Station naphthifin composition

Abstract

The present disclosure provides a topical sprayable composition comprising (a) about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof, (b) a film-forming agent comprising an octylacrylamide acrylate copolymer, and (c) an alcohol solvent, wherein the ratio of the alcohol solvent to the propellant in the composition is from about 1:1 to about 3:1 (w / w). The present disclosure also provides a method of treating dermatophyte skin infection or onychomycosis in a subject in need thereof, the method comprising topically administering to the subject the topical composition described herein.

Description

Technical Field

[0001] The present disclosure provides a topical sprayable composition comprising (a) about 0.05 wt% to about 5 wt% of naphthifine or a pharmaceutically acceptable salt thereof, (b) a film-forming agent comprising octylacrylamide acrylate copolymer, (c) an alcohol solvent, and (d) a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is from about 1:1 to about 3:1 (w / w). The present disclosure also provides a drug-device combination for dispensing the compositions disclosed herein. Additionally, the present disclosure also provides a method of treating dermatophyte skin infections or onychomycosis in a subject in need thereof, the method comprising topically administering to the subject a topical spray composition described herein. Background Art

[0002] Dermatophyte skin infections are common in human populations. Tinea pedis is commonly known as "athlete's foot" and is a fungal infection of the soles of the feet and the spaces between the toes, for example, by dermatophytes. Symptoms include itching, a stinging sensation, and a burning sensation, and include skin cracks, blisters, or peeling areas. Tinea cruris is a dermatophyte infection that affects the skin of the groin, genitals, perineum, and around the anus. It is common in athletes and people who often sweat in areas where moisture tends to accumulate, and tinea cruris is also referred to as "jock itch". The infection causes redness, scaling, peeling, or cracking of the skin in the groin area, and can cause an unpleasant odor if the infection is severe or left untreated. Tinea pedis and tinea cruris are caused by various fungi, the most common being Trichophyton rubrum, Trichophyton interdigitale, Tinea capitis, and Epidermophyton floccosum, Tinea corporis, also known as "ringworm", is a dermatophyte infection characterized by redness, itching, and circular rashes or lesions on the skin of any part of the body except the scalp, groin, palms, and soles. Dermatophyte infections can recur if not effectively treated and can lead to other serious medical conditions. In addition, individuals with at least one dermatophyte infection on their body can develop other dermatophyte infections in other parts of the body. Onychomycosis is a fungal infection of the nails that causes discoloration, thickening, and separation from the nail bed.

[0003] Currently, various creams and ointments are commercially available for the treatment of dermatophyte infections such as tinea pedis and onychomycosis. Commercial formulations include the active ingredients terbinafine (LAMISIL®) and Lamisil Once, naftifine (NAFTIN®), and luliconazole (LUZU®), as well as various azoles such as clotrimazole. However, creams and ointments can be difficult to apply, inconvenient, and may involve a cumbersome application process.

Summary of the Invention

[0004] The present disclosure relates to a sprayable topical composition comprising (a) about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof, (b) a film-forming agent comprising octylacrylamide acrylate copolymer; (c) an alcohol solvent; and (d) a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

[0005] In one embodiment, the present disclosure relates to a topical composition comprising (a) about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof, (b) a film-forming agent; (c) an alcohol solvent; and (d) a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is about 1:1 to about 3:1 (w / w).

[0006] In some embodiments, the naftifine or a pharmaceutically acceptable salt thereof is naftifine hydrochloride. In some embodiments, the composition comprises about 1% to about 3% of naftifine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 2% of naftifine or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the composition comprises about 2% to about 10% w / w of octylacrylamide acrylate copolymer. In some embodiments, the composition comprises about 2% to about 4% w / w of octylacrylamide acrylate copolymer. In some embodiments, the ratio of the film-forming agent to the alcohol solvent in the composition is about 1:15 to 1:30 (w / w). In some embodiments, the ratio of the film-forming agent to the alcohol solvent in the composition is about 1:18 to 1:22 (w / w).

[0008] In some embodiments, the composition comprises less than 4% of a hydrophilic polymer. In some embodiments, the composition comprises less than 0.5% of a hydrophilic polymer.

[0009] In some embodiments, the alcohol solvent is C 1-6 alcohol. In some embodiments, C 1-6The alcohol is methanol, ethanol, propyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol, or a combination thereof.

[0010] In some embodiments, the alcohol solvent has a viscosity of about 1 cp to about 150 cp. In some embodiments, the composition comprises about 10 wt% to about 70 wt% of an alcohol solvent. In some embodiments, the composition comprises about 50 wt% to about 70 wt% of an alcohol solvent. In some embodiments, the composition comprises less than 70 wt% of an alcohol solvent.

[0011] In some embodiments, the composition has a viscosity of about 0.1 cp to about 500 cp. In some embodiments, the composition has a viscosity of about 1 cp to about 150 cp.

[0012] In some embodiments, the propellant is a hydrocarbon propellant, a fluorocarbon propellant, a hydrofluorocarbon propellant, or a combination thereof. In some embodiments, the propellant is propane, isobutane, n-butane, isopentane, n-pentane, or a combination thereof. In some embodiments, the propellant is a hydrofluorocarbon propellant. In some embodiments, the hydrofluorocarbon propellant is 1,1,1,2-tetrafluoroethane (Norflurane 134A; HFA-134a) or 1,1-difluoroethane (HFA-152a). In some embodiments, the composition comprises about 10 wt% to about 50 wt% of a propellant. In some embodiments, the composition comprises about 25 wt% to about 45 wt% of a propellant.

[0013] In some embodiments, the ratio of the alcohol solvent to the propellant is from about 1.5:1 to about 2.5:1 (w / w). In some embodiments, the ratio of the alcohol solvent to the propellant is from about 1:1 to 2:1 (w / w). In some embodiments, the ratio of the alcohol solvent to the propellant is from about 2:1 to 3:1 (w / w). In some embodiments, the ratio of the film-forming agent to the propellant is from about 1:7 to 1:15 (w / w). In some embodiments, the ratio of the film-forming agent to the propellant is from about 1:8 to 1:12 (w / w).

[0014] In some embodiments, the composition further comprises a penetration enhancer, a co-solvent, an emulsifier, a solubilizer, or a combination thereof. In some embodiments, the penetration enhancer is diethylene glycol monoethyl ether, diethyl phthalate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactic acid ester, oleyl alcohol, alkyl glycoside, saccharide alkyl ester, dimethylformamide, isopropyl myristate, a mixture of Tween80, sodium lauryl sulfate, oleic acid and octyldimethyl para-aminobenzoic acid, or a combination thereof. In some embodiments, the penetration enhancer is a combination of propylene glycol and diethylene glycol monoethyl ether. In some embodiments, the composition comprises from about 0.1% to about 7% (w / w) of the penetration enhancer. In some embodiments, the composition comprises from about 0.5% to about 2.5% (w / w) of the penetration enhancer.

[0015] In some embodiments, the present disclosure provides a sprayable topical composition comprising: (a) from about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof; (b) a film-forming agent comprising an octylacrylamide acrylate copolymer; (c) from about 50 wt% to about 75 wt% of an alcohol solvent; and (d) from about 20 wt% to about 45 wt% of a propellant.

[0016] In some embodiments, the present disclosure provides a sprayable topical composition comprising (a) from about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof, (b) from about 1 wt% to about 5 wt% of a film-forming agent comprising octylacrylamide acrylate copolymer, (c) from about 25 wt% to about 45 wt% of a propellant, (d) from about 50 wt% to about 70 wt% of an alcohol solvent, and (e) from about 1 wt% to about 3.5 wt% of a penetration enhancer.

[0017] In one embodiment, the present disclosure provides a sprayable topical composition comprising (a) from about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof, (b) from about 1 wt% to about 5 wt% of a film-forming agent, (c) from about 25 wt% to about 45 wt% of a propellant, (d) from about 50 wt% to about 70 wt% of an alcohol solvent, and (e) from about 1 wt% to about 3.5 wt% of a penetration enhancer.

[0018] In some embodiments, the present disclosure provides a delivery device comprising the topical composition described herein. In some embodiments, the delivery device is a sealed pressurized device. In some embodiments, the pressure in the sealed pressurized device is from about 28 psi to about 145 psi at 25°C. In some embodiments, the delivery device comprises means for providing an aerosol spray of the topical composition. In some embodiments, the delivery device comprises means for providing a non-aerosol spray of the topical composition.

[0019] In some embodiments, the present disclosure provides a product for manufacture for the treatment of dermatophyte skin infection or onychomycosis in a subject in need thereof, comprising (a) (i) the topical composition described herein, and (ii) a sealed pressurized container comprising means for providing an aerosol spray of the topical composition, and (b) instructions for use of the topical composition for the treatment of dermatophyte skin infection or onychomycosis.

[0020] In some embodiments, the present disclosure provides a method of treating dermatophyte skin infections or onychomycosis in a subject in need thereof, the method comprising topically administering to the subject a topical composition described herein. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris. In some embodiments, administering comprises applying the topical composition to the subject in an aerosol spray.

[0021] In some embodiments, the composition is administered no more than once during a 3-day period. In some embodiments, the composition is administered no more than once during a 1-week period. In some embodiments, the composition is administered no more than once during a 2-week period. In some embodiments, the topical composition is administered to the subject no more than twice to reduce the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is administered to the subject once to reduce the dermatophyte skin condition or onychomycosis. In some embodiments, the method comprises a first administration of the topical composition and a second administration of the topical composition. In some embodiments, the second composition is 5 to 10 days after the first administration. In some embodiments, the second composition is about 7 days after the first administration.

[0022] In some embodiments, the efficacy of treatment of the dermatophyte skin condition is determined by (a) (i) comparing the clinical signs and symptoms associated with tinea pedis in a subject treated with the topical composition with (ii) a subject treated with a placebo treatment; and / or (b) (i) comparing the mycological cure rate (i.e., potassium hydroxide staining and fungal culture results) in a subject treated with the topical composition with (ii) a subject treated with a placebo. In some embodiments, the systemic average level of naftifine after a single application of the topical spray composition is about 100 pg / mL after 4 weeks.

[0023] In some embodiments, the present disclosure provides a method for treating dermatophyte skin infections or onychomycosis in a patient, the method comprising administering to the subject two doses of a topical composition comprising naftifine, the topical composition being a single-phase solution, the naftifine being present at at least 80% saturation under the conditions of use, and the second dose being administered approximately one week after the first dose. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0024] In some embodiments, the present disclosure provides a method for treating dermatophyte skin infections or onychomycosis in a patient, the method comprising administering to the subject one dose of a topical composition comprising naftifine, the topical composition being a single-phase solution, the naftifine being present at at least 80% saturation under the conditions of use. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0025] In some embodiments, the present disclosure provides a method for maintaining a therapeutic level of naftifine in the stratum corneum of a subject above the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antimicrobial agent required to inhibit the visible in vitro growth of a challenge microorganism.

[0026] In some embodiments, the present disclosure provides a method for maintaining a therapeutic level above the MIC of naftifine in the stratum corneum of a subject for 1, 2, 4, or 8 weeks, the method comprising administering to the subject two doses of a topical composition comprising naftifine, the composition being a single-phase solution, the pharmaceutical being present at at least 80% saturation under the conditions of use, and the second dose being administered approximately one week after the first dose. In some embodiments, the amount of naftifine in the stratum corneum of the subject 4 weeks after the first dose and 3 weeks after the second dose is on average half of the amount extracted with the second dose.

[0027] In some embodiments, the present disclosure provides a method for maintaining a therapeutic level in the stratum corneum of a subject that exceeds the MIC of naftifine for 1, 2, 4, or 8 weeks, the method comprising administering a single dose of a topical composition comprising naftifine to the subject, the composition being a single-phase solution, and the pharmaceutical being present at at least 80% saturation under the conditions of use.

[0028] In some embodiments, the present disclosure provides a method for treating dermatophyte skin infections or onychomycosis in a subject in need thereof, the method comprising administering a sprayable topical composition comprising 2% naftifine or a pharmaceutically acceptable salt thereof, the topical composition being administered to the patient in 1 or 2 doses, and when 2 doses are used, the second dose being administered approximately 1 week after the first dose, and the administration of the topical composition to the subject resulting in at least 10%, 20%, 30%, 40%, or 50% success in the efficacy evaluation items. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris. In some embodiments, efficacy is measured using mycological cure (KOH and fungal culture), treatment efficacy (defined as negative KOH staining, negative fungal culture, and absence or mild erythema, scaling, and pruritus), and clinical cure (defined as absence of erythema, scaling, and pruritus). In some embodiments, the primary efficacy evaluation item is to achieve complete clearance at day 42 (6 weeks), defined as negative KOH, negative fungal culture, and absence of individual signs and symptoms (i.e., erythema, scaling, and pruritus). In some embodiments, the percentage of subjects to whom the topical composition is administered achieves the primary efficacy evaluation item that is twice the percentage of subjects receiving placebo or not being treated.

[0029] In some embodiments, the present disclosure provides a method of treating dermatophyte skin infections or onychomycosis in a subject, the method comprising administering a topical composition comprising naftifine, the composition being a single-phase solution, the pharmaceutical being present at at least 80% saturation under the conditions of use, and the administration of the topical composition to the subject resulting in complete clearance of symptoms with improvement in relevant parameters selected from (a) a decrease in the severity of erythema from baseline with a score of 0 at day 42; (b) a decrease in the severity of scaling from baseline with a score of 0 at day 42; (c) a decrease in the severity of pruritus from baseline with a score of 0 at day 42, or combinations thereof. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0030] In some embodiments, the present disclosure provides a method of treating dermatophyte skin infections in a subject, the method comprising administering a topical sprayable composition comprising naftifine, the composition being a single-phase solution, the pharmaceutical being present at at least 80% saturation under the conditions of use, and the administration of the topical composition to the subject resulting in a treatment efficacy of at least 20%, the treatment efficacy being a negative KOH stain, a negative fungal culture, and the absence or mild erythema, scaling, and pruritus at 6 weeks post-treatment.

[0031] In some embodiments, the method comprises administering a single dose of the topical sprayable composition. In some embodiments, the method comprises administering 2 doses of the topical sprayable composition. In some embodiments, the administration of the topical composition to the subject results in a treatment efficacy of at least 40%. In some embodiments, the administration of the topical composition to the subject results in a treatment efficacy of at least 70%.

[0032] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a composition comprising naftifine or a pharmaceutically acceptable salt thereof, a film-forming agent comprising octylacrylamide acrylate copolymer, an alcohol solvent, and a container comprising a propellant, the drug-device combination being suitable for providing a spray comprising the composition, the spray having a D 90 droplet size greater than 1 μm.

[0033] In some embodiments, the composition of the drug-device combination has a D 90 droplet size of from about 140 μm to about 170 μm when sprayed from the device. In some embodiments, the composition of the drug-device combination has a D 90 droplet size of from about 150 μm to about 165 μm when sprayed from the device. In some embodiments, the composition of the drug-device combination has an average D 90 droplet size of from about 155 μm to 163 μm when sprayed from the device.

[0034] In some embodiments, the composition of the drug-device combination comprises naftifine or a pharmaceutically acceptable salt thereof is naftifine hydrochloride. In some embodiments, the composition of the drug-device combination comprises from about 1% to about 3% naftifine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition of the drug-device combination comprises about 2% naftifine or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the composition of the drug-device combination comprises from about 2% to about 10% w / w octylacrylamide acrylate copolymer. In some embodiments, the composition of the drug-device combination comprises from about 2% to about 4% w / w octylacrylamide acrylate copolymer. In some embodiments, the composition of the drug-device combination comprises a composition, and the ratio of the film-forming agent to the alcohol solvent in the composition is from about 1:15 to 1:30 (w / w). In some embodiments, the composition of the drug-device combination comprises a composition, and the ratio of the film-forming agent to the alcohol solvent in the composition is from about 1:18 to 1:22 (w / w).

[0036] In some embodiments, the composition of the drug-device combination comprises less than 4% hydrophilic polymer. In some embodiments, the composition of the drug-device combination comprises a composition comprising less than 0.5% hydrophilic polymer.

[0037] In some embodiments, the alcohol solvent of the composition of the drug-device combination is a C1-C6 alcohol. In some embodiments, the C1-C6 alcohol of the composition of the drug-device combination is methanol, ethanol, propyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol, or a combination thereof. In some embodiments, the C1-C6 alcohol of the composition of the drug-device combination is ethanol.

[0038] In some embodiments, the alcohol solvent of the composition of the drug-device combination has a viscosity of from about 1 cp to about 150 cp. In some embodiments, the composition of the drug-device combination comprises from about 10 wt% to about 70 wt% alcohol solvent. In some embodiments, the composition of the drug-device combination comprises from about 50 wt% to about 70 wt% alcohol solvent.

[0039] In some embodiments, the drug-device combination comprises a composition having a viscosity of from about 0.1 cp to about 500 cp. In some embodiments, the drug-device combination comprises a composition having a viscosity of from about 1 cp to about 150 cp.

[0040] In some embodiments, the propellant of the composition of the drug-device combination is a hydrocarbon propellant, a fluorocarbon propellant, a hydrofluorocarbon propellant, or a combination thereof. In some embodiments, the propellant of the composition of the drug-device combination is propane, iso-butane, n-butane, isopentane, n-pentane, or a combination thereof. In some embodiments, the propellant of the composition of the drug-device combination is a hydrofluorocarbon propellant. In some embodiments, the hydrofluorocarbon propellant of the composition of the drug-device combination is 1,1,1,2-tetrafluoroethane (norflurane 134A; HFA-134a) or 1,1-difluoroethane (HFA-152a).

[0041] In some embodiments, the composition of the drug-device combination comprises from about 10 wt% to about 50 wt% of a propellant. In some embodiments, the composition of the drug-device combination comprises from about 25 wt% to about 45 wt% of a propellant.

[0042] In some embodiments, the drug-device combination comprises a composition, and the ratio of the alcohol solvent to the propellant is from about 1.5:1 to about 2.5:1 (w / w). In some embodiments, the drug-device combination comprises a composition, and the ratio of the alcohol solvent to the propellant is from about 1:1 to 2:1 (w / w). In some embodiments, the drug-device combination comprises a composition, and the ratio of the alcohol solvent to the propellant is from about 2:1 to 3:1 (w / w). In some embodiments, the drug-device combination comprises a composition, and the ratio of the film-forming agent to the propellant is from about 1:7 to 1:15 (w / w). In some embodiments, the drug-device combination comprises a composition, and the ratio of the film-forming agent to the propellant is from about 1:8 to 1:12 (w / w). In some embodiments, the composition of the drug-device combination further comprises a penetration enhancer, a co-solvent, an emulsifier, a solubilizer, or a combination thereof.

[0043] In some embodiments, the penetration enhancer of the composition of the drug-device combination is diethylene glycol monoethyl ether, diethyl behenate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactate ester, oleyl alcohol, alkyl glycoside, saccharide alkyl ester, dimethylformamide, isopropyl myristate, a mixture of Tween80, sodium lauryl sulfate, oleic acid and octyldimethyl para-aminobenzoic acid, or a combination thereof.

[0044] In some embodiments, the pressure inside the drug-device combination is from about 28 psi to about 145 psi at 25°C.

[0045] In some embodiments, the present disclosure provides a method of treating dermatophyte skin infections or onychomycosis in a subject in need thereof, the method comprising applying an aerosol spray to the skin using the drug-device combination disclosed herein. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris. In some embodiments, the composition is administered no more than once during a 3-day period. In some embodiments, the composition is administered no more than once during a 1-week period. In some embodiments, the composition is administered no more than once during a 2-week period. In some embodiments, the composition is administered to the subject no more than twice, reducing the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is administered once. In some embodiments, the composition is administered in one application.

[0046] In some embodiments, the composition dries in less than 3 minutes after application of the composition to the skin. In some embodiments, the composition dries in less than 2 minutes after application of the composition to the skin. In some embodiments, the composition dries in less than 1 minute after application of the composition to the skin.

[0047] In some embodiments, the method comprises a first administration of the topical composition and a second administration of the composition. In some embodiments, the second administration is 5 to 10 days after the first administration. In some embodiments, the second administration is about 7 days after the first administration. DETAILED DESCRIPTION

[0048] The present disclosure relates to compositions and methods suitable for the treatment of dermatophyte skin infections such as tinea pedis, interdigital tinea pedis, tinea cruris, and tinea corporis or onychomycosis. In some embodiments, the present disclosure provides a topical composition comprising naftifine, such as a topical aerosol spray. Naftifine cream has been previously used in the treatment of dermatophyte infections such as tinea pedis, tinea cruris, and tinea corporis. However, the present disclosure provides a new composition that is a fast-acting, timely and effective treatment with limited / reduced side effects for dermatophyte infections and onychomycosis. The topical composition of the present invention is also non-greasy and dries rapidly. The present disclosure also provides a composition effective for the treatment of dermatophyte infections such as tinea pedis, interdigital tinea pedis, tinea cruris, and tinea corporis, with little blood absorption and thus having a low systemic effect. The topical compositions provided herein have reduced skin erythema, scaling, and itching. In addition, the present disclosure provides a composition for treating dermatophyte infections such as tinea pedis, interdigital tinea pedis, tinea cruris, tinea corporis, and tinea capitis, which is effective when applied in a reduced number of doses, for example, when applied one or two times to a subject in need thereof. In some embodiments, the sprayable composition described herein can be sprayed directly onto the skin surface and need not be spread onto the skin by contact with a finger and / or a separate applicator, avoiding contact of the dermatophyte-affected area with non-infected body parts. In some embodiments, direct application to the skin via spraying provides increased convenience and lower transfer of naftifine to the hands / fingers or other body parts where it is not needed. In some embodiments, the sprayable composition described herein can be applied rapidly. In some embodiments, the sprayable composition described herein can be efficiently applied to areas that are less accessible, such as the interdigital space. In some embodiments, the sprayable composition described herein can be rapidly applied over a large area of the skin.

[0049] Terbinafine is more soluble in alcohol than naftifine, but surprisingly, the topical naftifine compositions of the present invention are completely solubilized in the formulation, achieving skin permeability and skin retention, thereby enabling the clinical antifungal effect after a single application, as obtained with terbinafine Once products.

[0050] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings commonly understood by one of ordinary skill in the art. Further, unless the context requires otherwise, singular terms shall include pluralities and plural terms shall include singulars. As used herein, "a" or "an" can mean one or more. As used herein, when used in conjunction with the term "comprising," the term "a" or "an" can mean one or more. As used herein, "another" or "further" can mean at least a second or more.

[0051] Throughout this application, the term "about" is used to indicate that a value includes the inherent variability of error for the method / device used to determine the variability that exists between the value, or among the subjects being tested. Typically, the term "about" means that, depending on the context, it encompasses variability of approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or less thereof.

[0052] The use of the term "or" in the claims is used to mean "and / or" unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, but this disclosure supports definitions that refer to only alternatives as well as "and / or".

[0053] As used herein, the terms "comprising" (and any variant or form of "comprising", such as "comprise" and "comprises"), "having" (and any variant or form of "having", such as "have" and "has"), or "containing" (and any variant or form of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any embodiment contemplated herein is intended to be practiced with respect to any protein, composition, polynucleotide, vector, cell, method, and / or kit of the present disclosure. Further, the methods and proteins of the present disclosure can be achieved using the compositions, polynucleotides, vectors, cells, and / or kits of the present disclosure.

[0054] The use of the term "for example" and its corresponding abbreviation "e.g." (whether italicized or not) means that the specific terms described are representative examples and embodiments of the disclosure and are not intended to be limited to the specific examples referenced or cited unless expressly stated otherwise.

[0055] As used herein, "between" is an inclusive range of the endpoints of the range. For example, numbers between x and y expressly include the numbers x and y, and any number that falls within x and y.

[0056] The present disclosure provides a sprayable topical composition containing naphthifine, for example, a topical spray composition. In some embodiments, the present disclosure provides a topical composition comprising (a) from about 0.05 wt% to about 5 wt% of naphthifine or a pharmaceutically acceptable salt thereof, (b) a film-forming agent comprising octylacrylamide acrylate copolymer, and (c) an alcohol solvent, wherein the ratio of the alcohol solvent to the propellant in the composition is from about 1:1 to about 3:1 (w / w).

[0057] In one embodiment, the film-forming agent can be one or more of polyvinylpyrrolidone, polyvinyl alcohol, acrylic polymer, acrylic copolymer, methacrylate polymer, octylacrylamide acrylate copolymer, methacrylate copolymer, poly(vinyl acetate), cellulose-based polymer, cellulose-based copolymer, pyroxylin (nitrocellulose), pullulan (polysaccharide polymer), alginate.

[0058] Naphthifine can be represented by Formula I. [Chemical formula]

[0059] As used herein, the term "naphthifine" includes compounds of Formula I, as well as salts, solvates, and stereoisomers thereof. For example, in some embodiments, naphthifine includes naphthifine hydrochloride, as well as other pharmaceutically acceptable salts.

[0060] The concentration of naphthifine can vary in the composition. In some embodiments, the concentration of naphthifine is less than 5 wt% of the composition. In some embodiments, the concentration of naphthifine is less than 4.5 wt%, less than 4.0 wt%, less than 3.5 wt%, or less than 3.0 wt% of the composition. In some embodiments, the composition comprises from about 0.05 wt% to about 5 wt% of naphthifine. In some embodiments, the composition comprises from about 0.05 wt% to about 4 wt%, from about 0.1 wt% to about 3.5 wt%, from about 0.1 wt% to about 3.0 wt%, from about 0.2 wt% to about 3.0 wt%, from about 0.5 wt% to about 2.5 wt%, from about 1.0 wt% to about 3.0 wt%, from about 1.0 wt% to about 2.5 wt%, from about 1.5 wt% to about 2.5 wt%, from about 1.8 wt% to about 2.2 wt%, or about 2.0 wt% of naphthifine.

[0061] The present disclosure provides a topical composition for administration. In some embodiments, the present disclosure provides a topical aerosol spray composition for administration. In some embodiments, the term "topical aerosol spray composition" is a composition in a sealed container under pressure such that an aerosol can be formed upon release from the container, e.g., a pressurized composition. In some embodiments, the topical composition can include a composition with or without pressure. For example, the term "topical composition" can include (i) a liquid composition inside a pressurized container that becomes an aerosol spray when discharged from the container, and (2) an aerosol spray discharged from the container. Additionally, in some embodiments, the term "topical composition" can include a liquid composition on a surface, e.g., a skin surface, that forms when the aerosol spray contacts the surface. In some embodiments, administration by aerosol spray provides more consistent administration of the composition in the subject being treated. In some embodiments, administration by aerosol spray provides more thorough administration of the composition to the subject, e.g., more areas are covered. In some embodiments, administration by aerosol spray provides a more convenient method of administration. In some embodiments, administration by aerosol spray reduces the need for other applicators, e.g., wipes, gauze, cloth, etc. In some embodiments, administration by aerosol spray reduces exposure of the hand or other unintended body parts to the presence of naftifine that can occur with administration by cream, gel, or liquid. In some embodiments, administration by aerosol spray provides a more convenient mode of administration. This is because it allows the composition to dry rapidly after application.

[0062] In some embodiments, the treatment of dermatophyte skin infections or onychomycosis involves applying a topical composition in an aerosol spray. In some embodiments, the topical composition is a single-phase solution. In some embodiments, the topical composition is a saturated, single-phase solution as outlined in U.S. Patent No. 8,349,297, which is hereby incorporated by reference in its entirety. As used herein, the term "single-phase" indicates that the composition contains no undissolved components (such as naftifine or any other excipient), and that only one liquid phase is present and no colloidal or microcolloidal compositions are present. Thus, in some embodiments, the topical composition has only one phase, and the phase is liquid.

[0063] In some embodiments, the term "saturated" can include substantial saturation, with at least 80%, at least 90%, or at least 95% of the amount of naftifine required to achieve saturation being present. In some embodiments, at the temperature of use, the composition remains single-phase and as close to saturation as possible. The term "saturated" can also include supersaturated solutions under certain conditions.

[0064] In some embodiments, the amount of naftifine is as close to complete saturation as possible. In some embodiments, the addition of an anti-nucleating agent can be advantageous in that it can lower saturation slightly, down to 80%, but it can be considered a saturated amount for the purposes of the present invention.

[0065] The present disclosure provides a naftifine composition comprising a film-forming agent. The present disclosure demonstrates that in a topical composition, for example, a topical spray composition, a film-forming agent comprising an octylacrylamide acrylate copolymer provides a longer-lasting effect in the treated area while minimizing systemic exposure to naftifine. In some embodiments, the long-lasting effect of the composition allows for a reduced number of total administrations of the naftifine composition. In some embodiments, the long-lasting effect of the composition allows for a reduced frequency of administration of the naftifine composition.

[0066] In some embodiments, the composition comprises a film-forming agent comprising an octylacrylamide acrylate copolymer. The term "octylacrylamide acrylate copolymer" refers to an octylacrylamide polymer with one or more monomers of acrylic acid, methacrylic acid, or one of their simple esters. Various octylacrylamide acrylate copolymers are known in the art and may include octylacrylamide / acrylate / butylaminoethyl methacrylate copolymer. In some embodiments, the octylacrylamide acrylate copolymer is the hydrophobic, high molecular weight carboxylic acid acrylic copolymer DERMACRYL® polymer (Nouryon). DERMACRYL® is also known as acrylate-t-octylpropenamide. In some embodiments, the octylacrylamide acrylate copolymer is Dermacryl LT (a carboxylated acrylic copolymer of acrylate and octylacrylamide). In some embodiments, the octylacrylamide acrylate copolymer is Dermacryl E (a styrene-acrylate copolymer). In some embodiments, the topical composition can have more than one film-forming agent. In some embodiments, the octylacrylamide acrylate copolymer comprises more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% of the film-forming agent in the topical composition. In some embodiments, the topical composition comprises the octylacrylamide acrylate copolymer as the sole film-forming agent.

[0067] Film-forming agents of various concentrations are present in the topical composition. In some embodiments, the topical composition comprises less than 10 wt%, less than 8 wt%, less than 6 wt%, less than 5 wt%, or less than 4 wt% of the film-forming agent. In some embodiments, the topical composition comprises more than 0.5 wt%, more than 1.0 wt%, more than 1.5 wt%, more than 2.0 wt%, or more than 2.5 wt% of the film-forming agent. In some embodiments, the topical composition comprises from about 1 wt% to about 10 wt% of an octylacrylamide acrylate copolymer. In some embodiments, the topical composition comprises from about 1.5 wt% to about 8.0 wt%, from about 1.5 wt% to about 6.0 wt%, from about 2.0 wt% to about 4.0 wt%, or from about 2.5 wt% to about 3.5 wt% of the octylacrylamide acrylate copolymer.

[0068] The present disclosure provides various ratios of film-forming agents to alcohol solvents in topical compositions. In some embodiments, these ratios are still suitable for topical administration by, for example, spraying, such as aerosol spraying or mist spraying, while providing a stable composition suitable for solubilization of naftifine. In some embodiments, the ratio of film-forming agent to alcohol solvent in the composition is from about 1:10 to about 1:40 (w / w). In some embodiments, the ratio of film-forming agent to alcohol solvent in the composition is from about 1:15 to 1:30, from about 1:16 to about 1:25, or from about 1:18 to 1:22 (w / w). In some embodiments, the ratio of film-forming agent to alcohol solvent in the composition is about 1:20.

[0069] The applicant of the present disclosure has found that hydrophilic polymers previously used for skin compositions are not required in the compositions described herein in some embodiments. In some embodiments, the present disclosure provides topical compositions with low concentrations of hydrophilic polymers, such as less than 5% hydrophilic polymer. In some embodiments, the present disclosure provides topical compositions without hydrophilic polymers. In some embodiments, the composition comprises less than 4 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%, or less than 0.5 wt% of hydrophilic polymer. In some embodiments, the hydrophilic polymers reduced or excluded from the topical composition are polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxyalkylcellulose, and / or alkylcellulose. In some embodiments, topical compositions with reduced hydrophilic polymer (or without hydrophilic polymer) provide increased physical stability of the topical composition. In some embodiments, topical compositions with reduced hydrophilic polymer (or without hydrophilic polymer) provide increased chemical stability of the topical composition. In some embodiments, topical compositions with reduced hydrophilic polymer (or without hydrophilic polymer) provide an appropriate viscosity for spraying, such as aerosol spraying. In some embodiments, topical compositions with reduced hydrophilic polymer (or without hydrophilic polymer) provide a spray that is more uniformly dispersed and does not clog dispensing devices (e.g., aerosol devices). In some embodiments, topical compositions with reduced hydrophilic polymer (or without hydrophilic polymer) provide a faster drying time compared to compositions containing hydrophilic polymers. In some embodiments, topical compositions with reduced hydrophilic polymer (or without hydrophilic polymer) result in less residue on the skin of the subject being treated. In some embodiments, topical compositions with reduced hydrophilic polymer (or without hydrophilic polymer) provide a composition that adheres to the skin for a longer period of time than compositions containing hydrophilic polymers.In some embodiments, a topical composition with a reduced hydrophilic polymer (or without a hydrophilic polymer) provides a more economical composition, and the topical composition is easier to manufacture, faster to manufacture, less expensive to manufacture, and / or requires less equipment to manufacture, thereby streamlining the manufacturing process compared to compositions that require a hydrophilic polymer.

[0070] A variety of solvents can be used in the present invention. In some embodiments, the solvent is suitable for solubilizing naphthifene, for example, an organic solvent that is pharmaceutically acceptable. In some embodiments, the solvent is an alcohol solvent. In some embodiments, the alcohol solvent is a C 1-6 alcohol. In some embodiments, the C 1-6 alcohol is methanol, ethanol, propyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol, or a combination thereof. In some embodiments, the alcohol solvent has a viscosity suitable for administration via aerosol spray or mist. In some embodiments, the alcohol solvent has a viscosity of from about 1 cp to about 150 cp.

[0071] In some embodiments, the composition comprises from about 10 wt% to about 80 wt% of an alcohol solvent. In some embodiments, the composition comprises from about 20 wt% to about 80 wt%, from about 30 wt% to about 80 wt%, from about 40 wt% to about 80 wt%, or from about 50 wt% to about 80 wt% of an alcohol solvent. In some embodiments, the composition comprises from about 52 wt% to about 68 wt%, from about 54 wt% to about 66 wt%, from about 56 wt% to about 64 wt%, or from about 58 wt% to about 62 wt% of an alcohol solvent. In some embodiments, the composition comprises about 60 wt% of an alcohol solvent. In some embodiments, the composition comprises less than 80 wt%, less than 70 wt%, less than 65 wt%, less than 62 wt%, or less than 61 wt% of an alcohol solvent. In some embodiments, the composition comprises from about 70 wt% to about 85 wt% of an alcohol solvent, from about 72 wt% to about 82 wt% of an alcohol solvent, or from about 74 wt% to about 80 wt% of an alcohol solvent. In some embodiments, the composition comprises about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, or about 83 wt% of an alcohol solvent. In some embodiments, the reduced alcohol solvent concentration can result in reduced adverse effects, such as inflammation or irritation.

[0072] In some embodiments, the composition comprises from about 10 wt% to about 70 wt% of C 1-6 alcohol solvent. In some embodiments, the composition comprises from about 20 wt% to about 70 wt%, from about 30 wt% to about 70 wt%, from about 40 wt% to about 70 wt%, or from about 50 wt% to about 70 wt% of C 1-6 alcohol solvent. In some embodiments, the composition comprises from about 52 wt% to about 68 wt%, from about 54 wt% to about 66 wt%, from about 56 wt% to about 64 wt%, or from about 58 wt% to about 62 wt% of C 1-6 alcohol solvent. In some embodiments, the composition comprises from about 70 wt% to about 85 wt% of C 1-6 alcohol solvent, from about 72 wt% to about 82 wt% of C 1-6 alcohol solvent, or from about 74 wt% to about 80 wt% of C 1-6It contains an alcohol solvent. In some embodiments, the composition is about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, or about 83 wt% of C 1-6 It contains an alcohol solvent. In some embodiments, the composition is about 60 wt% of C 1-6 It contains an alcohol solvent.

[0073] In some embodiments, the present disclosure provides a sprayable topical composition comprising: (a) about 0.05 wt% to about 5 wt% of naphthifene or a pharmaceutically acceptable salt thereof; (b) a film-forming agent comprising an octylacrylamide acrylate copolymer; (c) about 50 wt% to about 80 wt% of an alcohol solvent; and (d) about 15 wt% to about 45 wt% of a propellant. In some embodiments, the present disclosure provides a sprayable topical composition comprising: (a) about 0.05 wt% to about 5 wt% of naphthifene or a pharmaceutically acceptable salt thereof, (b) about 1 wt% to about 5 wt% of a film-forming agent comprising an octylacrylamide acrylate copolymer, (c) about 15 wt% to about 45 wt% of a propellant, (d) about 50 wt% to about 80 wt% of an alcohol solvent, and (e) about 1 wt% to about 3.5 wt% of a penetration enhancer. In some embodiments, the present disclosure provides a sprayable topical composition comprising: (a) about 0.05 wt% to about 5 wt% of naphthifene or a pharmaceutically acceptable salt thereof, (b) a film-forming agent comprising an octylacrylamide acrylate copolymer, (c) an alcohol solvent; and (d) a propellant, and the time to film formation is less than about 30 seconds.

[0074] In some embodiments, the ratio of the alcohol solvent to the propellant is about 1:1 to about 3:1, about 1.1:1 to about 2.9:1, about 1.2:1 to about 2.8:1, about 1.3:1 to about 2.7:1, about 1.4:1 to about 2.6:1, about 1.5:1 to about 2.5:1, about 1.6:1 to about 2.4:1, about 1.7:1 to about 2.3:1, or about 1.8:1 to about 2.2:1.

[0075] In some embodiments, the topical composition has a viscosity suitable for administration via aerosol spray and / or mist. For example, in some embodiments, the topical composition has a viscosity of less than 1000 cp, less than 700 cp, less than 500 cp, or less than 300 cp. In some embodiments, the topical formation has a viscosity of about 1 cp to about 500 cp, about 5 cp to about 300 cp, or about 50 cp to about 250 cp. In some embodiments, the topical composition has a viscosity of about 1 cp to about 150 cp. As used throughout this disclosure, viscosity is measured under standard conditions, such as a temperature of 1 atmosphere and 25°C.

[0076] In some embodiments, the topical composition produces an aerosol when discharged from a pressurized container using a standard single-fluid aerosol nozzle, such as a plain orifice nozzle or a shaped orifice nozzle, such as a "V" notch nozzle. In some embodiments, the composition is discharged at a pressure drop of about 20 bar to about 30 bar, such as about 25 bar (2,500 kPa; 360 psi) at room temperature. In some embodiments, the aerosol has a droplet size of about 10 μm to about 100 μm. In some embodiments, at least 99% of the droplets are 100 μm or greater in diameter. In some embodiments, at least 99% of the droplets are 100 μm or less in diameter.

[0077] In some embodiments, the topical composition further comprises a penetration enhancer, a co-solvent, an emulsifier, a propellant, a solubilizer, or a combination thereof. In some embodiments, the topical composition further comprises a propellant. In some embodiments, the propellant is a hydrocarbon, a fluorocarbon, a hydrofluorocarbon propellant, or a combination thereof. In some embodiments, the propellant is propane, isobutane, n-butane, isopentane, n-pentane, or a combination thereof. In some embodiments, the propellant is a hydrofluorocarbon propellant. In some embodiments, the hydrofluorocarbon propellant is 1,1,1,2-tetrafluoroethane (NORFLURANE® 134A, HFA-134a) or 1,1-difluoroethane (HFA-152a, ZEPHEX® 152a).

[0078] In some embodiments, the propellant provides a high saturation level of naphthifene. In some embodiments, the propellant is a highly volatile liquid with a low boiling point, such as a CFC or HFA, so that it can extrude the composition from the dispenser. In some embodiments, the propellant provides that the evaporation is almost instantaneous and the boiling during the movement from the dispenser to the site of administration has the effect of causing evaporation of a substantial amount of the solvent. Thus, in some embodiments, the solvent is preferably a volatile solvent, preferably more volatile than water and often organic. In some embodiments, the decompression of the propellant during administration causes destruction and loss of the solvent by evaporation. This loss can be up to 50% and even higher.

[0079] In some embodiments, the topical composition contains propellants at various concentrations. In some embodiments, the concentration of the propellant is appropriate to provide an aerosol naphthifene spray. In some embodiments, the concentration of the propellant is appropriate to provide a naphthifene mist spray. In some embodiments, the composition contains about 10 wt% to about 50 wt% of the propellant. In some embodiments, the composition contains about 25 wt% to about 45 wt% of the propellant. [[ID=]10]

[0080] The present disclosure provides that film-forming agents and propellants in various ratios can be used in topical compositions. In some embodiments, the ratio of the film-forming agent to the propellant is about 1:7 to 1:15, about 1:7 to about 1:14, or about 1:8 to about 1:13 (w / w). In some embodiments, the ratio of the film-forming agent to the propellant is about 1:8 to 1:12 (w / w).

[0081] The present disclosure provides various ratios of alcohol solvents and propellants used in the topical compositions described herein. In some embodiments, the ratio of the alcohol solvent to the propellant is about 1:1 to about 3:1, about 1.5:1 to about 1:1, or about 2:1 to about 1:1 (w / w). In some embodiments, the ratio of the alcohol solvent to the propellant is about 1:2 to about 1:3. In some embodiments, the ratio of the alcohol solvent to the propellant is about 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, or 2.9:1, 3:1, or any range including any two of these ratios. In some embodiments, the disclosed ratios of alcohol solvent to propellant provide a composition that is physically stable, e.g., no particles are formed, the composition is homogeneous, the naphthifene is soluble, etc. In some embodiments, the disclosed ratios of alcohol solvent to propellant provide a composition that is chemically stable, e.g., the naphthifene does not decompose over a long period of time, e.g., 3 months, 6 months, 9 months, 1 year, 18 months, and / or 2 years, at RT conditions or accelerated conditions.

[0082] In some embodiments, the topical composition can include a penetration enhancer. The term "penetration enhancer" refers to any compound or composition that interacts with the components of the outermost layer of the skin and the stratum corneum (SC), the rate-limiting layer, and increases its permeability. The penetration enhancer can include substances that temporarily enhance skin permeability and thereby temporarily promote the absorption of naftifine into the skin. Using a penetration enhancer, the delivery of naftifine can be conveyed while minimizing the systemic delivery of naftifine into the blood. As used herein, the penetration enhancer can include diethylene glycol monoethyl ether, diethyl behenate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, polyethylene glycol, oleic acid, lactate esters, oleyl alcohol, alkyl glycosides, saccharide alkyl esters, dimethylformamide, isopropyl myristate, Tween 80, sodium lauryl sulfate, a mixture of oleic acid and octyl dimethyl para-aminobenzoic acid, or combinations thereof. In some embodiments, one, two, three, or more than three penetration enhancers are present in the topical composition. In some embodiments, two penetration enhancers are present in the composition. In some embodiments, the penetration enhancer is a combination of propylene glycol and diethylene glycol monoethyl ether (TRANSCUTOL®).

[0083] Various concentrations of the penetration enhancer can be present in the topical composition. The penetration enhancer can be adjusted to promote the penetration of naftifine while minimizing systemic absorption. In some embodiments, the topical composition includes from about 0.1 wt% to about 7 wt%, from about 0.2 wt% to about 5 wt%, from about 0.5 wt% to about 3 wt%, or from about 0.75 wt% to about 3 wt% of the penetration enhancer. In some embodiments, the composition includes from about 0.5 wt% to about 2.5 wt% of the penetration enhancer.

[0084] In some embodiments, the topical composition comprises two penetration enhancers, and each penetration enhancer is from about 0.1 wt% to about 4 wt%, from about 0.2 wt% to about 3 wt%, from about 0.5 wt% to about 2 wt%, or from about 0.5 wt% to about 1.5 wt% of the topical composition. In some embodiments, the topical composition comprises one or both of propylene glycol and diethylene glycol monoethyl ether, propylene glycol is from about 0.1 wt% to about 4 wt%, from about 0.2 wt% to about 3 wt%, from about 0.5 wt% to about 2 wt%, or from about 0.5 wt% to about 1.5 wt% of the topical composition, and / or diethylene glycol monoethyl ether is from about 0.1 wt% to about 4 wt%, from about 0.2 wt% to about 3 wt%, from about 0.5 wt% to about 2 wt%, or from about 0.5 wt% to about 1.5 wt% of the topical composition. In some embodiments, the topical composition comprises from about 1 wt% to about 3.5 wt% of a penetration enhancer. In some embodiments, the topical composition comprises a combination of propylene glycol and diethylene glycol monoethyl ether, propylene glycol is from about 0.5 wt% to about 2 wt% of the topical composition, and diethylene glycol monoethyl ether is from about 0.5 wt% to about 2 wt% of the topical composition. In some embodiments, the topical composition comprises a combination of propylene glycol and diethylene glycol monoethyl ether, propylene glycol is from about 0.5 wt% to about 1 wt% of the topical composition, and diethylene glycol monoethyl ether is from about 0.5 wt% to about 1 wt% of the topical composition.

[0085] In some embodiments, the topical composition dries rapidly after application. For example, in some embodiments, the topical composition dries within 120 seconds, within 90 seconds, within 80 seconds, within 70 seconds, within 60 seconds, or within 30 seconds after application.

[0086] In some embodiments, the sprayable topical composition consists essentially of: (a) from about 0.05% to about 5% by weight of naphthifene or a pharmaceutically acceptable salt thereof; (b) a film-forming agent comprising octylacrylamide acrylate copolymer; (c) a propellant; (d) an alcohol solvent; and (e) a penetration enhancer. In some embodiments, the above topical composition does not contain a hydrophilic polymer, such as a hydrophilic film-forming polymer.

[0087] In some embodiments, the sprayable topical composition comprises: (a) from about 0.05% to about 5% by weight of naphthifene or a pharmaceutically acceptable salt thereof; (b) from about 1% to about 5% by weight of a film-forming agent comprising octylacrylamide acrylate copolymer; (c) from about 25% to about 45% by weight of a propellant; (d) from about 50% to about 70% by weight of an alcohol solvent; and (e) from about 1% to about 3.5% by weight of a penetration enhancer.

[0088] The topical composition of the present invention can be administered by means known in the art. In some embodiments, the present disclosure provides a delivery device for administering the composition. In some embodiments, the present disclosure provides a delivery device comprising the topical composition described herein. In some embodiments, the delivery device is a sealed pressurized device, such as an aerosol container. In some embodiments, the delivery device is a sealed pressurized device, an aerosol container, with means for providing an aerosol spray of the topical composition, such as an aerosol nozzle. In some embodiments, the delivery device contains an amount of the topical composition sufficient for a single administration of the composition. In some embodiments, the delivery device contains an amount of the topical composition sufficient for two administrations of the composition. In some embodiments, the delivery device contains an amount of the topical composition sufficient for three or more administrations of the composition. In some embodiments, the present disclosure provides a kit, the kit comprising one or more, for example, two delivery devices. In one embodiment, the kit comprises two, three, four, five, six or more delivery devices, and one delivery device is used in its entirety for each administration. In some embodiments, the kit comprises two aerosol canisters comprising the topical composition described herein, and one aerosol canister is used in its entirety for each administration. In some embodiments, the kit comprises one aerosol canister comprising the topical composition described herein in an amount sufficient to completely cover both feet. In some embodiments, the kit comprises two aerosol canisters comprising the topical composition described herein, and each canister is in an amount sufficient to completely cover one foot.

[0089] In embodiments where the delivery device is a pressurized device, the pressure in the sealed and pressurized device can be any pressure appropriate for delivery of the topical composition. In some embodiments, the pressure is from about 28 psi to about 145 psi at 25°C.

[0090] In some embodiments, the delivery device comprising the topical composition is an aerosol device and involves means for providing an aerosol of the topical composition. As used herein, an aerosol device would include any device capable of producing fine aerosol droplets of the topical composition. In some embodiments, the aerosol device produces aerosol droplets of the topical composition having an average diameter of from about 20 μm to about 150 μm. In some embodiments, the aerosol device produces aerosol droplets of the topical composition having an average diameter of less than 300 μm, less than 250 μm, less than 200 μm, less than 150 μm, less than 100 μm, less than 50 μm, or less than 25 μm. In some embodiments, at least 99% of the droplets are 100 μm or greater in diameter. In some embodiments, at least 99% of the droplets are 100 μm or less in diameter.

[0091] In some embodiments, the present disclosure provides a manufactured product for the treatment of dermatophyte skin infections, such as tinea pedis or onychomycosis, in a subject in need thereof, comprising (a) (i) a topical composition described herein, and (ii) a sealed pressurized container comprising means for providing an aerosol spray of the topical composition, and (b) instructions for the use of the topical composition for treating dermatophyte skin infections.

[0092] Drug-device combination In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a container containing a composition comprising naftifine or a pharmaceutically acceptable salt thereof, a film-forming agent comprising an octylacrylamide acrylate copolymer, an alcohol solvent, and a propellant.

[0093] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a composition comprising about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof, a film-forming agent comprising an octylacrylamide acrylate copolymer, an alcohol solvent, and a container comprising a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is from about 1:1 to about 3:1 (w / w).

[0094] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a composition comprising naftifine or a pharmaceutically acceptable salt thereof, a film-forming agent comprising an octylacrylamide acrylate copolymer, an alcohol solvent, and a container comprising a propellant, wherein the ratio of the alcohol solvent to the propellant in the composition is from about 1:1 to about 3:1 (w / w).

[0095] In some embodiments, the present disclosure provides a drug-device combination for dispensing a composition, the drug-device combination comprising a composition comprising about 0.05 wt% to about 5 wt% of naftifine or a pharmaceutically acceptable salt thereof and a container comprising a film-forming agent comprising an octylacrylamide acrylate copolymer.

[0096] In some embodiments, the drug-device combination provides for the dispensing of the composition from the container. In some embodiments, the drug-device combination provides for the spraying of the composition from the container. In some embodiments, the drug-device combination provides for both the spraying and dispensing of the composition from the container. In some embodiments, the drug-device combination forms a pressurized system. In some embodiments, the drug-device combination is a metering system. In some embodiments, the drug-device combination is a self-administered drug-device combination.

[0097] A variety of containers can be used to hold, store, or contain the compositions disclosed herein in a drug-device combination. In some embodiments, the container comprises a metal body, e.g., a body lined with a chemically inert coating material, which can avoid decomposition of the composition due to any interaction between the body and the composition. In some embodiments, the container comprises a plastic body, e.g., a body lined with a chemically inert coating material, which can avoid decomposition of the composition due to any interaction between the body and the composition. In some embodiments, the container is a substantially rigid metal or plastic container adapted to contain a pressurized propellant positioned within the container and in contact with the dispensed product. In some embodiments, the container is an inner substantially rigid metal or plastic container adapted to contain a pressurized propellant positioned within an outer container made of the same material and away from contact with the dispensed product.

[0098] In some embodiments, the container body can be constructed from materials such as metals, glass, ceramics, polyesters, polyethylene terephthalate (PET), or other polymers. In some embodiments, a glass container can be provided with a safety coating of polypropylene, e.g., to include glass shards that can form upon impact with a hard surface. In some embodiments, a metal container body can be used, which can withstand impact and is suitable for a surface coating. In some embodiments, the container includes stainless steel, tinplate, and aluminum, or combinations thereof. In some embodiments, the aluminum is an aluminum alloy or anodized aluminum.

[0099] The container body can be lined with various inert coating materials, including any suitable coating materials known in the art, such as polymers, lacquers, resins, or other coating treatments, thereby creating a barrier between the container and the composition to prevent any chemical interaction between the composition and the container. In some embodiments, the inert material is a non-metallic coating. In some embodiments, known coatings for metal containers include acrylic resins, phenolic resins, polyester resins, epoxy resins, and vinyl resins, and can be used to line the container body of the drug-device combinations disclosed herein. Thus, the container coating for use with the compositions of the present invention can be selected such that it does not exhibit acidic or alkaline reactivity per se and acidic or alkaline reactive impurities do not leach therefrom in the presence of the composition.

[0100] In some embodiments, the interior of the metal container can be lined with materials such as polyamide, polyimide, polypropylene, polyethylene, fluoropolymers, perfluoroethylene propylene copolymer (FEP), fluororubber (FPM), ethylene-propylene-diene monomer rubber (EPDM), polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene copolymer (EFTE), perfluoroalkoxy alkane, perfluoroalkoxy alkylene, or a mixture of fluoropolymers and non-fluorocarbon polymers, etc. Fluoropolymers can be used, for example, in combination with polyimide-polyamide resins.

[0101] The coating material of the container can be applied as a single layer or in multiple layers. For example, each layer can be cured before the application of a further layer. The application of more than one coating can be used to shield the composition from the metal container and prevent the adhesion of the active ingredient on the container wall.

[0102] In some embodiments, the drug-device combination includes a pressurized system in which the composition dispensed as an aerosol is stored. The system can be pressurized, for example, by a propellant generally dissolved within the composition. The composition can be discharged from the container, for example, upon opening of a pressure actuator valve mechanism positioned at the top of the container.

[0103] In some embodiments, the drug-device combinations disclosed herein sometimes include a valve assembly provided with a valve cup, sometimes referred to as a mounting cup, a valve body or housing, a spring, a dip tube, and an actuator. In some embodiments, the valve assembly can also include a secondary shut-off valve for controlling the flow from the container, whereby the flow of the composition cannot occur outside the spray through the secondary valve when the spray is not in use, and contamination or evaporation of the composition in the container thus does not occur. In some embodiments, the valve assembly can be constructed such that the moving parts are held together by a snap-fit structure. In some embodiments, screws or bolts and fastening tools are not required for the construction of the valve assembly. In some embodiments, the parts of the valve assembly are snapped together one by one. In some embodiments, the actuator is also referred to as a trigger spray and can include more than one part. In some embodiments, the actuator can include a trigger integrally molded with the manifold. In some embodiments, the trigger can also serve as a cap for the body of the actuator. In some embodiments, the trigger and the cap can include an integrally formed spring or an integrally formed living hinge. In some embodiments, the spring or the living hinge can provide a resistance force when the trigger is actuated and can provide a force sufficient to disengage the manifold from the valve actuation when the force applied to the trigger during actuation is removed or reduced. In some embodiments, the spring or the living hinge can include a geometric shape that can improve the function of the spring or the living hinge. The actuator of the valve assembly can include a body or housing fixed to the upper part of the container body, and an actuator plunger or button is mounted within the housing. In some embodiments, the plunger or button can be mounted on or within the body in a certain manner to connect to the valve stem or at least indirectly interlock or actuate it.

[0104] In some embodiments, the actuator can be actuated by a compressible actuator. In some embodiments, a pull tab can be used to actuate the actuator. In some embodiments, the actuator can include an extensible handle. In other embodiments, the actuator can include a timer. In other embodiments, the actuator can include an integral hood or windshield. In some embodiments, the actuator can also include a selectable spray pattern. In some embodiments, the actuator can also include a locking mechanism.

[0105] In some embodiments, the actuator can be made of any desired material or combination of materials. In some embodiments, the actuator may be made of a plastic or resin-based material. In some embodiments, the actuator can include metal parts. In other embodiments, a flexible, extensible, or other elastomeric type material may be used or integrated during actuator design. In some embodiments, the actuator may be attached to, joined to, or otherwise assembled with a plastic or metal container having a valve.

[0106] In some embodiments, the actuator is connected to a protruding stem of a valve attached to a container and is adapted to be pressed by a user's finger to operate the associated valve, thereby enabling the release of the composition from the container. Any material for the valve stem is polyamide and acetal copolymer.

[0107] In some embodiments, the valve stem can be arranged such that the valve stem appears through a central opening in the pedestal portion of the mounting cup. In some embodiments, below the lower side of the pedestal, there is a gasket that surrounds the lateral orifice in the hollow valve stem and acts to seal the orifice in the valve stem when the valve is in the closed position. The stem gasket can be selected to withstand extreme chemical conditions and not soften, harden, or crack within the valve. Any of these changes in the material can cause improper valve function and / or loss of seal and product leakage. In some embodiments, the stem gasket is formed from rubber or other elastomeric material and is dimensioned to seal against the outer surface of the valve stem.

[0108] A product passage is generally provided to direct the released, dispensed, or sprayed composition out of the container and through the valve actuation assembly to a desired environment. In some embodiments, the drug-device combination disclosed herein includes a product passage. In some embodiments, the product passage of the drug-device combination disclosed herein is a dip tube. In some embodiments, the dip tube can be integral with either the container body or the button, or a separate structure that communicates between the valve stem and a product dispensing orifice formed in the actuator. In some embodiments, the dip tube extends through the neck of the container into the fluid contents of the container. In some embodiments, the dip tube fluidly connects the container to the fluid supply passage of the valve assembly. In some embodiments, the dip tube is a separate straw-like element. In some embodiments, the dip tube is produced from a low density polyethylene, medium density polyethylene, or high density polyethylene or polypropylene thermoplastic material.

[0109] The liquid composition dispensed or sprayed from the container can fill the pressure chamber and, when it is filled, can push against a pressure piston supported by a spring provided in the pressure chamber. Thus, when the user pumps the liquid into the pressure chamber, this liquid pushes the pressure piston, whereby the spring is loaded (compressed), and thus the liquid is placed in the pressure chamber under pressure in a manner similar to the pressurized contents of the container. In an exemplary embodiment, such a pressure spring can be a spring in the broadest sense, and thus, for example, an air or gas shock absorber or spring, a spring of various compositions and materials, and any elastic device capable of storing potential energy, including the like.

[0110] The characterization of the spray, e.g., the droplet size distribution (DSD) of the plume released following the spray, is measured under specific experimental and instrument conditions by suitable analytical procedures and can be validated and / or calibrated as known in the art. This can be, but is not limited to, photography, laser diffraction, and collision systems (including water - fall collision, next - generation collision (NGI), etc.). The droplet size distribution can be controlled with respect to intervals for percentages. The nomenclature of particle diameter “(D)” refers to the representative diameter, where 90% (D 90 ) of the total volume of the sprayed liquid, 50% (D 90 ), and 10% (D 50 ) are composed of droplets with a diameter smaller than or equal to the stated value. The spray characteristics can refer to the average or median value collected for a plurality of sprays. The plurality of sprays can be at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more sprays. 10 ) of the total volume of the sprayed liquid, 50% (D

[0111] In some embodiments, the drug - device combination is suitable for providing a spray of the composition, and the spray has a D greater than 1 μm, greater than 10 μm, greater than 20 μm, greater than 30 μm, greater than 50 μm, greater than 70 μm, or greater than 100 μm 90It has a droplet size. In some embodiments, the drug-device combination is suitable for providing a spray of the composition, and the spray has a D of less than 500 μm, less than 400 μm, less than 300 μm, or less than 200 μm 90 It has a droplet size. In some embodiments, the composition has a D of about 140 μm to about 170 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 140 μm to about 145 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 145 μm to about 150 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 140 μm to about 150 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 140 μm to about 160 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 150 μm to about 160 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 150 μm to about 165 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 160 μm to about 165 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has a D of about 165 μm to about 170 μm when sprayed from the drug-device combination 90 It has a droplet size.

[0112] In some embodiments, the composition has an average D of about 155 μm to about 163 μm when sprayed from the drug-device combination 90 It has a droplet size. In some embodiments, the composition has an average D of about 155 μm to about 160 μm when sprayed from the drug-device combination 90It has a droplet size. In some embodiments, when the composition is sprayed from a drug-device combination, the average D is from about 160 μm to about 163 μm 90 It has a droplet size. In some embodiments, when the composition is sprayed from a drug-device combination, the average D is from about 155 μm to about 157 μm 90 It has a droplet size. In some embodiments, when the composition is sprayed from a drug-device combination, the average D is from about 157 μm to about 160 μm 90 It has a droplet size.

[0113] In some embodiments, the naftifine or a pharmaceutically acceptable salt thereof in the composition of the drug-device combination is naftifine hydrochloride. The concentration of naftifine can vary in the composition of the drug-device combination. In some embodiments, the concentration of naftifine in the composition of the drug-device combination is less than 5% by weight of the composition. In some embodiments, the concentration of naftifine in the composition of the drug-device combination is less than 4.5% by weight, less than 4.0% by weight, less than 3.5% by weight, or less than 3.0% by weight of the composition. In some embodiments, the composition of the drug-device combination comprises from about 0.05% to about 5% by weight of naftifine. In some embodiments, the composition of the drug-device combination comprises from about 0.05% to about 4% by weight, from about 0.1% to about 3.5% by weight, from about 0.1% to about 3.0% by weight, from about 0.2% to about 3.0% by weight, from about 0.5% to about 2.5% by weight, from about 1.0% to about 3.0% by weight, from about 1.0% to about 2.5% by weight, from about 1.5% to about 2.5% by weight, from about 1.8% to about 2.2% by weight, or about 2.0% by weight of naftifine.

[0114] The present disclosure provides a drug-device combination comprising a topical composition for administration. In some embodiments, the present disclosure provides an aerosol spray composition for administration from a drug-device combination. In some embodiments, the term "aerosol spray composition" is a pressurized composition, e.g., a composition in a sealed container under pressure, and the aerosol can be formed upon release from the container in the drug-device combination. In some embodiments, the drug-device combination can include the composition with or without pressurization. For example, the term "topical composition" can include (i) a liquid composition inside a pressurized container that becomes an aerosol spray when discharged from the container, and (2) the aerosol spray discharged from the container. Additionally, the term "topical composition" in some embodiments can include a liquid composition on a surface, e.g., a skin surface, that forms when the aerosol spray contacts the surface. In some embodiments, administration of an aerosol spray from a drug-device combination provides more consistent administration of the composition to the subject being treated. In some embodiments, administration of an aerosol spray from a drug-device combination provides more thorough administration of the composition to the subject, e.g., more areas are covered. In some embodiments, administration of an aerosol spray from a drug-device combination provides a more convenient method of administration. In some embodiments, administration of an aerosol spray from a drug-device reduces the need for other applicators, e.g., wipes, gauzes, cloths, etc. In some embodiments, administration of an aerosol spray from a drug-device combination reduces exposure of the hand or other unintended body parts to naphthifine that can occur with administration by cream, gel, or liquid. In some embodiments, administration of an aerosol spray from a drug-device combination provides a more convenient mode of administration. Because it allows the composition to dry rapidly after application.

[0115] Method of treatment The topical compositions and drug-device combinations described herein can be used in the treatment of dermatophyte skin infections. The term "dermatophyte skin infection" can refer to any skin condition caused by dermatophyte fungi, including, for example, Microsporum, Trichophyton, and Epidermophyton fungal species. In some embodiments, the term "dermatophyte skin infection" refers to tinea pedis, interdigital tinea pedis, tinea cruris, tinea corporis, and / or tinea capitis. In some embodiments, the term "dermatophyte skin infection" refers to tinea pedis, interdigital tinea pedis, or tinea cruris. In some embodiments, the present disclosure provides a method of treating a dermatophyte skin infection in a subject in need thereof, the method comprising topically administering to the subject a topical composition of any of the topical spray compositions described herein.

[0116] The topical compositions and drug-device combinations described herein can be used in the treatment of onychomycosis. The term "onychomycosis" refers to a fungal infection of one or more nails in a subject, such as toenails, resulting in nail discoloration, thickening, and / or separation from the nail bed. In some embodiments, onychomycosis refers to brittle, friable, or crumbly nails caused by a fungal infection. In some embodiments, onychomycosis refers to a distorted shape of the nail caused by a fungal infection. In some embodiments, onychomycosis begins with a fungal infection in the skin, such as tinea pedis. In some embodiments, onychomycosis is caused by a weakened immune system, reduced blood circulation (e.g., as a result of diabetes), or advanced age.

[0117] As used herein, the terms "treatment" and "alleviation" of dermatophyte skin infections refer to reducing the severity of symptoms associated with dermatophyte skin infections. Thus, in some embodiments, the methods provided herein provide palliative care. In some embodiments, the term "treatment" refers to removing the symptoms associated with dermatophyte skin infections. Thus, in some embodiments, the methods provided herein provide curative care. In some embodiments, the symptoms associated with dermatophyte skin infections include one or more of skin itching, burning sensation, whitening or breakdown, scaling, blister formation, inflammation, pustules, or ulcers. In some embodiments, the methods described herein reduce and / or eliminate the severity of one, two, three, or more than three symptoms associated with dermatophyte skin infections.

[0118] As used herein, the terms "treatment" and "alleviation" of onychomycosis refer to reducing the severity of symptoms associated with onychomycosis. Thus, in some embodiments, the methods provided herein provide palliative care for onychomycosis. In some embodiments, the term "treatment" refers to removing the symptoms associated with onychomycosis. Thus, in some embodiments, the methods provided herein provide curative care associated with onychomycosis. In some embodiments, the methods described herein reduce and / or remove the severity of one, two, three, or more than three symptoms associated with onychomycosis.

[0119] In some embodiments, the treatment methods described herein provide an increased mycological cure rate. As used herein, the term "mycological cure rate" refers to the percentage of specimens (skin scrapings from tinea pedis lesions) taken that have (a) negative KOH staining after microscopy; and (b) negative fungal culture results.

[0120] In some embodiments, the composition has a mycological cure rate of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a single-dose treatment. In some embodiments, the composition has a mycological cure rate of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a two-dose treatment. The mycological cure rate is determined by defining a cure as a negative KOH stain and a negative fungal culture using a microscope of a skin scraping taken from the lesion 6 weeks after treatment.

[0121] In some embodiments, the composition has a complete clinical cure rate of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a single-dose treatment. In some embodiments, the composition has a complete clinical cure rate of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a two-dose treatment. The complete clinical cure rate is defined as the absence of erythema, scaling, and pruritus 6 weeks after treatment.

[0122] In some embodiments, the composition has a treatment efficacy of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a single-dose treatment. In some embodiments, the composition has a treatment efficacy of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a two-dose treatment. Treatment efficacy is defined as negative KOH staining, negative fungal culture, and absent or mild erythema, scaling, and pruritus at 6 weeks after treatment.

[0123] In some embodiments, the composition has a complete clearance rate of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a single-dose treatment. In some embodiments, the composition has a complete clearance rate of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% with a two-dose treatment. Complete clearance is defined as negative KOH staining, negative fungal culture, and complete absence of erythema, scaling, and pruritus six weeks after treatment. One of ordinary skill in the art will understand that not all subjects will respond equally to the methods described herein. Thus, when referring to a treatment that reduces and / or eliminates symptoms, one of ordinary skill in the art can appreciate any statistical significance of the clinical results related to the present invention and is within the scope of the present invention. One of ordinary skill in the art will also understand that "treatment" can be dependent on the frequency of administration, the amount of active agent administered, the predisposition of the subject being treated (e.g., age, condition, gender, height, weight, underlying health status, etc.). In some embodiments, the methods provided herein provide a "treatment" for dermatophyte skin infections or onychomycosis in a population of subjects, wherein the treatment provides a reduction in the severity of symptoms associated with dermatophyte skin infections or onychomycosis and / or elimination of symptoms associated with dermatophyte skin infections or onychomycosis in more than 30%, more than 40%, more than 50%, more than 60%, or more than 70% of the subjects in the population.

[0124] In some embodiments, the topical composition is administered to the site of infection as well as to the healthy surrounding skin. In some embodiments, the topical composition is dispensed from an aerosol canister as a topical film-forming spray applied to both feet in a single opportunity (per single application), even if only one foot has signs and symptoms of infection. A single continuous spray is intended to cover between and around the toes and the healthy adjacent skin with lesions on the bottom and sides of each foot. For example, in some embodiments, the topical composition is applied such that the entire affected area is covered by the topical composition. In some embodiments, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% of the affected area is covered by the topical composition. In some embodiments, if the infection affects a particular body part, e.g., the foot, then the topical composition is applied to the entire body part. For example, in some embodiments, the topical composition can be applied to an area beyond the affected area. For example, in some embodiments, if dermatophyte skin infection affects the foot, the topical composition can be applied to more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% of the foot. The same will apply to any other particular body part affected by dermatophyte skin infection. Thus, in some embodiments, the topical composition can cover both feet without accompanying infection on the application area.

[0125] In some embodiments, the present disclosure provides a topical composition that requires a reduced frequency of administration for the treatment of dermatophyte skin infection. For example, in some embodiments, the composition is administered no more than once in 3 days. In some embodiments, the composition is administered no more than once during a period of 4 days, no more than once during a period of 5 days, no more than once during a period of 6 days, no more than once during a period of 7 days (one week), no more than once during a period of 10 days, or no more than once during a period of 14 days (two weeks). In some embodiments, the composition is administered no more than once

[0126] In some embodiments, the present disclosure provides a topical composition that requires a reduced number of administrations for the treatment of dermatophyte skin infections or onychomycosis. In some embodiments, the topical composition is administered to a subject one or fewer times during the course of treatment and reduces the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is administered to a subject two or fewer times and reduces the dermatophyte skin condition or onychomycosis. In some embodiments, the topical composition is administered to a subject three, four, or five or fewer times and reduces the dermatophyte skin condition or onychomycosis.

[0127] In some embodiments, more than one administration is required and various dosing regimens can be used. In some embodiments, the methods described herein include a first administration of the topical composition and a second administration of the topical composition. In some embodiments, the second composition is 5 to days after the first administration. In some embodiments, the second composition is 6 - 9 days, 7 - 8 days, or about 7 days after the first administration.

[0128] The effectiveness of treatment of a dermatophyte skin condition can be determined by methods known to those of skill in the art. For example, in some embodiments, the effectiveness of treatment of a dermatophyte skin condition is determined by (a)(i) comparing the clinical signs and symptoms associated with tinea pedis in a subject treated with the topical composition to (ii) a subject treated with a placebo treatment; and / or (b)(i) comparing the mycological cure rate (i.e., potassium hydroxide staining and fungal culture results) in a subject treated with the topical composition to (ii) a subject treated with a placebo.

[0129] In some embodiments, efficacy is measured using mycological cure (KOH and fungal culture), treatment efficacy (defined as negative KOH staining, negative fungal culture, and the absence or mild erythema, scaling, and pruritus), and clinical cure (defined as the absence of erythema, scaling, and pruritus). In some embodiments, the primary efficacy endpoint is to achieve complete clearance at day 42, defined as negative KOH, negative fungal culture, and the absence of individual signs and symptoms (i.e., erythema, scaling, and pruritus). In some embodiments, the percentage of subjects in whom the topical composition is administered achieves the primary efficacy endpoint that is twice the percentage of subjects receiving placebo or not being treated.

[0130] In some embodiments, the topical composition provides low naftifine systemic exposure. In some embodiments, the systemic level of naftifine after a single application of the topical spray composition is, on average, from about 10 pg / mL to about 250 pg / mL, or from about 50 pg / mL to about 150 pg / mL after 4 weeks. In some embodiments, the systemic level of naftifine after a single application of the topical spray composition is, on average, about 100 pg / mL after 4 weeks.

[0131] In some embodiments, the present disclosure provides a method for treating dermatophyte skin infections in a patient, the method comprising administering to the subject two doses of a topical composition comprising naftifine, the topical composition being a single-phase solution, naftifine being present at at least 80% saturation under the conditions of use, and the second dose being administered about 1 week after the first dose. In some embodiments, the dermatophyte skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris. In some embodiments, the present disclosure provides a method for treating onychomycosis in a patient, the method comprising administering to the subject two doses of a topical composition comprising naftifine, the topical composition being a single-phase solution, naftifine being present at at least 80% saturation under the conditions of use, and the second dose being administered about 1 week after the first dose.

[0132] In some embodiments, the present disclosure provides a method for maintaining a therapeutic level of naftifine in the stratum corneum in a subject to reduce symptoms associated with dermatophyte skin conditions. In some embodiments, the therapeutic level of naftifine in the stratum corneum is measured using a stripping assay. In some embodiments, the therapeutic level of naftifine includes having a naftifine tape stripping concentration of greater than 10,000 pg / mL, greater than 12,000 pg / mL, or greater than 15,000 pg / mL. In some embodiments, the therapeutic level is at least 10,000 pg / mL. In some embodiments, the therapeutic level is maintained for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

[0133] In some embodiments, the present disclosure provides a method for maintaining a therapeutic level of naftifine in the stratum corneum in a subject for 4 weeks, the method including administering two doses of a topical composition comprising naftifine to the subject, the composition being a single-phase solution, the pharmaceutical being present at at least 80% saturation under the conditions of use, and the second dose being administered approximately 1 week after the first dose.

[0134] In some embodiments, the amount of naftifine in the stratum corneum of the subject 4 weeks after the first dose and 3 weeks after the second dose is on average half the amount extracted with the second dose.

[0135] In some embodiments, the present disclosure provides a method for treating a dermatophyte skin infection in a subject in need thereof, the method including administering a topical composition, wherein administration of the topical composition to the subject results in at least 10% success, at least 20% success, at least 30% success, at least 40% success, at least 50% success, at least 60% success, at least 70% success, or at least 80% success in an efficacy evaluation item.

[0136] Various efficacy evaluation items are known to those skilled in the art, and the primary efficacy evaluation item in clinical trials is to achieve complete clearance. In some embodiments, complete clearance is measured on day 21, day 28, day 35, day 42, day 47, or day 54. In some embodiments, complete clearance is measured on day 42. Complete clearance can be defined as a negative KOH, negative fungal culture, and / or a score of 0 "none" for individual signs and symptoms selected from erythema, scaling, and pruritus. In some embodiments, the efficacy evaluation item is to achieve complete clearance on day 42, which is defined as a negative KOH, negative fungal culture, and / or a score of 0 "none" for individual signs and symptoms selected from erythema, scaling, and pruritus.

[0137] In some embodiments, the present disclosure provides a method of treating dermatophyte skin infections in a subject in need thereof, the method comprising administering a topical composition comprising 2% naftifine or a pharmaceutically acceptable salt thereof, the topical composition being administered to the subject in 2 doses, the second dose being administered approximately 1 week after the first dose, and the administration of the topical composition to the subject resulting in at least 50% success in the efficacy evaluation item. In some embodiments, the dermatophyte skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris.

[0138] In some embodiments, the topical composition is administered to a population of subjects. In some embodiments, the percentage of subjects receiving the topical composition achieves the primary efficacy evaluation item that is twice the percentage of subjects receiving the placebo.

[0139] In some embodiments, the primary efficacy evaluation item is a measure of mycological cure, treatment efficacy, and complete clearance defined as a negative KOH, negative fungal culture, and the absence of individual signs and symptoms selected from erythema, scaling, and pruritus.

[0140] In some embodiments, the present disclosure provides a method for treating onychomycosis in a subject in need thereof, the method comprising administering a topical composition, wherein the administration of the topical composition to the subject results in at least 10% success, at least 20% success, at least 30% success, at least 40% success, at least 50% success, at least 60% success, at least 70% success, or at least 80% success in an efficacy evaluation item. Onychomycosis is a fungal infection of the nail that causes discoloration, thickening, and separation from the nail bed.

[0141] In some embodiments, the efficacy evaluation item associated with onychomycosis is one or more symptoms associated with onychomycosis, such as discoloration of the nail, thickening, and / or separation from the nail bed, brittleness, crumbling, or at least a 50% reduction, at least an 80% reduction, or at least a 90% reduction of a ragged nail. In some embodiments, the efficacy evaluation item is determined 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after the final administration of the topical spray.

[0142] In some embodiments, the efficacy evaluation item associated with mycological cure is greater than 40%, greater than 50%, or greater than 60%. In some embodiments, the efficacy evaluation item associated with mycological cure is about 40% to about 80% or about 50% to about 70%.

[0143] In some embodiments, the efficacy evaluation item associated with complete clinical cure is greater than 20%, greater than 25%, or greater than 300%. In some embodiments, the efficacy evaluation item associated with mycological cure is about 20% to about 50% or about 25% to about 40%.

[0144] In some embodiments, the efficacy evaluation item associated with treatment efficacy is greater than 40%, greater than 45%, or greater than 50%. In some embodiments, the efficacy evaluation item associated with treatment efficacy is about 40% to about 80% or about 45% to about 70%.

[0145] In some embodiments, the efficacy evaluation items associated with complete clearance are greater than 5%, greater than 10%, or greater than 50%. In some embodiments, the efficacy evaluation items associated with mycological cure are from about 5% to about 40% or from about 10% to about 35%.

[0146] In some embodiments, the present disclosure provides a method of treating dermatophyte skin infections in a subject, the method comprising administering a topical composition comprising naftifine, the composition being a single-phase solution, the pharmaceutical being present at at least 80% saturation under the conditions of use, the administration of the topical composition to the subject resulting in complete clearance of the signs and symptoms of tinea pedis, the complete clearance being defined as achieving the following scores for all of the clinical signs and symptoms listed below: (a) A decrease in the severity of erythema from baseline with a score of 0 on day 42; (b) A decrease in the severity of scaling from baseline with a score of 0 on day 42; (c) A decrease in the severity of pruritus from baseline with a score of 0 on day 42; and achieving mycological clearance in the KOH test and in mycological culture.

[0147] In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0148] In some embodiments, the arithmetic mean AUC t (pg*h / mL) of naftifine after a single application of the naftifine topical composition is 300,000 pg*h / mL or less, 250,000 pg*h / mL or less, or 200,000 pg*h / mL or less.

[0149] In some embodiments, the C max( (pg / mL) of naftifine after a single application of the naftifine topical composition is 3000 pg / mL or less, 2500 pg / mL or less, 2000 pg / mL or less, 1500 pg / mL or less, or 1000 pg / mL or less.

[0150] In some embodiments, the median Tmax of naftifine after a single application of the naftifine topical composition is 12 hours, 18 hours, 24 hours, 30 hours, or 36 hours.

[0151] In some embodiments, the present disclosure provides a method of treating dermatophyte skin infections or onychomycosis in a subject in need thereof, the method comprising applying an aerosol spray or mist to the skin using a drug-device combination disclosed herein. In some embodiments, the dermatophyte skin condition is tinea pedis or interdigital tinea pedis or tinea cruris.

[0152] In some embodiments, the composition of the drug-device combination is administered to the site of infection. For example, in some embodiments, the composition of the drug-device combination is applied such that the entire affected area is covered by the composition using a spray droplet size (D 90 ). In some embodiments, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% is covered by the composition using a spray droplet size (D 90 ).

[0153] In some embodiments, the present disclosure provides a composition administered from a drug-device combination described herein that requires less frequent dosing for the treatment of dermatophyte skin infections. For example, in some embodiments, the composition is administered no more than once during a 3-day period using a spray droplet size (D 90 ). In some embodiments, the composition is administered no more than once during a 4-day period, no more than once during a 5-day period, no more than once during a 6-day period, no more than once during a 7-day (one-week) period, no more than once during a 10-day period, or no more than once during a 14-day (two-week) period using a spray droplet size (D 90 ).

[0154] In some embodiments, the present disclosure provides a composition dispensed from a drug-device combination using a spray droplet size (D 90 ) that requires a reduced number of administrations for the treatment of dermatophyte skin infections or onychomycosis, as described herein. In some embodiments, the composition is administered using a spray droplet size (D 90 ) as described herein such that one or fewer administrations during the course of treatment of the subject are sufficient to reduce the dermatophyte skin condition or onychomycosis. In some embodiments, the composition is administered to the subject two or fewer times and reduces the dermatophyte skin condition or onychomycosis. In some embodiments, the composition is administered to the subject three, four, or five or fewer times and reduces the dermatophyte skin condition or onychomycosis.

[0155] In some embodiments, more than one administration is required and various dosing regimens can be used. In some embodiments, the methods described herein include a first administration of the composition and a second administration of the composition. In some embodiments, the second composition is 5 to 10 days after the first administration. In some embodiments, the second composition is 6 to 9 days, 7 to 8 days, or about 7 days after the first administration.

[0156] To prevent dripping and runoff, it is important for the composition to dry rapidly after application. In some embodiments, the composition of the drug-device combination dries rapidly after application. In some embodiments, the composition dries in less than 3 minutes after application to the skin. In some embodiments, the composition dries in less than 2 minutes after application to the skin. In some embodiments, the composition dries in less than 1 minute after application to the skin. For example, in some embodiments, the composition of a drug-device combination using a spray droplet size (D 90 ) dries within 120 seconds, 90 seconds, 80 seconds, 70 seconds, 60 seconds, or 30 seconds after application, as described herein. In some embodiments, the composition dries within 90 seconds, 80 seconds, 70 seconds, or 60 seconds after application of 500 μL, 250 μL, 100 μL, or 50 μL of the composition to the skin at room temperature and 1 atmosphere pressure.

[0157] All references cited in this specification are hereby incorporated by reference into this specification in their entirety to the extent that they are not yet cited, including patents, patent applications, papers, textbooks, and the like, as well as references cited therein.

Examples

[0158] Example 1 - Naphtifine Composition for Local Use: Various Film-Forming Agents Various topical compositions containing 2% naphthifine were prepared as outlined in Tables 1 and 2.

Table 1

[0159]

Table 2

[0160] The samples were then analyzed for (i) visual precipitation, (ii) naphthifine penetration, (iii) antifungal efficacy, (iv) resistance of the resulting film to water and artificial sweat (pH 4.0 and 6.5) 24 hours after application, and (v) drying time. The results are presented in Tables 3 and 4.

Table 3

[0161]

Table 4

[0162] The following terms used above can be defined as follows: Penetration rank: 1 = maximum. Antifungal efficacy: 1 = maximum kill. (i) Resistance: “+” indicates that the composition was resistant to the condition, and “×” indicates that the composition was not resistant to the condition. Tested in water at pH 7.0, pH 4.0, and pH 6.5.

[0163] As is apparent from Tables 3 and 4, Sample 9 showed the shortest drying time while having good antifungal activity and skin penetration, as well as high resistance to both water and artificial sweat.

[0164] Example 2 - Naphtifine Composition for Local Use: Various Solvents: Propellant Ratios Various topical compositions containing naftifine were prepared by varying the amounts of ethanol and propellant as outlined in Table 5. Various compositions were sprayed onto artificial skin and the following parameters were tested: the appearance of the spray during discharge, the time to film formation (evaluated by the appearance of the film and the complete drying time). [Table 5]

[0165] As is apparent from Table 5, the preferred time to film formation (evaluated by the appearance of the film and the complete drying time) was obtained using a composition having about 60% ethanol and about 30% propellant, i.e., an alcohol solvent:propellant ratio of 1.8:1.

[0166] Example 3 - Naphtifine Composition for Local Use. A topical composition (F5) containing naftifine was prepared based on Sample 9 from Example 1 as outlined in Table 6. [Table 6]

[0167] Example 4 - Skin Penetration - Tape Stripping Test in Human Subjects The presence of naftifine in the stratum corneum (SC) was evaluated on days 1 and 8 after two applications of F5 (sample 9 from Example 1) and F3 (sample 11 from Example 1) to the forearms of 10 healthy adults. The skin was tape-stripped at time points up to 28 days after the first application for quantification of naftifine levels. Naftin® cream was applied at 2% once daily for 14 days and resulted in higher median naftifine skin levels compared to F5 applied on days 1 and 8. By day 29, the naftifine levels in the skin after two applications of F5 were at least similar to the levels achieved after 2 weeks of daily application with Naftin®. This study demonstrated sustained naftifine levels in the skin that were measurable up to 29 days after the F5 dosing regimen.

Table 7

[0168] Example 5 - Proof-of-Concept Clinical Trial - Naphtifine Film-Forming Aerosol, 2% - F5 A randomized, double-blind, placebo-controlled, parallel-group trial was conducted using F5 as a topical composition. F5 (N = 42) and placebo (N = 40) were administered once to subjects experiencing interdigital tinea pedis. On days 14, 28, and 42, the subjects were evaluated for the clinical signs and symptoms of the disease, while mycological cure was evaluated on day 42. The results at day 42 of the experiment are shown in Table 8.

Table 8

[0169] Clinical results revealed a clear advantage of F5 over placebo in the tested efficacy evaluation items.

[0170] Example 6: Skin Penetration and Toxicity Tests in Hanford Miniature Swine F1 (Sample 7 from Example 1), F3 (Sample 11 from Example 1), F4 (Sample 15 from Example 1), and F5 were each topically applied twice to a group of Hanford miniature pigs on days 1 and 8. This test produced no test substance-related effects on any organ or system. Systemic levels of naftifine were detectable in all treated miniature pigs at an early time of 0.5 hour after a single application (2 ml / kg), and peaked between 6 and 16 hours after application. Slight to no accumulation was observed after the second application of F5, and there were no significant gender differences in skin uptake with any application. Based on the lack of adverse evidence from the test, all formulations of naftifine at the tested concentrations are considered safe in Hanford miniature pigs when applied as two skin administrations at a dose level of 2 ml / kg to 10% of the body surface area, at 1-week intervals. The mean data from this test are presented in Table 9 below, thereby revealing the minimal systemic absorption using F5 in the miniature pig animal model.

Table 9

[0171] Example 7: Naphtifine Levels in Blood after Single Application of F5 in Human Subjects The naftifine levels in blood after a single application of F5 were determined in 7 human subjects. The values obtained were as follows: arithmetic mean AUC t (h*pg / mL) - 183,425; C max (pg / mL) - 1051; median Tmax (h): 24.

[0172] Example 8: Chemical and Physical Stability of a Topical Composition (F5) Containing Naphtifine The chemical and physical stability parameters of the naftifine composition were evaluated at 25°C and 60% relative humidity (referred to as "RT conditions") or at 40°C and 75% relative humidity (referred to as "accelerated (ACC) conditions") over specific periods of T0 and 6 months.

[0173] The topical composition (F5) containing naphthifine showed both physical and chemical stability, with no significant changes in the naphthifine assay (100% at T = 0, 99.5% after 6 months at RT, and 98.2% after 6 months under accelerated conditions) and the related compound levels (total) of less than 0.07% at T = 0 and after 6 months at RT and under accelerated conditions. See Table 10.

Table 10

[0174] The data presented demonstrate that the naphthifine formulations described herein are not only more stable and suitable for spray administration, but also that the same formulation is effective in vivo in the treatment of dermatophyte skin infections. The composition allows the activity to be present on the skin over an extended period, thereby providing sufficient time for the treatment of dermatophyte skin infections using a reduced number of administrations, e.g., only one or two administrations. Compliance of the patient is enhanced by one or two dosing regimens as compared to the current regimen of daily administration over 14 days.

[0175] Example 9: Measurement of Droplet Size Distribution of a Composition Sprayed from a Drug - Device Combination A 2% naphthifine composition was prepared according to the formulation disclosed in Example 1. The prepared naphthifine composition was placed and sealed in the drug-device combination described herein. The droplet size distribution (DSD) produced by the spray and aerosol generated by the drug-device combination was measured using a SprayVIEW® measurement system device. Five actuations of each composition were sprayed at a distance of 15 cm. The average values of the spray DSD are shown in Table 11 below.

Table 11

Claims

1. A sprayable topical composition, a. Approximately 0.05% to 5% by weight of naphthiphine or a pharmaceutically acceptable salt thereof. b. Film-forming agents containing octylacrylamide acrylate copolymer; c. Alcoholic solvents; and d. A spray, including A sprayable topical composition in which the ratio of the alcohol solvent to the spray agent in the composition is about 1:1 to about 3:1 (w / w).

2. The topical composition according to claim 1, wherein the naphthifine or a pharmaceutically acceptable salt thereof is naphthifine hydrochloride.

3. The topical composition according to claim 1, wherein the composition comprises about 1% to about 3% naphthifine or a pharmaceutically acceptable salt thereof.

4. The topical composition according to claim 1, wherein the composition comprises about 2% to about 10% w / w octylacrylamide acrylate copolymer.

5. The topical composition according to claim 1, wherein the ratio of film-forming agent to alcohol solvent in the composition is about 1:15 to 1:30 (w / w).

6. The topical composition according to claim 1, wherein the composition comprises less than 4% of a hydrophilic polymer.

7. The topical composition according to claim 1, wherein the alcohol solvent is a C1-6 alcohol selected from the group consisting of methanol, ethanol, propyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, 2-butanol, isobutanol, pentanol, hexanol, cyclohexanol, or combinations thereof.

8. The topical composition according to claim 1, wherein the composition comprises about 10% to about 70% by weight of an alcohol solvent.

9. The topical composition according to claim 1, wherein the composition has a viscosity of about 0.1 cp to about 500 cp.

10. The topical composition according to claim 1, wherein the spray agent is a hydrocarbon spray agent such as propane, isobutane, n-butane, isopentane or n-pentane, a fluorocarbon spray agent, a hydrofluorocarbon spray agent such as 1,1,1,2-tetrafluoroethane or 1,1-difluoroethane, or a combination thereof.

11. The topical composition according to claim 1, wherein the composition comprises about 10% to about 50% by weight of a spray agent.

12. The topical composition according to claim 1, wherein the ratio of the alcohol solvent to the spray agent is about 1.5:1 to about 2.5:1 (w / w).

13. The topical composition according to claim 1, wherein the ratio of film-forming agent to spray agent is approximately 1:7 to 1:15 (w / w).

14. The topical composition according to claim 1, further comprising a penetration enhancer, a cosolvent, an emulsifier, a solubilizer, or a combination thereof.

15. The topical composition according to claim 14, wherein the composition comprises about 0.1% to about 7% (w / w) of a penetration enhancer.

16. A topical composition according to any one of claims 1 to 15 for use in a method of treating a dermatophyte skin infection or onychomycosis in a subject requiring such treatment, wherein the method comprises topically administering the topical composition to the subject.

17. The use according to claim 16, wherein the dermatophytic skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris.

18. The use according to claim 16, wherein the administration includes applying the topical composition to the target in an aerosol spray or mist.

19. A topical sprayable composition comprising naphthifine for use in a method for treating dermatophytic skin infections in a subject, wherein the method comprises administering the topical sprayable composition comprising naphthifine, the composition being a single-phase solution, the pharmaceutical being present at least 80% saturation under the conditions of use, and the administration of the topical composition to the subject resulting in complete clearance of clinical signs and symptoms. The complete clearance is characterized by achieving at least one of the scores for the clinical signs and symptoms listed in (a) to (c): (a) Decrease in erythema severity from baseline, with a score of 0 on day 42; (b) Decrease in scaling severity from baseline, with a score of 0 on day 42; (c) A decrease in the severity of pruritus from baseline, accompanied by a score of 0 on day 42; Furthermore, a method for achieving mycological cure in KOH tests and mycological cultures.

20. A method for treating a dermatophyte skin infection in a subject, the method comprising administering a topical sprayable composition comprising naphthiphine, wherein the composition is a single-phase solution, the pharmaceutical is present at least 80% saturation under the conditions of use, the administration of the topical composition to the subject results in a therapeutic efficacy rate of at least 20%, the therapeutic efficacy being negative KOH staining, negative fungal culture, and absence or mild erythema, scaling, and itching at 6 weeks post-treatment.

21. The use according to claim 20, wherein the dermatophytic skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris.

22. A drug-device combination for dispensing a composition, wherein the drug-device combination is A container containing a composition including the following: i. Naphthifine or a pharmaceutically acceptable salt thereof; ii. Film-forming agents containing octylacrylamide acrylate copolymer; iii. Alcohol solvents; and iv. A spray, including The drug-device combination is suitable for providing a spray containing the composition, wherein the spray has a D90 droplet size greater than 1 μm.

23. A drug-device combination according to claim 22 for use in a method of treating a dermatophyte skin infection or onychomycosis in a subject requiring such treatment, comprising applying an aerosol spray or mist to the skin using the device.

24. The use according to claim 23, wherein the dermatophytic skin condition is tinea pedis, interdigital tinea pedis, or tinea cruris.

25. The method according to claim 23, wherein the composition dries in less than three minutes after application of the composition to the skin.