycline, minocycline, erythromycin, metronidazole, ivermectin, etc. In some cases, the calcineurin inhibitor is cyclosporine, pimecrolimus or tacrolimus. In some cases, the JAK inhibitor is ruxolitinib, tofacitinib, baricitinib or upadacitinib. In some cases, the retinoid agent is azelaic acid, tretinoin, retinol. In some cases, the vasoconstrictor is brimonidine, midodrine or oxymetazoline. In other preferred embodiments, any of these components may be excluded from the composition or from use in the methods of the invention. Chronic use of corticosteroids is excluded from the compositions according to some preferred embodiments as being contraindicated.

[0034] Furthermore, since the compositions and methods of the preferred embodiments involve topical application to the skin or the membranes of the eye, other non-active additives that can assist or induce the penetration of the active benzimidazole agent into the facial skin or eye tissue may be used. Substances referred to as "penetration enhancers" are typically used in compositions designed to deliver drugs transdermally to increase the amount of the active substance delivered into the systemic circulation. Penetration enhancers are various types of compounds, including specific compounds such as dimethyl sulfoxide, methylsulfonylmethane, pyrrolidone, ethanol, propylene glycol, dimethylacetamide, and other compounds that can disrupt the barrier function of the stratum corneum. Other substances have also been found to increase the flux of certain active agents through the skin or mucosa. These include lipophilic compounds such as laurocapram (azone), α-hydroxy acids and β-hydroxy acids, fatty acids or alcohols such as oleic acid, oleyl alcohol, linoleic acid, and fatty acid esters such as isopropyl myristate, methyl nonanoate, methyl caprate. Mixtures of certain penetration enhancers with propylene glycol, butylene glycol, pentylene glycol, isopentyl glycol, hexylene glycol, diethylene glycol monoethyl ether (also known as ethoxydiglycol), acetamide MEA, and propylene glycol monolaurate are also known to improve the delivery of certain active ingredients. Among the surfactants, there are those that increase the penetration of the active agent through solubilization of the active agent and reduction of the interfacial tension or encapsulation of the active agent, including PEG-40 hydrogenated castor oil, Cremophor® and other surfactants that combine glyceryl polyethylene glycol oxy stearate, glyceryl polyglyceryl fatty acid ester, polyethylene glycol, and glyceryl ethoxylate.Also, the encapsulation medium for the benzimidazole drug substance or composition in the preferred embodiment may include soy or egg-based lecithin or chemically modified lecithin, phosphatidylcholine or modified phosphatidylcholine, β-cyclodextrin, PLGA [poly(lactic acid-co-glycolic acid)], dextran, chitosan, d-α-tocopheryl polyethylene glycol succinate polymer, and poloxamer (polyoxyethylene-polyoxypropylene) block polymer. The composition according to the preferred embodiment may include one or more of these components or other penetration enhancers. In other preferred embodiments, any of these components may be excluded from the composition or excluded from use in the method of the present invention.

[0035] A number of components may be used with the composition according to certain preferred embodiments, but they are excluded in other preferred embodiments. Compositions according to some preferred embodiments do not include NSAIDs, 2,6-di-tert-butyl-4-methylphenol, phenyl-pentanedione / or pyridine / or phenylbenzene / or benzoxazine compounds (such as 3-(4-methoxyphenyl)-1,5-bis(2-methoxyphenyl)-1,5-pentanedione). Hyaluronic acid / salt may be included in some preferred compositions or may not be included in other preferred compositions according to the present invention.

[0036] Regarding the amount of mebendazole incorporated into each topical formulation, typically, when the topical formulation is applied to the treatment area of a subject in need thereof, a compound for reducing inflammation (e.g., for treating acne) is present in an amount effective to achieve at least one of (i) reduction of T cell survival rate, (ii) reduction of T cell proliferation, (iii) reduction of T cell activation, and (iv) reduction of T cell activity, and the mebendazole content is adjusted accordingly.

[0037] Provided is the use of the topical composition disclosed herein in the preparation of a medicament for treating the diseases and disorders described herein.

Examples

[0038] In the following Examples 1 and 2, a method for evaluating mebendazole for its effectiveness in the regulation of T lymphocytes in an in vitro platform applicable to human skin diseases, and its clinical application using a composition for MBZ treatment according to a preferred embodiment of the present invention are described. The results of these examples demonstrate that mebendazole is a promising immunomodulatory agent for the treatment of psoriasis and other inflammatory and neoplastic skin diseases caused by T lymphocytes, ultimately improving the quality of life of patients. In the following Examples 3 to 7, a composition containing MBZ based on a preferred embodiment of the present invention, a method for preparing the composition, a solubility analysis of MBZ in a selected solvent, and a skin PAMPA test of the selected composition for evaluating skin penetration are described. The following examples are provided for illustrative purposes and are not intended to limit the scope of the present disclosure.

[0039] <Example 1 - In Vitro Test>

[0040] The effectiveness of mebendazole was evaluated using an in vitro screening platform for immune modification. CTLL-2 (ATCC® TIB-214™) is a cytotoxic T lymphocyte purchased and cultured according to the ATCC protocol. Once confluent, the cells were seeded in a 12-well plate at a concentration of 55,000 cells / mL and treated three times with solutions of mebendazole dissolved in dimethyl sulfoxide (DMSO) at various mebendazole concentrations of 1 nM, 5 nM, 500 nM, and 1 μM, and compared to a control to which only DMSO was applied (containing no mebendazole at all). The maximum volume added to each 1 mL of the 12 wells was 10 μL for the highest test concentration of mebendazole and the control. The concentration of mebendazole is within the range of the preferred embodiments of the therapeutic composition according to the present invention, although the preferred therapeutic composition for use does not contain DMSO. MBZ has good solubility (about 2% by weight) in DMSO. This is the reason it was selected as the solvent for this example. However, considering safety in skin application, it is preferred not to use DMSO as the solvent for the MBZ therapeutic composition according to the present invention. As shown in Figure 1, mebendazole kills T lymphocytes in a dose-dependent manner. These results indicate that mebendazole significantly reduces T lymphocytes in cell culture starting at a test concentration of 1 nM (0.295 microgram).

[0041] The in vitro data disclosed shows a significant decrease in inflammatory CD+8 T cells starting at a concentration of 1 nM or 0.295 μg / mL in DMSO. This extremely low concentration that reduces T cells is important when formulating mebendazole (i.e., methyl 5-benzoylbenzimidazole-2-carbamate) into a topical cream, lotion, gel, suspension, emulsion, patch, or any topical pharmaceutical vehicle for application to human or mammalian skin, most preferably to the facial skin of a human suffering from rosacea.

[0042] <Example 2 - Application of Mebendazole to the Treatment of Rosacea>

[0043] Although not wishing to be bound by theory in the rosacea immune model, the inflammatory process induced by activated T cells results in the following changes that give rise to all subtypes of rosacea already described: angiogenesis, the formation of papules and pustules, and granulomatous inflammation leading to neoplastic changes in the skin. The recovery process is complex. Again, not wishing to be bound by theory, activated T cells need to be inactivated (e.g., with mebendazole), after which the skin achieves homeostasis and symptoms such as skin erythema, telangiectasia, papules, pustules, and neoplastic changes resolve.

[0044] Clinical trials were conducted to determine the effect on the remission of rosacea after 12 weeks when a 10% mebendazole cream based on a preferred MBZ treatment composition was applied daily according to a preferred treatment method. To collect preliminary information regarding the remission of rosacea, a facial split test was conducted, and patients applied the MBZ treatment composition (containing 10 wt% mebendazole) to the left side of the face and a vehicle cream (control, containing no mebendazole) to the right side of the face every night for 12 weeks.

[0045] The patient had clinically diagnosed facial papulopustular rosacea (PPR) for decades. She had received many treatments including topical ivermectin, topical metronidazole, topical steroids, topical antibiotics, and systemic antibiotics. After discontinuing the above treatments, the rosacea had recurred with erythema, telangiectasia, papules, and pustules. The patient underwent a 4-week washout period without using topical or systemic active drug therapy before starting the active (10% mebendazole) and control (vehicle) creams. The amount of mebendazole in the cream used in Example 2 corresponded to a molar concentration of 0.339 M, and approximately 0.25 - 0.5 mL of the cream was applied once a day to the patient's left cheek.

[0046] The results are summarized in Figure 2. The reported categories are treatment (10% mebendazole, left cheek) and control (vehicle, right cheek). In these results, the active ingredient (10% mebendazole) showed a decrease (70.37%) in the total number of papules and pustules on the left face, while the vehicle did not cause a decrease, indicating an improvement in rosacea when treated according to a preferred embodiment of the present invention.

[0047] The results are shown in the photograph of Figure 3. When the active ingredient (10% mebendazole) cream was applied every night for 12 weeks, the rosacea on the left cheek improved, but when the control (vehicle) cream was applied every night for 12 weeks, the rosacea on the right cheek did not improve. The improvement was recognized by a decrease in papules and pustules, and a decrease in erythema and telangiectasia.

[0048] The MBZ treatment composition used for the treatment of the patient was prepared by pulverizing mebendazole tablets, USP, 500 mg into fine powder and adding it in an amount sufficient to prepare a 10% by mass mebendazole suspension in a commercially available Vanicream® moisturizing skin cream vehicle, and mixing until uniform. No attempt was made to increase the solubility of MBZ in the commercially available Vanicream vehicle. The label ingredient list (INCI; International Nomenclature of Cosmetic Ingredients) of Vanicream moisturizing skin cream, which is an oil-in-water emulsion cream base, is as follows. Purified water, petrolatum, sorbitol, cetearyl alcohol, propylene glycol, ceteth-20 (polyethylene glycol ether of cetearyl alcohol), simethicone, glyceryl stearate, PEG-30 stearate (polyethylene glycol ester of stearic acid), sorbic acid, BHT (butylated hydroxytoluene). Note that MBZ is sparingly soluble in water and the water solubility of MBZ is about 0.035 mg / mL (polymorph C, 25 °C). MBZ not only has low solubility in water, but also has low solubility in most solvents other than DMSO (about 2% by weight). MBZ is also freely soluble in formic acid. Neither DMSO nor formic acid is a suitable pharmaceutical vehicle component for facial treatment products from a safety perspective. Therefore, a method for increasing the solubility of MBZ in a pharmaceutical vehicle suitable for use on human and animal skin, particularly human facial skin, is needed.

[0049] <Example 3 - Permeation and Solubility Increase Test>

[0050] Additional laboratory experiments were conducted to increase the skin penetration of MBZ, and as shown in Table 1 below, the maximum solubility of MBZ in specific topical pharmaceutical skin penetration enhancers was determined. The maximum solubility of MBZ was tested for various preferred solvent components and combinations of components. Specifically, (1) dimethyl isosorbide (solvent composition 1), (2) diethylene glycol monoethyl ether (Transcutol P®) (solvent composition 2), (3) propylene glycol monolaurate (Lauryl Glycol®) (solvent composition 3), and (4) a combination of Transcutol P and lauryl glycol in a weight ratio of approximately 60:40 (solvent composition 4) were evaluated by adding 1 wt% of MBZ to each of them in the formulations listed in Table 1. All formulations were mixed at 20 - 25 °C for 24 hours with magnetic stirring and then filtered through a 0.45 micron (μm) membrane filter to remove undissolved solid particles of MBZ larger than 0.45 microns. Also, a second batch of solvent composition 1 (dimethyl isosorbide) and solvent composition 2 (diethylene glycol monoethyl ether (Transcutol P)) was prepared and further treated by exposing it to a temperature of 100 °C for 15 minutes after filtration to form solvent composition 5 and solvent composition 6, respectively. The filtered formulations were colorless and clear except for compositions 1 and 5. Compositions 1 and 5 appeared milky white after filtration and contained dimethyl isosorbide showing solid MBZ with a particle size less than 0.45 μ. This visual appearance indicates that solvent compositions 2 - 4 and 6 had better solubility than solvent compositions 1 and 5 (containing dimethyl isosorbide or DMI). This is because small solid particles that did not dissolve remained in solvent compositions 1 and 5. However, each solvent composition was analyzed by UV - VIS spectrophotometry (300 - 325 nm) or HPLC (mebendazole, USP - NF monograph) method to determine the amount of MBZ in the composition after the filtration step.

[0051] As shown in Table 1, the results of the two analytical methods generally agree, except for solvent compositions 5 and 6 prepared by exposing to a temperature of 100°C for 15 minutes, which show lower analytical results by HPLC analysis, indicating the possibility of MBZ decomposition by an additional heating step.

[0052]

Table 1

[0053] It was found that the solubility of MBZ is highest in either solvent composition 1 (DMI) or 2 (Transcutol P). However, this solubility decreases to 10 - 20% of the theoretical maximum when solvent compositions 1 and 2 are diluted 50% with deionized water. In undiluted solvent compositions containing (1) only MBZ and Transcutol P or (2) only MBZ and DMI, a concentration of up to 0.5 wt% of MBZ can be achieved, but the resulting liquid solvent compositions have undesirable cosmetic or aesthetic qualities and leave an oily residue when applied to the skin. These problems can be avoided by diluting such solvent compositions with water (preferably deionized water or purified water), but the diluted solvent compositions may be too runny and difficult to apply to the skin, especially facial skin. These problems can be avoided by preparing an MBZ therapeutic composition containing a topical gel or thickened liquid using a suitable viscosity modifier or gelling agent. Such a viscosity modifier or gelling agent may be part of the topical application vehicle to which MBZ (or an MBZ - enriched composition) is added, or may be part of the MBZ gel composition described later herein.

[0054] <Example 4 - Mixed Solvent Composition Test>

[0055] Additional laboratory experiments were conducted to evaluate the combination of Trancutol P and DMI as solvents for MBZ that maximizes its solubility and skin penetration. DMI and Trancutol P were used at levels shown to be safe for application to human skin. For these tests, 0.05 - 0.2 wt% MBZ and the balance deionized water were added and diluted with deionized water to a concentration of 40 wt% Trancutol P and 15% DMI. In these tests, deionized water was used as the diluent to effectively replace topical application vehicles such as the preferred embodiments of the aqueous MBZ cream base compositions described further herein.

[0056] Experiments using a blend of 40% w / w Trancutol P, 15% DMI and 43 - 44% deionized water with MBZ at a concentration of 0.05 - 0.2 wt% required heating the mixture of this solvent, water and MBZ to effect more complete dissolution of the MBZ. To avoid decomposition of the MBZ by maintaining the temperature as low as possible, the solvent / water / MBZ mixture was first stirred at 50°C for 18 hours and then at 60°C for 18 hours. The test results showed some turbidity due to incomplete solubility and a color shift to yellow. This color shift was not observed with exposure of similar formulations heated at higher temperatures (90 - 100°C) for shorter times (5 - 15 minutes) such as Compositions 5 - 6 of Example 3 (Table 1). Further, the tests also showed that a more pronounced turbid precipitate can occur after overnight storage when using more than 0.15% of the amount of MBZ with Transcutol P / DMI / deionized water (40 / 15 / 45% w / w) and when using an MBZ solution that was initially clear (indicating good solubility of the MBZ). Based on these results, further formulation development tests were conducted with the conditions of MBZ concentration at 0.05 - 0.2% w / w and heating at 60 - 90°C for 5 - 15 minutes before adding the diluting water.

[0057] In these tests, it was found that by heating the MBZ / DMI / Transcutol P solvent mixture before dilution with deionized water, the solubility of MBZ increased in the final dilution composition or when mixed with an aqueous-based vehicle such as the preferred embodiment of the MBZ cream base composition herein. By heating at 60 °C to 90 °C, more complete dissolution of 0.05 to 0.15 wt% of MBZ can be achieved by mixing for 5 to 15 minutes. At 60 °C and 70 °C, complete dissolution of MBZ is achieved at a concentration of 0.05 wt%. As the concentration increases beyond 0.05 wt%, 0.10% w / w of MBZ requires 80 °C and 0.15% w / w of MBZ requires 90 °C.

[0058] Thus, according to a preferred embodiment, the MBZ concentrate composition comprises: (1) a step of mixing an ethylene or propylene glycol-based solvent (preferably diethylene glycol monoethyl ether (Transcutol P)) with a sorbitol-based solvent (preferably dimethyl isosorbide) and 0.05 to 0.2% w / w of MBZ (more preferably 0.05 to 0.15% w / w of MBZ); (2) a step of heating to a temperature within a first temperature range; and (3) a step of mixing or stirring during the heating step, for example, using a magnetic stirrer. Preferably, the first period is about 5 to 20 minutes, more preferably about 5 to 15 minutes. Most preferably, the heating temperature and the first period do not result in more than 10% degradation of MBZ, more preferably, the resulting degradation of MBZ is 8% or less, and most preferably 5% or less. The first temperature range is most preferably at least 60 °C and less than the temperature at which MBZ experiences more than 5% degradation. More preferably, the first temperature range is 60 to 90 °C, most preferably 70 to 90 °C. Preferably, steps 1 to 3 are carried out before mixing the MBZ or the first mixture with any water or aqueous application vehicle.

[0059] <Example 5 - Test Formulation>

[0060] To potentially increase the vehicle solubility and skin permeability of MBZ, a MBZ-concentrated composition was prepared based on a preferred embodiment of the present invention and added to a topical MBZ cream base (or vehicle) formulation based on a preferred embodiment of the present invention (further described in Example 6) for testing. Preferred embodiments of the MBZ-concentrated composition are shown in Table 2, and preferred embodiments of the topical MBZ cream base composition are shown in Table 3. Based on a certain preferred embodiment, a MBZ solvent / skin penetrant concentrated composition (formulation 45-147) was prepared as follows. (1) MBZ was micronized to an average particle size of about 3.5 to 4.0 microns. (2) The micronized MBZ powder was added to a liquid mixture of (a) a sorbitol-based solvent (preferably dimethyl isosorbide), (b) an ethylene and / or propylene glycol-based solvent (preferably diethylene glycol monoethyl ether (Transcutol), propylene glycol monolaurate (Lauryl lycol) 60:40), and (c) a solubilizer and / or emulsifier (preferably Cremophor RH 40 / poloxyl 40 hydrogenated castor oil). (3) The MBZ powder was mixed with the liquid components at preferably 25 to 50 °C, more preferably 35 to 50 °C, for 15 to 30 minutes or until the MBZ powder was uniformly suspended white in the liquid.

[0061]

Table 2

[0062] A laboratory batch of 1 Kg of the MBZ concentrate composition (formulation 45 - 147) was prepared according to the proportions of Test Example 6 in Table 2, prepared according to the proportions of Test Example 6 in Table 2, and divided into two substantially equal parts for use in the preparation of the MBZ therapeutic composition used in Example 6. The first half of the concentrate batch was separately and completely processed at 35 - 35 °C three times at 14,000 psi with a Microfluidics EH - 110 microfluidizer, while the second half of the concentrate batch was not further processed. These concentrate batches were then mixed with an MBZ cream - based vehicle (formulation 45 - 149 based on the proportions of Test Example 6 in Table 3) and the final MBZ therapeutic composition containing 0.05%, 0.1%, 0.25%, 0.5%, 1% MBZ in the cream - based vehicle in proportions such that the final MBZ therapeutic composition was obtained (the component amounts are shown in Table 4).

[0063] The topical MBZ cream - based composition (also referred to as formulation 45 - 149) is an oil - in - water (O / W) type cream emulsion - based vehicle, and its preferred embodiments are shown in Table 3.

[0064]

Table 3

[0065] The MBZ cream base preferably comprises an aqueous phase composition and an oil phase composition. The aqueous phase composition is preferably prepared as follows: (1) Mix glycerin and phenoxyethanol until a clear and homogeneous solution is formed. (2) Add deionized water to the solution while mixing. (3) Heat the aqueous mixture to 60 - 70°C while continuing mixing / stirring. (4) Add disodium EDTA while mixing until it is dissolved in the aqueous phase. (5) Slowly add Carbomer 940 to the heated aqueous phase by sprinkling it on the water surface and mix for 45 minutes until a uniform hydrous dispersion of the carbomer is formed (maintain the temperature at 60 - 70°C). The oil phase composition is preferably separately manufactured as follows: (1) Mix (a) cetyl alcohol, (b) stearyl alcohol, (c) glyceryl stearate (and) PEG 100 stearate (an emulsifier composition), and (d) polysorbate 80. (2) Heat the mixture to 60 - 70°C while mixing until a uniform liquid oil phase is formed. The MBZ cream base is preferably manufactured by: (1) a step of adding together the aqueous phase composition and the oil phase composition; (2) a step of heating to 60 - 70°C while homogenizing (using a Silverson L4RT - A homogenizer) at 5000 - 7000 rpm for 15 - 30 minutes; (3) a step of cooling to about 35 - 50°C, more preferably about 35°C, and adding triethanolamine while mixing until a smooth and homogeneous mixture is formed; and (4) a step of further cooling to around 25°C (around room temperature). As further explained below, the MBZ concentrated composition is most preferably added to and mixed with the MBZ cream base composition before the cooling in step (4).

[0066] The final MBZ therapeutic composition was prepared by mixing a required amount of the MBZ concentrated composition pre - heated to 35 - 50°C with a required amount of the MBZ cream base composition pre - heated to 35 - 50°C in a desired ratio, and then cooling to room temperature.

[0067] Table 4 shows the amounts of the components of the MBZ cream base added to various amounts of the MBZ concentrate composition to prepare various MBZ topical treatment compositions A to E having 0.05% to 1% by weight of MBZ.

[0068]

Table 4

[0069] <Example 6 - Skin PAMPA Test on Permeation of MBZ>

[0070] The MBZ treatment compositions A to E of Example 5 were prepared twice. Here, one set of the treatment compositions used the first half of the laboratory batch of MBZ concentrate 45 - 147 processed with a microfluidizer as described above (shown as batches A1 to E1 in Table 5), and the other set of the treatment compositions used the second half of the laboratory batch of MBZ concentrate 45 - 147 that was not processed with a microfluidizer (shown as batches A2 to E2 in Table 5). These sets of the compositions were used in the test of this Example 6.

[0071] Compositions A1 - E1 for MBZ treatment (including microfluidization of the MBZ concentrate) and A2 - E2 (without microfluidization) were evaluated for skin penetration using a skin PAMPA - Parallel Artificial Membrane Permeability Assay - in vitro artificial skin model (Pion, Inc.). Also, another therapeutic composition containing Vaniceam and 10 wt% MBZ as used in Example 2 was tested as a control for comparison with the MBZ - containing therapeutic compositions using the MBZ - enriched composition and MBZ cream - based composition according to the preferred embodiments of the present invention. What was obtained by adding 10 wt% MBZ to Vanicream was considered to be the MBZ - containing therapeutic composition according to the preferred embodiments of the present invention, but was treated as a control for the purposes of these tests. Table 5 shows the compositions tested in the skin model of skin PAMPA, and 150 microliters of each composition was applied to a 20% aqueous solution of hydroxypropyl - β - cyclodextrin in the skin PAMPA artificial skin membrane and PAMPA acceptor (or acceptor medium). For all tests, measurements were taken at intervals of 0.25, 0.5, 1, 6, and 24 hours, and the temperature was 32°C. In addition to the listed compositions, negative controls of MBZ cream base (without MBZ) and Vaniceam (without added MBZ) were also evaluated in the skin PAMPA test, and the interference of the negative control vehicles (Vaniceam or MBZ cream base) on the UV assay of MBZ in the PAMPA acceptor plate solution was measured. The UV absorbance of the negative control vehicle (Vaniceam or MBZ cream base) was subtracted from the UV assay of the corresponding test composition containing MBZ. Table 6 shows the average permeation mass and standard deviation of MBZ passing through the artificial skin membrane for each of the tested MBZ - containing therapeutic compositions.

[0072]

Table 5

[0073] Skin PAMPA method reference: Pharmaceutics 2021 Oct 21;13(11):1758. doi: 10.3390 / pharmaceutics13111758.

[0074]

Table 6

[0075] The summary of the skin PAMPA test results of the MBZ formulation showed that the permeation of mebendazole across the skin PAMPA membrane was slow, and mebendazole was not observed in the acceptor plate at the 0.25, 0.5, and 1-hour time points. After 6 hours, mebendazole could be measured in the acceptor plate, indicating that mebendazole had permeated the skin PAMPA membrane, and a concentration dependence was observed, where the higher the concentration of the sample in the vehicle, the higher the membrane permeation flux.

[0076] At low therapeutic composition usage levels (low concentration of MBZ or 0.05 - 0.25% MBZ of % API), a slight increase in flux is observed in the microfluidized compositions (A1 - E1) compared to the compositions without microfluidization (A2 - E2). This indicates that the microfluidization process is beneficial for increasing skin penetration at low concentrations of MBZ. At low therapeutic composition usage levels, a significant decrease in the MBZ flux rate is also observed after 6 hours, which may be due to the decrease of mebendazole in the composition. Without being bound by theory, this decrease is probably due to a change in the flux dynamics rather than an oxidation or other reaction that causes a measurable decrease in MBZ, and it is considered that the concentration gradient of soluble and insoluble MBZ has changed as MBZ saturates the membrane and enters the acceptor. A similar trend is observed at higher therapeutic composition usage levels (0.5 - 1%), but the changes in flux and permeation amount are not as significant. Increasing the usage amount in the therapeutic composition (increasing the concentration of MBZ or % API to 0.5 - 1% MBZ) seems to cancel out these observed differences, and usage levels of 0.5% and above containing Vanibleam show similar permeation and consistent flux on both short and long time scales regardless of the vehicle type (presence or absence of microfluidization of MBZ cream base or Vanibleam, MBZ concentrate).

[0077] The flow rate and permeation amount of mebendazole are observed to increase with the increase in the filling amount of the therapeutic composition, but the permeation amount does not seem to increase proportionally to the concentration of MBZ in the therapeutic composition. Further, the amount of Vanicream used as the base vehicle for MBZ is slightly larger than that when using the MBZ cream base as the base vehicle, but no significant increase is observed between the MBZ cream base vehicle containing 0.5% or 1% MBZ and the control with 10% MBZ added to Vanicream. Considering that the Vaniceam control with 10% MBZ uses 10 - 20 times the amount of MBZ compared to the formulations of 1% and 0.5% in the therapeutic composition using the MBZ concentrate (the solvent of which is designed to increase the solubility and penetration of mebendazole) in the MBZ cream base as the vehicle, significantly less effective MBZ is required to achieve similar skin penetration, so a significant improvement is achieved by using the MBZ cream base according to the preferred embodiments herein.

[0078] Topical skin treatment of scabies is most likely to be a chronic daily use with the topical MBZ therapeutic composition according to the preferred embodiments, so the 24 - hour cumulative permeation data regarding the skin PAMPA test samples is considered to be the most relevant. The 24 - hour cumulative permeation of mebendazole for the control with 10% MBZ added to Vaniceam is in the range of about 13 - 17 μg of MBZ and is not statistically different from the 0.5% and 1% MBZ therapeutic compositions D1 - E1, D2 - E2, indicating that the skin penetrant and MBZ solvent used in the MBZ - enriched composition 45 - 147 are most likely responsible for the increase in MBZ permeation regarding the MBZ content of the D2 - E2 and D1 - E1 therapeutic compositions compared to the control with 10% MBZ added to Vaniceam. The microfluidization treatment done with the MBZ concentrate 45 - 147 used in the D1 - E1 therapeutic composition does not seem to have a significant effect on MBZ permeation over the longer 24 - hour test.

[0079] <Example 7 - MBZ - enriched Gel Composition>

[0080] For topical application to the skin, thickened or gelled compositions containing MBZ are advantageous. MBZ gel compositions can preferably be applied directly to the skin, whether or not pre-mixed with a separate vehicle such as an MBZ cream base composition or another vehicle component such as Vanicream. The use of the term "gel" is not intended to be limiting, but includes thickened compositions such as creams, ointments, and emulsions having a viscosity suitable for application to human and / or animal skin, preferably about 10,000 to 400,000 centipoise, more preferably about 50,000 to 200,000 centipoise.

[0081] In an MBZ gel composition according to a preferred embodiment, MBZ is combined with one or more of the other components as shown in Table 8.

[0082]

Table 8

[0083] Table 9 below lists the MBZ gel compositions 45-173A to 45-173F of preferred embodiments. Based on certain preferred embodiments, these compositions were prepared, and the dissolution of MBZ in these compositions was achieved by: (1) a step of moderately mixing Transcutol P, DMI, and MBZ with a magnetic stirrer; (2) a step of heating at the specified temperature (60, 70, 80, or 90 °C) for a first period of 5 to 15 minutes; (3) a step of mixing or stirring, for example, using a magnetic stirrer during the heating step; followed by (4) a step of slowly adding water (preferably deionized water) and any other components (such as a Natrosol gelling agent) at 35 to 50 °C while continuing to mix / stir and cooling to room temperature within 15 minutes. For the best solubility of MBZ, it is important that steps (1) to (3) are carried out before the addition of water in step (4). In other preferred embodiments, one or more other components such as a viscosity modifier or gelling agent may be pre-mixed or pre-dissolved in water before step (4).

[0084]

Table 9

[0085] To prevent precipitation of MBZ from the compositions of Table 2, 8 or 9, 2-10% cyclodextrin compound (preferably hydroxypropyl β-cyclodextrin (Cavasol® W7 HP)) may optionally but preferably be added to the composition. When using a cyclodextrin compound, it is preferably first dissolved in deionized water before adding a viscosity modifier (preferably hydroxyethyl cellulose (Natrosol)). In other preferred embodiments, other viscosity modifiers such as carboxymethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate, carbomer, or other pharmaceutically acceptable viscosity modifiers may be used instead of or in addition to hydroxyethyl cellulose (Natrosol). As will be understood by those skilled in the art, other components that can improve or maintain the stability of the compositions according to the present invention, for example, antioxidants including ascorbic acid or ascorbate or ascorbyl ester, ferulic acid, ubiquinone, dl-α tocopherol, BHT, BHA, or other pharmaceutically acceptable antioxidants, may be added to the compositions according to the preferred embodiments herein. Such antioxidant components may be beneficial to improve or maintain the stability of MBZ products.

[0086] Various other approaches have been made and published to increase the water solubility and GI absorption of the use of mebendazole as an anthelmintic. Any known method or composition for increasing the water solubility and / or dermal absorption of mebendazole may also be used in combination with the compositions and methods according to the preferred embodiments of the present invention.

[0087] According to still other preferred embodiments, topical compositions, MBZ concentrated compositions, and MBZ therapeutic compositions comprise the components and amounts described in one or more of the following paragraphs.

[0088] (A) A topical composition for treating or preventing an inflammatory or autoimmune disease or condition of human skin, the topical composition containing 0.25 to 20% of one or more benzimidazole compounds based on the weight of the topical composition.

[0089] (B) Further comprising a carrier suitable for application to human skin, and / or the topical composition having a viscosity of about 10,000 to 400,000 centipoises, and / or the benzimidazole having a particle size of about 3.5 to 4.0 microns as a component before dissolving in the topical composition, the topical composition according to paragraph (A).

[0090] (C) The topical composition according to paragraph (B), wherein the carrier comprises a cream, a gel, a lotion, a liquid, an emulsion, a microemulsion, an aerosol spray, a non-aerosol spray, a serum, a solution, a suspension, or an ointment.

[0091] (D) The topical composition according to paragraph (B) or (C), wherein the carrier is non-aqueous.

[0092] (E) The topical composition according to paragraph (B) or (C), wherein the carrier is aqueous.

[0093] (F) The topical composition according to any one of paragraphs (A) to (E), wherein the one or more benzimidazole compounds include mebendazole.

[0094] (G) The topical composition according to any one of paragraphs (A) to (F), wherein the disease or condition includes any form of eczema.

[0095] (H) The topical composition according to any one of paragraphs (A) to (G), wherein the one or more benzimidazole compounds include one or more of mebendazole, fenbenzadole, albenzadole, and thiabenzadole.

[0096] (I) The topical composition contains about 1 to 30% mebendazole concentrate composition and / or about 70 to 99% vehicle or carrier composition suitable for application to human skin, and these ratios are based on the weight of the topical composition. The topical composition described in any of paragraphs (A) to (H).

[0097] (J) The topical composition of paragraph (I), wherein the mebendazole concentrate composition contains: (1) about 1 to 10% mebendazole, (2) about 32 to 45% sorbitol-based solvent, (3) about 15 to 25% glycol-based solvent including ethylene glycol-based solvent, propylene glycol-based solvent or both, and / or (4) a total of about 32 to 45% solubilizer, emulsifier or both, and these ratios are based on the weight of the mebendazole concentrate. The topical composition.

[0098] (K) The sorbitol-based solvent contains dimethyl isosorbide, the ethylene glycol-based solvent contains diethylene glycol monoethyl ether, the propylene glycol-based solvent contains propylene glycol monolaurate, and / or the solubilizer contains polyoxyl 40 hydrogenated castor oil. The topical composition described in paragraph (J).

[0099] (L) The topical composition contains about 0.01 to 1% mebendazole based on the weight of the topical composition. The topical composition described in any of paragraphs (A) to (K).

[0100] (M) An aqueous mebendazole therapeutic composition for topically treating or preventing inflammatory or autoimmune diseases or conditions of human skin, which contains about 0.01 to 1% of one or more benzimidazole compounds, about 5 to 25% sorbitol-based solvent, and / or about 15 to 50% glycol-based solvent including ethylene glycol-based solvent, propylene glycol-based solvent or both, and these ratios are based on the weight of the mebendazole therapeutic composition. The aqueous mebendazole therapeutic composition.

[0101] (N) The one or more benzimidazole compounds include mebendazole, the sorbitol-based solvent includes dimethyl isosorbide, the ethylene glycol-based solvent includes diethylene glycol monoethyl ether, the propylene glycol-based solvent includes propylene glycol monolaurate, the aqueous mebendazole composition has a viscosity of about 10,000 to 400,000 centipoise, and / or mebendazole has a particle size of about 3.5 to 4.0 microns as a component before dissolving in the aqueous mebendazole composition, the aqueous mebendazole therapeutic composition described in paragraph (M).

[0102] (O) The aqueous mebendazole therapeutic composition according to any one of paragraphs (M) to (N) further includes a solubilizer, an emulsifier, or both of them in a total amount of about 1 to 10%, a cyclodextrin compound in an amount of about 1 to 15%, and / or a viscosity modifier in an amount of about 0.5 to 3%.

[0103] (P) The solubilizer includes polyoxyl 40 hydrogenated castor oil, the cyclodextrin compound includes hydroxypropyl β-cyclodextrin, and / or the viscosity modifier includes hydroxyethyl cellulose, the aqueous mebendazole therapeutic composition described in paragraph (O).

[0104] (Q) The composition is a gel, the aqueous mebendazole therapeutic composition according to any one of paragraphs (M) to (P).

[0105] (R) The glycol-based solvent is diethylene glycol monoethyl ether and propylene glycol monolaurate with a weight ratio of about 55:45 to 65:35, the aqueous mebendazole therapeutic composition according to any one of paragraphs (M) to (R).

[0106] According to still another preferred embodiment, a method for treating or preventing an inflammatory or autoimmune disease or condition of the skin of a human or an animal includes the steps, components, and amounts described in one or more of the following paragraphs.

[0107] (S) A method for treating or preventing an inflammatory or autoimmune disease or condition of human skin, comprising applying to a skin area of a subject suffering from said disease or condition a topical composition comprising (1) one or more benzimidazole compounds in an amount of 0.25 to 20% by weight and a carrier, (2) a topical composition as described in any of paragraphs (A)-(L), or (3) an aqueous mebendazole therapeutic composition as described in any of paragraphs (M)-(R).

[0108] (T) The method according to paragraph (S), wherein the carrier is aqueous.

[0109] (U) The method according to paragraph (S), wherein the carrier is non-aqueous.

[0110] (V) The method according to any of paragraphs (S)-(U), wherein the carrier comprises a cream, gel, lotion, liquid, emulsion, microemulsion, aerosol spray, non-aerosol spray, serum, solution, suspension, or ointment for topical application to the skin.

[0111] (W) The method according to any of paragraphs (S)-(V), wherein the one or more benzimidazole compounds comprise mebendazole and the disease or condition comprises any form of rosacea.

[0112] (X) The method according to any of paragraphs (S)-(W), wherein the applying step is repeated at least once a day for a treatment period of at least 2 weeks.

[0113] (Y) The method according to any of paragraphs (S)-(X), wherein the applying step comprises applying about 0.025 to 0.5 g of the topical composition to each side of the skin of the face affected by rosacea.

[0114] (Z) The method according to any of paragraphs (S)-(Y), wherein a reduction of at least 50% is achieved in the number of cytotoxic CD+8 cells in the skin area at the end of the treatment period as compared to the number of cytotoxic CD+8 T cells in that area before the treatment period.

[0115] The method according to any one of paragraphs (S) to (Z), achieving a reduction of 25% or more in the number of papules or pustules or the intensity of diffuse erythema in the area of the skin at the end of the treatment period compared to the number of papules or pustules or the intensity of diffuse erythema in the area before the treatment period.

[0116] (BB) Further comprising repeating the step of applying at least once a day over a treatment period including at least 12 weeks, wherein the one or more benzimidazole compounds include mebendazole, and the carrier includes a cream, gel, lotion, liquid, emulsion, microemulsion, aerosol spray, non-aerosol spray, serum, solution, suspension, or ointment for topical application to the skin, the disease or condition includes any form of rosacea, and / or the method achieves a reduction of 50% or more in the number of skin cytotoxic CD+8 T cells in the area of the skin at the end of the treatment period compared to the number of skin cytotoxic CD+8 T cells in the area before the treatment period, the method according to any one of paragraphs (S) to (AA).

[0117] According to yet another preferred embodiment, a method for manufacturing a mebendazole therapeutic composition for topically treating or preventing an inflammatory or autoimmune disease or condition of human skin includes the steps, components, and amounts described in one or more of the following paragraphs.

[0118] (CC) A method for manufacturing a mebendazole therapeutic composition for topically treating or preventing an inflammatory or autoimmune disease or condition of human skin, comprising: (1) adding an amount of one or more solvents and an amount of mebendazole to form a first mixture; and (2) heating the first mixture to a first temperature within a first temperature range for a first period while mixing or stirring to form a heated mixture, wherein the amount of mebendazole is about 0.05 - 0.2% by weight of the mebendazole therapeutic composition.

[0119] (DD) The first period is about 5 to 20 minutes, and / or the first temperature range is at least 60 °C and less than the temperature at which mebendazole experiences a decomposition of 5% or more, the method described in paragraph (CC).

[0120] (EE) The amount of mebendazole is 0.05 to 0.15%, the method described in any of paragraphs (CC) to (DD).

[0121] (FF) The first temperature range is 60 to 90 °C, the method described in any of paragraphs (CC) to (EE).

[0122] (GG) The first temperature range is 70 to 90 °C, the method described in any of paragraphs (CC) to (EE).

[0123] (HH) The first period is 5 to 15 minutes, the method described in any of paragraphs (CC) to (GG).

[0124] (II) The one or more solvents include a sorbitol-based solvent, a glycol-based solvent, or both, the method described in any of paragraphs (CC) to (HH).

[0125] (JJ) The method described in paragraph (II), wherein (1) the sorbitol-based solvent includes dimethyl isosorbide, and / or (2) the glycol-based solvent includes diethylene glycol monoethyl ether, propylene glycol monolaurate, or both.

[0126] (KK) Further including the step of cooling the heated composition to a second temperature within a second temperature range by adding water and mixing or stirring, the second temperature range being about 35 to 50 °C, the method described in any of paragraphs (CC) to (JJ).

[0127] (LL) The cooling step is completed within 15 minutes, the method described in paragraph (KK).

[0128] The method according to any one of paragraphs (KK) to (LL), further comprising the step of dissolving an amount of a viscosity modifier, an amount of an anti-precipitant, or both in water before the step of cooling.

[0129] The method according to paragraph (MM), wherein the viscosity modifier comprises hydroxyethyl cellulose.

[0130] The method according to (OO), wherein the precipitant comprises a cyclodextrin compound, the anti-precipitant comprises a cyclodextrin compound, and the amount of the anti-precipitant is about 2 to 10% based on the weight of the mebendazole therapeutic composition.

[0131] The method according to paragraph (OO), wherein the cyclodextrin compound comprises hydroxypropyl β-cyclodextrin.

[0132] The method according to any one of (CC) to (PP), wherein the heated composition is microfluidized at least once at 14,000 psi with a microfluidizer.

[0133] The method according to paragraph (QQ), wherein the heated composition is microfluidized at least three times at 14,000 psi with a microfluidizer.

[0134] The method according to any one of (CC) to (PP), which does not include the microfluidization step.

[0135] The method according to any one of (CC) to (SS), wherein the mebendazole therapeutic composition has a viscosity of about 10,000 to 400,000 centipoises.

[0136] The method according to any one of (CC) to (TT), further comprising the step of micronizing mebendazole to a particle size of about 3.5 to 4.0 microns before the adding step.

[0137] (VV) The method of any of paragraphs (CC), (EE), or (II)-(SS), wherein the first temperature range is 25 to 50° C. and the first period of time is 15 to 30 minutes.

[0138] Preferred embodiments of the compositions and methods according to the present invention can achieve one or more of the following benefits: (1) reducing T-lymphocyte cell density by at least about 50%, more preferably at least about 90%, compared to before treatment with the mebendazole composition; (2) reducing the number of papules and / or pustules or diffuse redness on the skin of a rosacea patient by at least about 25%, more preferably at least about 75%, compared to before treatment with the mebendazole composition; (3) reducing the appearance of skin swelling compared to before treatment with the mebendazole composition; (4) reducing the level of skin itching compared to before treatment with the mebendazole composition; and (5) reducing the level of redness "a" or "b" of facial skin with topical mebendazole treatment in the treatment of erythematotelangiectatic rosacea. * A significant decrease in the value of "a" or "a * " values ​​are Hunter L, a, b (Hunter Lab) and CIE L * a * b * It is an objective measurement of redness as measured by a CIELAB colorimeter, a Minolta CR type colorimeter, or other suitable colorimeter or color difference meter. The visible change in redness can vary as low as 0.2 colorimeter a units. * can be detected in units of 1 (1.0) or more after topical treatment of erythematotelangiectatic rosacea. * A reduction in colorimetric units is generally considered to indicate clinical effectiveness.

[0139] Preferred embodiments of the MBZ therapeutic compositions and methods according to the present invention are also capable of achieving cumulative skin penetration after 24 hours of at least 5 μg of MBZ, more preferably at least 10 μg, and most preferably at least 15 μg. These amounts were measured in receptor solutions using the skin PAMPA test described herein, and were measured using a 0.3 cm dose of the MBZ therapeutic composition. 2It is premised on applying 150 μL to the artificial skin membrane.

[0140] All numerical values, ratios, or percentages shown in this specification as ranges include any subset combination within the range, including each individual quantity, numerical value, or ratio within those ranges and overlapping subsets from a preferred range to a more preferred range. Also, any component other than benzimidazole described as being included in the embodiments of this specification may be excluded from such embodiments. Unless otherwise specified, any preferred feature described in this specification, any optional component, any embodiment of a composition, and / or any step of a method can be used in combination with any other embodiment even if not specifically described for that particular embodiment in this specification. When referring to water (without any modifiers) in this specification, examples include drinking water, distilled water, deionized water, or other forms of purified water, filtered water, or clean water suitable for use in topical skin treatment compositions. These forms of water can be used in place of the reference to deionized water in this specification outside of the claims. Those skilled in the art will understand, upon reading this specification, that modifications and changes to the preferred embodiments of the compositions and their methods of use, including the examples included in this specification, are possible within the scope of the present invention. Also, the scope of the present invention disclosed in this specification is limited only by the broadest interpretation of the appended claims.

Claims

1. A topical composition for treating or preventing diseases or conditions of human skin, A topical composition comprising one or more benzimidazole compounds in an amount of 0.01 to 0.10% by weight of the topical composition.

2. A carrier suitable for application to human skin, An ethylene glycol-based solvent containing diethylene glycol monoethyl ether, It includes, The aforementioned one or more benzimidazole compounds include mebendazole. The topical composition is suitable for application to areas of human skin having the aforementioned disease or condition. The topical composition according to claim 1, wherein the disease or condition is essentially inflammatory or autoimmune.

3. The carrier includes creams, gels, lotions, liquids, emulsions, microemulsions, aerosol sprays, non-aerosol sprays, serums, solutions, suspensions, or ointments. The topical composition according to claim 2, wherein no active ingredients other than the one or more mebendazole compounds are present in the topical composition.

4. The aforementioned topical composition does not contain dimethyl sulfoxide and does not contain dimethylacetamide. The topical composition according to claim 1, wherein no active ingredients other than mebendazole are present in the topical composition.

5. The aforementioned carrier is aqueous, Mebendazole and the ethylene glycol-based solvent are heated to 60°C to 90°C for 5 to 20 minutes to form a mebendazole solution. The topical composition according to claim 3, wherein the topical composition comprises a mixture of the mebendazole solution and the carrier.

6. The one or more benzimidazole compounds and the solvent are part of a benzimidazole solution that is heated to a temperature in the range of 60°C to 90°C for 5 to 20 minutes. The topical composition comprises the benzimidazole solution and the carrier, The aforementioned solvent contains diethylene glycol monoethyl ether, The aforementioned one or more benzimidazole compounds include mebendazole. The topical composition according to claim 1, wherein the disease or condition includes any form of rosacea.

7. The topical composition according to claim 1, wherein the one or more benzimidazole compounds include one or more of mebenzador, fenbenzador, albenzador, and thiabenzador.

8. The aforementioned topical composition contains approximately 0.15 to 5.5% diethylene glycol monoethyl ether. The topical composition according to claim 2, wherein the disease or condition includes any form of rosacea.

9. The topical composition according to claim 2, wherein the topical composition has a viscosity of about 10,000 to 400,000 centipoise.

10. The topical composition according to claim 2, wherein mebendazole is micronized to a particle size of approximately 3.5 to 4.0 microns.

11. The aforementioned topical composition further contains 56% or more water, The aforementioned one or more benzimidazole compounds contain a mebendazole solution. The mebendazole solution comprises mebendazole and a solvent, which are heated together at a temperature in the range of 60°C to 90°C for 5 to 20 minutes. The aforementioned solvent contains diethylene glycol monoethyl ether, No active ingredients other than mebendazole are present in the aforementioned topical composition. The aforementioned topical composition does not contain dimethyl sulfoxide and does not contain dimethylacetamide. The topical composition according to claim 1, wherein the disease or condition includes any form of rosacea.

12. The aforementioned one or more benzimidazole compounds include mebendazole. The topical composition comprises, by weight percentage, about 1 to 30% of a mebendazole concentrate and about 70 to 99% of a vehicle composition suitable for application to human skin. The mebendazole concentrate is, in weight percentage of the mebendazole concentrate, (1) Approximately 1-10% mebendazole, (2) Approximately 32-45% sorbitol-based solvent, (3) an ethylene glycol-based solvent, a propylene glycol-based solvent, or a glycol-based solvent containing both thereof, (4) A total of approximately 32-45% solubilizers, emulsifiers, or both, A topical composition according to claim 1, comprising:

13. The sorbitol-based solvent contains dimethyl isosorbide, The ethylene glycol-based solvent contains diethylene glycol monoethyl ether, The aforementioned propylene glycol-based solvent contains propylene glycol monolaurate, The topical composition according to claim 12, wherein the solubilizer comprises polyoxyl 40 hydrogenated castor oil.

14. A topical aqueous mebendazole therapeutic composition, Suitable for treating or preventing inflammatory or autoimmune human skin diseases or conditions, the aqueous mebendazole therapeutic composition for topical use contains an active ingredient comprising approximately 0.01 to 0.10% mebendazole by weight percentage, An ethylene glycol-based solvent containing diethylene glycol monoethyl ether, The aforementioned aqueous mebendazole therapeutic composition for topical use contains 56% or more water by weight, Dimethyl isosorbide and, Propylene glycol monolaurate and A topical aqueous mebendazole therapeutic composition containing the above-ground components.

15. A total of approximately 1-10% solubilizer or emulsifier, or both, Approximately 1-15% cyclodextrin compounds, Approximately 0.5-3% viscosity modifier, The aqueous mebendazole therapeutic composition according to claim 14, further comprising:

16. The aforementioned solubilizer contains polyoxyl 40 hydrogenated castor oil, The cyclodextrin compound mentioned above contains hydroxypropyl β-cyclodextrin, The topical aqueous mebendazole therapeutic composition according to claim 15, wherein the viscosity modifier comprises hydroxyethylcellulose.

17. The benzimidazole compound is present in a mebendazole concentrate composition comprising mebendazole, oil, and a solvent. The mebendazole concentrate is formed by (1) mixing mebendazole, oil, and a solvent, heating at 60°C to 90°C for 5 to 20 minutes to form a mebendazole solution, and (2) passing the mebendazole solution through a microfluidizer to form a mebendazole concentrate. The topical composition according to claim 1, wherein the topical composition contains 0.01 to 0.25% by weight of mebendazole.

18. The topical composition comprises an emulsion of 70 to 99% by weight of an aqueous carrier and 1 to 30% by weight of the mebendazole concentrate composition, The topical composition according to claim 17, wherein the solvent comprises diethylene glycol monoethyl ether.

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