Improved compositions and methods for topical treatment

Abstract

Disclosed herein are compositions for topical treatment that can include a therapeutic agent (preferably a topical antimicrobial or antifungal agent such as efinaconazole, tavaborole, or ciclopirox), a non-volatile organic solvent (preferably natural or synthetic vitamin E or vitamin E acetate), and optionally an emollient (such as cholesterol). Also disclosed herein are methods of treating diseases or disorders (preferably as a disease or disorder of the nail, nail bed, or skin, such as onychomychosis) by topically administering compositions that can include a therapeutic agent, a non-volatile organic solvent, and optionally an emollient.

Description

BT Ref. 104448-429411 PATENTIMPROVED COMPOSITIONS AND METHODS FOR TOPICAL TREATMENTRELATED APPLICATIONSThis application claims priority to U.S. Provisional Application No. 63 / 683,084 filed on August 14, 2024, which are incorporated by reference in their entirety herein.BACKGROUNDTechnical Field

[0001] The present application relates to the fields of pharmaceuticals and / or chemistry. More particularly, disclosed herein are compositions containing therapeutic agents and methods for the topical treatment and / or inhibition of microbial infections such as onychomycosis.Description of Related Art

[0002] Onychomycosis is a common, chronic, and recurring fungal infection of the nail bed, matrix, or plate caused by fungi such as dermatophytes, non-derm atophyte molds, and yeasts (mainly Candida species). It may be classified as distal subungual onychomycosis, white superficial onychomycosis, proximal subungual onychomycosis, or candidal onychomycosis. It is estimated that 35 million individuals suffer from the disease, although only about 6.3 million of these individuals have been formally diagnosed. However, infection rates are increasing and onychomycosis is expected to affect half the population by the time they reach 70 years of age.

[0003] The vast majority of cases of onychomycosis are caused by dermatophyte fungi. For example, dermatophytes are identified in 90% of toenail and 50% of fingernail onychomycosis, with Trichophyton rubrum or Trichophyton mentagrophytes identified as the causative pathogen in 80-98% of the individuals. The most common form of Tinea unguium is distal subungual onychomycosis (90%), which can be distal and lateral. Candida albicans accounts for about 2%BT Ref. 104448-429411 PATENT of onychomycosis, occurring especially in fingernails, while non-dermatophytic mold onychomycosis is primarily cultured from toenails. Examples of these nondermatophytic molds include Fusarium, Aspergillus, Acremonium, Scytalidium, and Scopulariopsis brevicaulis and they account for about 8% of nail infections.

[0004] Individuals with onychomycosis are often embarrassed about their nail disfigurement. Left untreated, it can lead to progressive destruction and deformity of the toenails and fingernails. Moreover, onychomycosis can also limit mobility and may indirectly decrease peripheral circulation. This can lead to worsening of additional co-morbidities, such as venous stasis and diabetic foot ulcers. Thus, affected subjects may exhibit significant physical and psychological effects from this disease.

[0005] Onychomycosis treatment strategies include both oral and topical administration of antimicrobial agents. Successful treatment can be complicated by several factors: (1) slow nail growth; (2) the physical presence of the nail plate interfering with nail bed access after application of a topical antimicrobial agent; (3) difficulty in finding compounds with the pharmacologic / pharmacokinetic profile to allow adequate nail unit penetration; (4) challenges in achieving therapeutic substantivity of drug levels after topical or oral administration; (5) development of optimal vehicles for topical use that allow delivery of effective drug levels to the site(s) of nail infection (primarily nail bed); (6) the anatomic nature of the nail unit and its vascular access, which allows for higher drug levels in nail bed / plate centrally as compared to laterally after oral antifungal administration; (7) the high incidence of recurrence after clearance with therapy; (8) widespread environmental exposure to dermatophytes and other fungal organisms; and (9) the genetic predisposition of many individuals to pedal colonization and infection with T. rubrum, which eventually leads to invasion of the nail unit with reinfection.BT Ref. 104448-429411 PATENT

[0006] In addition to oral and topical treatments, adjunctive physical modalities (chemical debridement, mechanical debridement, nail avulsion) and approaches to minimize the risk of recurrence or re-infection (e.g., topical therapy to suppress pedal colonization or infection) may be implemented. However, oral therapy has generally been considered the most effective regiment for severe onychomycosis. Nevertheless, oral treatment of onychomycosis is not always successful, particularly due to the previously mentioned complications.

[0007] Furthermore, many patients have a strong preference for avoiding oral antimicrobial therapies and the resulting systemic levels of drug in their bodies. Similarly, many of the commonly administered antimicrobial agents for treating onychomycosis are unsuitable for use in certain patients or with concurrent medications. For example, terbinafine alters the metabolism of a number of drugs and may produce severe side effects such as blood and lymphatic system disorders, immune system disorders, or cause taste disturbance (including taste loss) in certain patients. Terbinafine is also contraindicated for concurrent use with the phenothiazines and pimozide because of increased risk of QT prolongation. Moreover, drug-to-drug interactions are known to occur between the widely used azole treatment class and other therapeutics. For example, itraconazole is contraindicated with a significant number of other medications and should not be used in patients with evidence of ventricular dysfunction such as congestive heart failure. Considering that oral antifungal agents require long treatment periods, generally have more side effects, and there are safety concerns with these agents, many patients prefer to treat their onychomycosis by topical administration.

[0008] Topical medications may be formulated as a cream, solution, lotion, powder, gel, spray, or lacquer that are then applied to the affected area(s) for treating onychomycosis. However, nail plate interference and poor nail unit penetration often limits the usefulness of current topical agentsBT Ref. 104448-429411 PATENT in the treatment of onychomycosis. As an example, until 2014 only one topical medication, ciclopirox 8% nail lacquer, was FDA approved for the treatment of onychomycosis. It requires 48 weeks of once-daily application and regular surgical intervention to remove unattached and infected nail. Patient compliance was poor and efficacy was disappointing. This has resulted in topical ciclopirox being reserved for mild cases, palliative benefit, or when oral therapy was not an option for the patient.

[0009] Tavaborole represents a class of protein synthesis inhibitors that exhibit antifungal properties. It is FDA approved for topical use as a 5% solution containing alcohol, propylene glycol, and edetate calcium disodium for treating onychomycosis of the toenails due to T. rubrum and T. mentagrophytes. Tavaborole 5% requires 48 weeks of once-daily application and complete cure rates (defined as 0% clinical involvement of the target toenail plus negative KOH and negative culture) were low, ranging from 6.5% to 9.1%. See, e.g., Kerydin® Product Insert, which is incorporated by reference in its entirety.

[0010] Efinaconazole was subsequently identified as having broad spectrum in vitro activity against dermatophytes, non-dermatophytes, and yeasts. Against the most common pathogens, T. rubrum and T. mentagrophytes (MIC90: 0.008-0.015 pg / mL) and C. albicans (MIC50: 0.004 pg / mL), it was more potent than currently marketed alternatives for treating onychomycosis. Efinaconazole is FDA approved for topical use as a 10% solution containing alcohol, anhydrous citric acid, butylated hydroxytoluene, C12-15 alkyl lactate, cyclomethicone, diisopropyl adipate, di sodium edetate, and purified water for treating onychomycosis of the toenails due to T. rubrum and T. mentagrophytes . Efinaconazole 10% solution requires 48 weeks of once-daily application and complete cure rates (defined as 0% clinical involvement of the target toenail plus negativeBT Ref. 104448-429411 PATENTKOH and negative culture) were marginal, ranging from 17.8% to 15.2%. See, e.g., Jublia® Product Insert, which is incorporated by reference in its entirety.

[0011] Improved compositions for the treatment of microbial infections such as onychomycosis are needed.SUMMARY OF THE INVENTION

[0012] Embodiments disclosed herein relate to compositions for topical treating that include a therapeutic agent, a non-volatile organic solvent in the amount of greater than or equal to about 50% (w / w), and optionally an emollient. Preferably, the compositions are liquid. Additional aspects of the compositions include the following embodiments.

[0013] In one embodiment described herein is a composition for topical treatment, comprising, consisting of, or consisting essentially of: a therapeutic agent, a non-volatile organic solvent in the amount of greater than or equal to about 50% (w / w), and optionally an emollient. In one embodiment, the composition is formulated as a solution, a cream, a gel, a lotion, a shampoo, a suspension, an emulsion, a nail lacquer, an ointment, a lozenge, a capsule, a suppository, or a vaginal insert.

[0014] In one embodiment, the therapeutic agent is an antimicrobial agent. In one embodiment, the therapeutic agent is an antifungal agent. In one embodiment, the therapeutic agent is useful for treating a skin infection caused by dermatophytes, yeasts, or molds. In another embodiment, the therapeutic agent is a therapeutic agent approved by a regulatory authority for topical treatment. In one embodiment, the therapeutic agent is a therapeutic agent approved by the FDA for topical treatment. In one embodiment, the therapeutic agent is selected from the group consisting of: salicylic acid, benzoic acid, undecylenic alkanolamide, ciclopirox, butenafine, naftifine, nystatin, bifonazole, clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, miconazole,BT Ref. 104448-429411 PATENT sulconazole, tioconazole, itraconazole, terbinafine, tolciclate, tolnaftate, tavaborole, and pharmaceutically acceptable salts thereof. In another embodiment, the therapeutic agent is selected from the group consisting of: 3% salicylic acid, and 6% benzoic acid, undecylenic alkanolamide, ciclopirox, ciclopirox olamine, butenafine hydrochloride, naftifine hydrochloride, nystatin, bifonazole, clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, miconazole, sulconazole, tioconazole, itraconazole, terbinafine, tolciclate, tolnaftate, and tavaborole.

[0015] In one embodiment, the therapeutic agent is useful for treating tinea pedis, tinea cruris, or tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, or Microsporum canis; seborrheic dermatitis; cutaneous candidiasis (moniliasis) due to Candida albicans, tinea (pityriasis) versicolor due to Malassezia furfur, onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes, cutaneous or mucocutaneous mycotic infections due to Candida albicans and other susceptible Candida species; yeast infections; vaginal yeast infections; superficial skin infections due to yeast; Trichophyton tonsurans, blastomycosis; pulmonary and extrapulmonary histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.; oropharyngeal candidiasis; vulvovaginal candidiasis; or vaginal yeast infection. In another embodiment, the therapeutic agent is useful for treating onychomycosis.

[0016] In one embodiment, the therapeutic agent is approved by a regulatory authority for treating onychomycosis. In one embodiment, the therapeutic agent is approved by the FDA for treating onychomycosis. In another embodiment, the therapeutic agent is an antifungal agent that is selected from the group consisting of azoles, allylamines, hydroxypyridinones, morpholines,BT Ref. 104448-429411 PATENT and oxaboroles. In one embodiment, the therapeutic agent is an antifungal agent that is selected from the group consisting of: terbinafine, itraconazole, griseofulvin, ciclopirox, amorolfine, tavaborole, fluconazole, and efinaconazole. In one embodiment, the therapeutic agent is an antifungal agent that is selected from the group consisting of: terbinafine, itraconazole, cicloprox, cicloprox olamine, tavaborole, and efinaconazole. In one embodiment, the therapeutic agent is an azole antifungal agent that is a triazole antifungal agent. In one embodiment, the therapeutic agent is efinaconazole. In one embodiment, the therapeutic agent is tavaborole. In one embodiment, the therapeutic agent is ciclopirox or ciclopirox olamine. In another embodiment, the therapeutic agent is nystatin. In one embodiment, the therapeutic agent is clotimazole. In another embodiment, the therapeutic agent is miconazole. In one embodiment, the therapeutic agent is butenafine hydrochloride. In one embodiment, the therapeutic agent is naftifine hydrochloride. In another embodiment, the therapeutic agent is luliconazole. In another embodiment, the therapeutic agent is itraconazole.

[0017] In another embodiment described herein the therapeutic agent is present in the amount of about l%-40% (w / w), about 5%-20% (w / w), about 8%-12% (w / w), about 10% (w / w), or 10% (w / w). In one embodiment, the therapeutic agent is efinaconazole and is present in the composition in the amount of about l%-30% (w / w), 3%-20% (w / w), about 5%-15% (w / w), about 8%-12% (w / w), about 10% (w / w), or 10% (w / w). In one embodiment, the therapeutic agent is tavaborole and is present in the composition in the amount of about 1%-15% (w / w), about l%-10% (w / w), about 2%-8% (w / w), about 5% (w / w), or 5% (w / w). In one embodiment, the therapeutic agent is ciclopirox and is present in the composition in the amount of about 1%-15% (w / w), about 2%- 12% (w / w), about 3%- 10% (w / w), about 5%-l 0% (w / w), about 8% (w / w), or 8% (w / w). In one embodiment, the therapeutic agent is ciclopirox and is present in the composition in the amount ofBT Ref. 104448-429411 PATENT about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l% (w / w), about 0.77% (w / w), about 1% (w / w), 0.77% (w / w), or 1% (w / w). In another embodiment, the therapeutic agent is ciclopirox olamine and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l% (w / w), about 0.77% (w / w) or 0.77% (w / w). In another embodiment, the therapeutic agent is nystatin and is present in the composition in the amount of about 50,000- 150,000 USP Nystatin Units, about 75,000-125,000 USP Nystatin Units, about 100,000 USP Nystatin Units or 100,000 USP Nystatin Units. In another embodiment, the therapeutic agent is clotimazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%- 2% (w / w), about 0.7%-1.5% (w / w), about 1% (w / w) or 1% (w / w). In one embodiment, the therapeutic agent is miconazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.75%-3% (w / w), about l%-2.5% (w / w), about 2% (w / w) or 2% (w / w). In one embodiment, the therapeutic agent is butenafme hydrochloride and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%- 1.5% (w / w), about 1% (w / w) or 1% (w / w). In another embodiment, the therapeutic agent is naftifine hydrochloride and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.75%-3% (w / w), about l%-2.5% (w / w), about 1% (w / w), about 2% (w / w), 1% (w / w), or 2% (w / w). In one embodiment, the therapeutic agent is luliconazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l .5% (w / w), about 1% (w / w) or 1% (w / w). In another embodiment, the therapeutic agent is itraconazole.

[0018] In one embodiment described herein, the ratio by weight of the therapeutic agent to the non-volatile solvent is about 1 : 1, about 1 : 1.5, about 1 :2, about 1 :2.5, about 1 :3, about 1 :3.5, about 1 :4, about 1 :4.5, about 1 :5, about 1 :5.5, about 1 :6, about 1:6.5, about 1:7, about 1:7.5, about 1 :8, about 1 :8.5, about 1 :9, about 1 :9.5, about 1 : 10, about 1 :10.5, about 1 : 11, about 1 :11.5, about 1 : 12,BT Ref. 104448-429411 PATENT about 1 : 12.5, about 1 :13, about 1 :13.5, about 1 : 14, about 1 : 14.5, about 1 : 15, about 1 : 16, about 1 : 17, about 1 : 18, about 1 : 19, about 1 :20, about 1 :25, about 1 :30, about 1:35, about 1 :40, about 1 :45, about 1 :50, about 1:55, about 1 :60, about 1 :65, about 1 :70, about 1:75, about 1 :80, about 1 :85, about 1:90, about 1 :95, or about 1 :99.

[0019] In another embodiment, the composition comprises about l%-20% (w / w) therapeutic agent and about 80%-99% (w / w) non-volatile solvent, about 5%- 15% (w / w) therapeutic agent and about 85%-95% (w / w) non-volatile solvent, 8%- 12% (w / w) therapeutic agent and about 88%-92% (w / w) non-volatile solvent, about 10% (w / w) therapeutic agent and about 90% (w / w) non-volatile solvent, 10% (w / w) therapeutic agent and 90% (w / w) non-volatile solvent. In another embodiment, the composition comprises about 1%-15% (w / w) therapeutic agent and about 85%- 99% (w / w) non-volatile solvent, about l%-10% (w / w) therapeutic agent and about 90%-99% (w / w) non-volatile solvent, about 2%-8% (w / w) therapeutic agent and about 92%-98% (w / w) nonvolatile solvent, about 5% (w / w) therapeutic agent and about 95% (w / w) non-volatile solvent, or 5% (w / w) therapeutic agent and 95% (w / w) non-volatile solvent.

[0020] In another embodiment, the non-volatile solvent is an organic solvent. In another embodiment, the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure that is greater than or equal to 125° C, 130° C, 135° C, 140° C, 145° C, 150° C, 155° C, 160° C, 165° C, 170° C, 175° C, 180° C, 185° C, 190° C, 195° C, 200° C, 205° C, 210° C, 215° C, 220° C, 225° C, 230° C, or 235° C. In one embodiment, the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure that is greater than or equal to 200° C, 205° C, 210° C, 215° C, 220° C, 225° C, 230° C, or 235° C. In another embodiment, the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressureBT Ref. 104448-429411 PATENT that is greater than or equal to 225° C, 230° C, or 235° C. In one embodiment, the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure of between about 200° C to 240° C. In one embodiment, the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and begins to decay at about 240° C at standard pressure. In one embodiment, the non-volatile solvent is a lipophilic compound. In one embodiment, the non-volatile solvent is a lipophilic compound that is miscible with acetone, chloroform, ether, and vegetable oils. In one embodiment, the non-volatile solvent has a hydrophilic-lipophilic balance of less than or equal to 5, less than or equal to 4, less than or equal to 3, less than or equal to 2, less than or equal to 1, or equal to 0.

[0021] In another embodiment, the non-volatile solvent is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, an ester of tocopherols excipient, and mixtures thereof. In one embodiment, the non-volatile solvent is aCi-Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, or tocopherols excipient. In one embodiment, the non-volatile solvent is an acetate ester of vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, or tocopherols excipient. In one embodiment, the non-volatile solvent is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, a synthetic ester of tocopherols excipient, and mixtures thereof. In another embodiment, the non-volatile solvent is a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, or tocopherols excipient. In one embodiment, the non-volatileBT Ref. 104448-429411 PATENT solvent is a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E. In one embodiment, non-volatile solvent is vitamin E. In another embodiment, the non-volatile solvent is synthetic vitamin E. In one embodiment, the non-volatile solvent is vitamin E acetate. In one embodiment, the non-volatile solvent is synthetic vitamin E acetate.

[0022] In one embodiment, the non-volatile solvent is a single solvent. In one embodiment, the non-volatile solvent is a mixture of two or more solvents. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, and an ester of tocopherols excipient. In one embodiment, the the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, and a synthetic ester of tocopherols excipient. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, and gamma tocopherol. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, and synthetic gamma tocopherol. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of theBT Ref. 104448-429411 PATENT non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, and an ester of gamma tocopherol. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, is a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an acetate ester of vitamin E, an acetate ester of beta tocopherol, an acetate ester of delta tocopherol, an acetate ester of gamma tocopherol, and an acetate ester of tocopherols excipient. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, and a synthetic ester of gamma tocopherol. In another embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol.

[0023] In another embodiment the volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic acetate ester of vitamin E, a synthetic acetate ester of betaBT Ref. 104448-429411 PATENT tocopherol, a synthetic acetate ester of delta tocopherol, a synthetic acetate ester of gamma tocopherol, a synthetic acetate ester of tocopherols excipient. In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is vitamin E, vitamin E acetate, synthetic vitamin E, or synthetic vitamin E acetate. In another embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is synthetic vitamin E acetate.

[0024] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, and an ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition.

[0025] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from theBT Ref. 104448-429411 PATENT group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, and a synthetic ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition.

[0026] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, and gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the totalBT Ref. 104448-429411 PATENT amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0027] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, and synthetic gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0028] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, and an ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in theBT Ref. 104448-429411 PATENT composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0029] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an Ci-Cio, Ci-Cs, Ci-Cs, C2-C4, or C2 ester of vitamin E, a C1-C10, Ci-Cs, Ci- C5, C2-C4, or C2 ester of beta tocopherol, is a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0030] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an acetate ester of vitamin E, an acetate ester of beta tocopherol, an acetate ester of delta tocopherol, an acetate ester of gamma tocopherol, and an acetate ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than aboutBT Ref. 104448-429411 PATENT50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 60%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 65%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 70%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 75%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 80%(w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0031] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, and a synthetic ester of gamma tocopherol and at least one of the nonvolatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition.

[0032] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from theBT Ref. 104448-429411 PATENT group consisting of: a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a syntheticC1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0033] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic acetate ester of vitamin E, a synthetic acetate ester of beta tocopherol, a synthetic acetate ester of delta tocopherol, a synthetic acetate ester of gamma tocopherol, and a synthetic acetate ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-BT Ref. 104448-429411 PATENT volatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition.

[0034] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, vitamin E acetate, synthetic vitamin E, or synthetic vitamin E acetate and at least one of the non-volatile solvents is present in the amount of greater than about50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 60%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 65%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 70%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 75%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 80%(w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85%(w / w) of the total amount of non-volatile solvents in the composition.

[0035] In one embodiment, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is vitamin E acetate and the vitamin E acetate is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the totalBT Ref. 104448-429411 PATENT amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0036] In one embodiment, the the non-volatile solvent is present in the amount of greater than about 50% (w / w), greater than about 55% (w / w), greater than about 60% (w / w), greater than about 65% (w / w), greater than about 70% (w / w), greater than about 75% (w / w), greater than about 80% (w / w), or greater than about 85% (w / w). In another embodiment, the non-volatile solvent is present in the amount of about 50% (w / w), about 55% (w / w), about 60% (w / w), about 65% (w / w), about 70% (w / w), about 75% (w / w), about 80% (w / w), about 85% (w / w), about 90% (w / w), or about 95% (w / w).

[0037] In another embodiment of the composition described herein, emollient is present. In one embodiment, the emollient is selected from the group consisting of: adipate esters, glycols, lanolin, lanolin alcohols, glycerin, stearates, shea butter, beeswax, dimethicone, cyclomethicone, diisopropyl adipate, ceramide, Ceratonia extract, cetostearyl alcohol, cetyl alcohol, petrolatum, oils, paraffin, dibutyl sebacate, glycerol behenate, glycerol monooleate, isopropyl myristate, isopropyl palmitate, lecithin, ethyl linoleate, medium chain triglycerides, myristyl alcohol, octyldodecanol, oleyl alcohol, stearyl alcohol, tricaprylin, triolein, waxes, and sterols. In one embodiment, the emollient is selected from the group consisting of: diisopropyl adipate, propylene glycol, lanolin, lanolin alcohols, glycerin, glycerol monostearate, ethylene glycol stearates, shea butter, beeswax, dimethicone, cyclomethicone, ceramide, Ceratonia extract, cetostearyl alcohol, cetyl alcohol, petrolatum, almond oil, canola oil, castor oil, coconut oil, cottonseed oil, mineral oil, mineral oil light, jojoba oil, olive oil, safflower oil, soybean oil, sunflower oil, squalene, paraffin, monostearates, dibutyl sebacate, glycerol behenate, glycerol monooleate, isopropylBT Ref. 104448-429411 PATENT myristate, isopropyl palmitate, lecithin, ethyl linoleate, medium chain triglycerides, myristyl alcohol, octyldodecanol, oleyl alcohol, stearyl alcohol, tricaprylin, triolein, carnauba wax, cetyl ester wax, xylitol, zinc acetate, and cholesterol. In one embodiment, the is cholesterol. In one embodiment, the emollient is present in the amount of about 0. l%-5% (w / w), about 0.5%-3% (w / w), about l%-2% (w / w), about 1% (w / w), or about 2% (w / w).

[0038] In one embodiment, the composition does not further include any emollient or additional emollient. In one embodiment, the composition does not further include any emulsifier or additional emulsifier. In one embodiment, the composition does not further include any preservative or additional preservative. In one embodiment, the composition does not further include any antioxidant or additional antioxidant. In one embodiment, the composition does not further include any chelating agent or additional chelating agent. In one embodiment, the composition does not further include any thickener or additional thickener. In one embodiment, the composition does not further include any humectant or additional humectant. In one embodiment, the composition does not further include any wetting agent or additional wetting agent. In another embodiment, the composition does not further include any permeation enhancer or additional permeation enhancer. In one embodiment, the composition does not further include any buffering agent or additional buffering agent. In one embodiment, the composition does not further include any pH adjusting agent or additional pH adjusting agent. In one embodiment, the composition does not further include any volatile solvent or additional volatile solvent. In one embodiment, the composition does not further include any additional non-volatile solvent. In one embodiment, the composition does not further include any fragrances, perfumes, or fragrance compounds. In one embodiment, the composition does not further include any additional therapeutic agent. In one embodiment, the composition does not include any additional ingredientsBT Ref. 104448-429411 PATENT that were liquid before incorporation into the composition. In one embodiment, the composition does not include any additional ingredients that were solid before incorporation into the composition. In one embodiment, the composition does not further include one or more of an additional alcohol, citric acid, butylated hydroxytoluene, Cl 2- 15 alkyl lactate, cyclomethicone, diisopropyl adipate, disodium edetate, or water. In one embodiment, the composition does not include any polymeric film forming compounds.

[0039] In one embodiment, the composition is suitable for topical application to a subject in need of treatment. In another embodiment, the composition is formulated as a solution. In one embodiment, the composition is formulated for delivery of the therapeutic agent to the nail or nail bed of a subject. In one embodiment, the surface tension of the composition is about 40 dynes / cm or less, about 35 dynes / cm or less, about 30 dynes / cm or less, or about 25 dynes / cm or less.

[0040] In one embodiment, the composition includes one or more emulsifiers. In one embodiment, the composition includes one or more preservatives. In one embodiment, the composition includes one or more antioxidants. In one embodiment, the composition includes one or more chelating agents. In one embodiment, the composition includes one or more thickeners. In one embodiment, the composition includes one or more humectants. In one embodiment, composition includes one or more wetting agents. In one embodiment, the composition includes one or more permeation enhancers. In one embodiment, the composition includes one or more buffering agents. In one embodiment, the composition includes one or more pH adjusting agents. In one embodiment, the composition includes one or more volatile solvents. In one embodiment, the composition includes two or more non-volatile solvents.

[0041] In one embodiment, the composition includes two or more therapeutic agents. In one embodiment, the composition includes one or more fragrances, perfumes, or fragrance compounds.BT Ref. 104448-429411 PATENT

[0042] Embodiments disclosed herein also relate to methods for treating a subject having a disease or disorder by administering any of the compositions described herein. In one embodiment, the the disease or disorder may be one that is amenable to topical treatment, it may be a disease or disorder of the nail, nail bed, and / or skin, the disease or disorder may be a fungal disease, the disease or disorder may be a skin infection, or the disease or disorder may be onychomychosis.

[0043] In one embodiment described herein is a method for treating a subject having a disease or disorder amenable to topical treatment comprising, consisting, or consisting essentially of: topically administering to the subject any of the compositions described herein.

[0044] In one embodiment is a method for treating a subject having a disease or disorder of the nail, nail bed, and / or skin comprising, consisting, or consisting essentially of: topically administering to the subject any of the compositions described herein.

[0045] In one embodiment is a method for treating a subject having a disease or disorder of the nail and / or nail bed comprising, consisting, or consisting essentially of: topically administering to the subject any of the compositions described herein. In one embodiment, the method for treating a subject having a disease or disorder of the skin comprising, consisting, or consisting essentially of: topically administering to the subject any of the compositions described herein.

[0046] In one embodiment is a method for treating a subject having a fungal disease or disorder comprising, consisting of, or consisting essentially of: administering to the subject any of the composition described herein. In one embodiment is a method for treating a subject having a fungal skin infection comprising, consisting, or consisting essentially of: topically administering to the subject any of the compositions described herein.BT Ref. 104448-429411 PATENT

[0047] In one embodiment is a method for treating a subject having onychomychosis, comprising, consisting, or consisting essentially of: topically administering to a nail of the subject a pharmaceutically effective amount of any of the compositions described herein. In one embodiment is a method for treating a subject having tinea pedis, tinea cruris, or tinea corporis due to Trichophyton rubrum, Trichophyton mentcigrophytes, Epidermophyton floccosum, or Microsporum canis; seborrheic dermatitis; cutaneous candidiasis (moniliasis) due to Candida albicans,' tinea (pityriasis) versicolor due to Malassezia furfur,' onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes, cutaneous or mucocutaneous mycotic infections due to Candida albicans and other susceptible Candida species; yeast infections; vaginal yeast infections; superficial skin infections due to yeast; Trichophyton tonsurans, blastomycosis; pulmonary and extrapulmonary histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy; oropharyngeal candidiasis; vulvovaginal candidiasis; or vaginal yeast infection, comprising, consisting of, or consisting essentially of: topically administering to the subject a pharmaceutically effective amount of any of the compositions described herein.

[0048] In one embodiment of the method, the subject is a human. In one embodiment the subject is an adult human. In one embodiment the subject is a juvenile human. In one embodiment the subject is immunocompromised. In one embodiment the the subject is not immunocompromised. In one embodiment the disease or is a disease or disorder of the nail. In one embodiment the disease or disorder is a disease or disorder of the nail bed. In one embodiment the disease or disorder is a disease or disorder is a fungal infection. In one embodiment the disease or disorder is a disease or disorder is a skin infection.BT Ref. 104448-429411 PATENT

[0049] In one embodiment the disease or disorder is onychomychosis. In one embodiment the disease or disorder is caused by dermatophytes, yeasts, and / or molds. In one embodiment the disease or disorder is caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis. Candida albicans, Malassezia furfur, or Trichophyton tonsurans. In one embodiment the disease or disorder is caused by a fungus selected from the group consisting of: Trichophyton rubrum, Trichophyton mentagophytes, and both Trichophyton rubrum and Trichophyton mentagophytes. In one embodiment the disease or disorder is tinea pedis, tinea cruris, tinea corporis, seborrheic dermatitis, tinea versicolor, blastomycosis, histoplasmosis, or aspergillosis. In one embodiment the disease or disorder is tinea pedis, tinea cruris, or tinea corporis.

[0050] In one embodiment the treatment of the subject includes topically administering to the subject the any of the compositions described herein. In one embodiment the administration of the composition is repeated in an amount and for a time sufficient to ameliorate the signs or symptoms of the disease or disorder. In one embodiment the composition is administered for about 60 weeks, about 48 weeks, about 36 weeks, about 24 weeks, or about 12 weeks. In one embodiment the composition is administered for about 48 weeks. In one embodiment the composition is administered for about 36 weeks. In one embodiment the composition is administered for about 24 weeks. In one embodiment the composition is administered for about 12 weeks.

[0051] In one embodiment the composition is administered 1 -4 times daily to the affected area. In one embodiment the composition is administered once daily to the affected area. In one embodiment the affected area is the subject’s nail, nail fold, nail bed, cuticle, hyponychium, skin, and / or nail plate. In one embodiment the affected area is a toenail. In one embodiment the affectedBT Ref. 104448-429411 PATENT area is completely covered by the administration. In one embodiment the composition is administered to each affected area of the subject. In one embodiment the composition is administered to each nail or nail bed of the subject. In one embodiment the composition is administered to each toenail or toenail bed of the subject. In one embodiment the subject administers the composition only to affected toes and / or fingers.

[0052] In one embodiment of the method, the average amount of therapeutic agent delivered to each cm2of the affected area is about 0.15 mg / cm2to about 0.45 mg / cm2. In one embodiment the administration to the surface of a nail or nail bed does not form a solid film. In one embodiment the affected area is not debrided initially or during the treatment period. In one embodiment the composition is not removed from the treatment area during the treatment period.

[0053] In one embodiment the method is performed without occluding or partially occluding the nail, nail associated tissue, or affected area. In one embodiment the method is performed with occluding or partially occluding the nail, nail associated tissue, or affected area.

[0054] In another embodiment the the subject waits at least 10 minutes before administering the composition if the treatment area was previously in contact with water. In one embodiment the the subject waits at least 10 minutes to administer the composition after showering, bathing, or washing the treatment area. In one embodiment the subject avoids pedicures, the use of nail polish, and / or cosmetic nail products during the treatment period. In one embodiment the method includes a step of cleaning the affected area prior to administering the composition. In one embodiment the subject cleans the affected area prior to treatment and waits for at least 10 minutes before administering the composition if the cleaning includes wetting the affected area with water.BT Ref. 104448-429411 PATENT

[0055] In one embodiment the method comprises cutting nails once every two weeks or more frequently. In one embodiment the method does not comprise cutting nails more often than every two weeks.

[0056] In one embodiment of the method, the composition is not administered in an occluded or semi-occluded manner. In one embodiment the method comprises spreading the composition throughout the treatment area with an applicator. In one embodiment the method comprises administering the composition from a container that is in fluid communication with an applicator, loading the applicator, and applying the composition with the applicator.

[0057] In one embodiment the composition is in a container that is suitable for storing the composition for pharmaceutical use that comprises an applicator that is capable of dispensing a pharmaceutically effective dose of the composition and spreading an approximately uniform amount of the composition to the treatment area by manual action after loading, loading the applicator with the dose of the composition, and administering the composition to the treatment area to be treated by manual spreading. In one embodiment the method comprises manually loading the applicator with the dose of the composition. In one embodiment the container is a squeeze sensitive container and the applicator is a flow through applicator that delivers the composition to the treatment area when a user applies sufficient pressure on the container. In one embodiment the volume of the composition contained in the applicator is about 75 to about 150 microliters.

[0058] In one embodiment the performance of the method in a subject population results in a mycological cure rate of at least about 40%, a clinical efficacy rate of at least about 20%, a complete cure rate of at least about 10%, or a combination of any or all thereof. In one embodiment the method of treatment results in a In one embodiment the cure for the subject or a subjectBT Ref. 104448-429411 PATENT population. In one embodiment the method of treatment results in a mycological cure for the subject or a subject population.

[0059] In one embodiment the method of treatment results in an almost complete cure for the subject or a subject population. In one embodiment the method of treatment results in clinical efficacy for the subject or a subject population.

[0060] Additional aspects of embodiments of the compositions and methods are described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1. Treatment of onychomycosis affecting a subject’s left hallux with images taken at baseline, 2 months, 6 months, and 16 months.

[0062] Figure 2. Treatment of onychomycosis affecting a subject’s right hallux with images taken at baseline, 2 months, 6 months, and 16 months.

[0063] Figure 3. Treatment of onychomycosis affecting a subject’s right fore toe with images taken at baseline, 2 months, 6 months, and 16 months.DETAILED DESCRIPTION

[0064] Described herein are improved compositions and methods for the treatment of diseases or disorders resulting from microbial agents, such as onychomycosis. In order to treat a subject, therapeutic levels of antimicrobial agent should be delivered to the affected location. Several factors complicate treatment of nail infections, e.g.: (1) slow nail growth; (2) the physical presence of the nail plate interfering with nail bed access after application of a topical antimicrobial agent; (3) difficulty in finding compounds with the pharmacologic / pharmacokinetic profile to allow adequate nail unit penetration; (4) challenges in achieving therapeutic substantivity of drug levels after topical or oral administration; (5) development of optimal vehicles for topical use that allowBT Ref. 104448-429411 PATENT delivery of effective drug levels to the site(s) of nail infection (primarily nail bed); (6) the anatomic nature of the nail unit and its vascular access, which allows for higher drug levels in nail bed / plate centrally as compared to laterally after oral antifungal administration; (7) the high incidence of recurrence after clearance with therapy; (8) widespread environmental exposure to dermatophytes and other fungal organisms; and (9) the genetic predisposition of many individuals to pedal colonization and infection with T. rubrum, which eventually leads to invasion of the nail unit with reinfection. However, only factors (3), (4), and (5) are non-physiological, patient-independent complications that may be addressed by the development of improved compositions for treatment. Described herein are compositions that address these factors, and the common problem of delivering therapeutic levels of antimicrobial agents to the affected location, by discerning that existing topical treatments are poorly formulated for delivering therapeutic agents for the treatment of nail infections.

[0065] As previously indicated, Kerydin® (tavaborole 5% solution) is formulated with alcohol and propylene glycol as solvents for the tavaborole active ingredient. See, e.g., Kerydin® Product Insert, which is incorporated by reference in its entirety. Similarly, Jublia® (efmaconazole 10% solution) is formulated with alcohol, cyclomethicone, and diisopropyl adipate as solvents for the efmaconazole active ingredient. See, e.g., Jublia® Product Insert, which is incorporated by reference in its entirety. Each of these formulations include high amounts of volatile solvent / vehicle (e.g., ethanol) to dissolve the therapeutic agent. Due to the highly volatile nature of the solvent, the solvent rapidly vaporizes upon topical application. Although this provides a high localized drug concentration gradient between the surface of the affected area and the underlying tissue, permeation enhancers are needed in these formulations to improve drug penetration. See, e.g., Park et al., “Effect of Penetration Enhancers on Toenail Delivery ofBT Ref. 104448-429411 PATENTEfinaconazole from Hydroalcoholic preparations,” Molecules (2021), Vol. 26, 1650, pages 1-12, which is incorporated by reference. The result is often low efficacy resulting from poor drug delivery.

[0066] Described herein are improved upon topical compositions by identifying and utilizing much less volatile (e.g., non-volatile) vehicles / solvents in which the therapeutic agent (e.g., efinaconazole) was determined to have acceptable solubility at the desired concentration. Moreover, the compositions described herein do not need to rely on the generation of a localized drug concentration gradient that conventional formulations obtain through reliance on volatile solvent evaporation. Likewise, use of non-volatile solvents provide the formulator with flexibility by permitting the exclusion of separate permeation enhancers. Moreover, improved treatment outcomes may be obtained for such compositions that are needed in conventional formulations to facilitate drug penetration. In some embodiments, additional characteristics of the composition include less volatility of the solvent / composition, enhanced contact time of the composition, better therapeutic agent absorption, health benefits to the skin and / or nail attributable to the use of the non-volatile solvent, less irritation attributable to the non-volatile solvent, less toxicity, and / or less side effects.General

[0067] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.BT Ref. 104448-429411 PATENT

[0068] As described herein, it is intended that where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the embodiments. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the embodiments, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the embodiments. It is further intended that when a series of whole integers are reported for any particular value, e.g., 1, 2, 3, 4, 5, 6, etc., a range may be enumerated from any of the aforementioned whole integers, e.g., 1-6, 2-6, 3-5, 1-4, etc.

[0069] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a given value, per the practice in the art. Alternatively, and particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value, per the practice in the art. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed. Unless otherwise indicated, when the term “about” is used to modify a numerical range (e.g., 25%-75% or from 25% to 75%), it is understood that the term modifies both endpoints of the range (e.g., about 25% to about 75% or from about 25% to about 75%).BT Ref. 104448-429411 PATENT

[0070] As used herein, the terms “treat,” treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition, unless otherwise indicated. Any alleviation of any undesired signs or symptoms of a disease, disorder, or condition, to any extent can be considered treatment and / or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0071] By use of the phrases “at least one” or “one or more”, it is understood that the referenced category may be present as two, three, four, or five or more items that are individual members of the category. Unless otherwise indicated (such as, e.g., when a specific member of the referenced category is identified), when “at least one” or “one or more” referenced items are indicated as being present in a certain percentage or amount, the percentage or amount is intended to encompass the summation of the collective amounts or collective percentages of all items that satisfy the referenced category.

[0072] The term “effective amount” means the total amount of each active therapeutic agent of the drug delivery compositions or methods that is sufficient to show a meaningful benefit to the subject, e.g., healing of a disease or disorder, an increase in rate of healing of such a disease or disorder, or a reduction in an aberrant condition associated with a disease or disorder. This includes both therapeutic and prophylactic treatments. Accordingly, the therapeutic agents can be used at very early stages of a disease, or before early onset, or after significant progression. When applied to an individual therapeutic agent, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the therapeutic agents that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

[0073] As used herein, “Cato Cb ' or “Co-Cz>” in which “a” and “£>” are integers refer to the number of carbon atoms in a referenced functional group. That is, the functional group can containBT Ref. 104448-429411 PATENT from to “Z>”, inclusive, carbon atoms. Thus, for example, a “C1-C3” ester refers to all esters having from 1 to 3 carbons, e g., HC(=O)-, CH3C(=O)-, and CH3CH2C(=O)-.

[0074] As used herein, the term “complete cure” means 0% clinical involvement of treated (previously affected) area plus negative KOH examination and negative fungal culture. This refers to the complete absence of any visible signs or symptoms of the infection in the area that was being treated. For example, in the case of onychomycosis, this would mean the treated nail appears entirely healthy and clear, with no discoloration, thickening, or other abnormalities. A negative Potassium Hydroxide (KOH) examination signifies that no fungal elements (like hyphae or spores) are observed under the microscope in the treated area. The KOH test is a rapid and inexpensive way to diagnose onychomycosis, but it has limitations in sensitivity and can't identify the specific organism.

[0075] As used herein, the term “mycological cure” means a negative fungal culture and a negative KOH examination for treated (previously affected) area. A negative fungal culture indicates the absence of growth of pathogenic fungi from the treated area, suggesting successful eradication of the infection. However, it's important to remember that fungal cultures can have limitations, including high false-negative rates and long turnaround times.

[0076] As used herein, the term “almost complete cure” means <5% affected treated area involved and negative KOH examination and negative fungal culture.

[0077] As used herein, the term “clinical efficacy” means an affected treated area of less than 10%. .

[0078] As used herein, the terms “optional” or “optionally,” particularly when used in reference to an ingredient in the compositions or embodiments described herein, means that the referenced ingredient may or may not be included in the composition or embodiment. Thus, when anBT Ref. 104448-429411 PATENT ingredient is referred to as “optional” or “optionally contained]” in a composition or embodiment, it should be understood that in some embodiments, the ingredient is present. It should be equally understood that in some embodiments, the ingredient referred to as “optional” or “optionally contain[ed]” in the composition or embodiment is absent.

[0079] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to closed or limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the terms “example,” “e.g.,” or “for example” are used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as “known,” “normal,” “standard,” and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention.

[0080] Likewise, a group of items linked with the conjunction “and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should beBT Ref. 104448-429411 PATENT read as “and / or” unless expressly stated otherwise. Similarly, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should be read as “and / or” unless expressly stated otherwise.

[0081] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. Moreover, as used herein, the terms “a” or “an” in reference to an entity refers to one or more of that entity.

[0082] A term or phrase should not be interpreted or construed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof in accordance with 35 U.S.C. § 112(f) unless the words “means for” or “step for” are explicitly utilized in the term or phrase at issue.

[0083] Certain embodiments described herein are indicated as “comprising” specified components. However, Applicants specifically envision and hereby contemplate additional embodiments that “consist of’ and / or “consist essentially of’ the same specified components as indicated for embodiments that are said to “comprise” specified components.Compositions

[0084] Described herein are compositions for topical treatment, e.g., a disease or disorder of the nail, nail bed, skin, oral cavity (e.g., the mouth, throat, and / or esophagus), vagina, and / or vulva. Some embodiments relate to a composition for topical treatment, comprising, consisting of, or consisting essentially of: a therapeutic agent, a non-volatile organic solvent in the amount of greater than or equal to about 50% (w / w), and optionally an emollient. Additionally, some embodiments comprise, consist of, or consist essentially of: a therapeutic agent, a non-volatileBT Ref. 104448-429411 PATENT solvent in the amount of greater than or equal to about 50% (w / w) and, optionally, one or more of the additional ingredients described herein.

[0085] The compositions may be formulated as a solution, a cream, a gel, a lotion, a shampoo, a suspension, a nail lacquer, an ointment, a lozenge, a capsule, a suppository, or a vaginal insert. Liquid formulations (e.g., a solution) are preferred for certain conditions, such as the treatment of a nail or nail bed. However, a skilled artisan will understand that the compositions may be formulated as a solution, a cream, a gel, a lotion, a shampoo, a suspension, a nail lacquer, an ointment, a lozenge, a capsule, a suppository, or a vaginal insert depending upon the intended use of the composition (e.g., for scalp treatment a shampoo would be the preferred formulation whereas for skin treatment a cream, lotion, or ointment may be preferred, while for treatment of the oral cavity a lozenge or dissolving capsule would be preferred, and while treatment of an infection affecting the anus of vagina a suppository or vaginal insert would be preferred). In view of the disclosure herein, a skilled artisan will understand how to prepare such dosage forms. See, e.g., Remington’s: The Science and Practice of Pharmacy (21stEd.) and its discussion of medicated topi cals; see also Aulton’s Pharmaceutics: The Design and Manufacture of Medicines (6thEd.) and its discussion of “Dosage form design and manufacture” in Part 5.

[0086] Moreover, for the treatment of a condition affecting a nail, the compositions are typically a solution and are generally not a lacquer. The compositions are also generally not an enamel, a varnish, or a polish. The compositions are typically clear (e.g., constituent ingredients are dissolved) and / or colorless to slightly yellow in color. The compositions generally do not form a film in that they not create a solid film layer that is detectable for a significant period of time, such as after about 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, or 48 hours.BT Ref. 104448-429411 PATENTTherapeutic Agents

[0087] The embodiments described herein contain one or more therapeutic agents that are useful for topical treatment of a disease or disorder, e.g., a disease of disorder of the nail and / or nail bed and / or skin and / or eye. In some embodiments, the therapeutic agent is an antimicrobial agent. In some embodiments, the antimicrobial agent that is an antifungal agent. In preferred embodiments, the therapeutic agent is an antifungal agent. In more preferred embodiments, the therapeutic agent is useful for treating a fungal skin infection. By way of non-limiting example, fungal skin infections are often caused by dermatophytes, resulting in tinea corporis, tinea cruris, tinea faciei, tinea manuum, tinea pedis, tinea capitis and tinea barbae; yeasts, resulting in Candida intertrigo and pityriasis versicolor; and molds, resulting in tinea nigra and nail plate infections. In more preferred embodiments, the therapeutic agent is useful for treating infections caused by dermatophytes, yeasts, and / or molds. Even more preferably, in some embodiments the therapeutic agent is a topical antifungal agent. By way of non-limiting example, the following therapeutic agents are known to be useful as topical antifungal agents: salicylic acid, benzoic acid, undecylenic alkanolamide, ciclopirox, butenafine, naftifme, nystatin, bifonazole, clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, miconazole, sulconazole, tioconazole, itraconazole, terbinafine, tolciclate, tolnaftate, tavaborole, and pharmaceutically acceptable salts thereof. Certain therapeutic agents are formulated as pharmaceutically acceptable salts, which are well- known and include, e.g., acid addition salts such as hydrochloric acid and / or basic addition salts such ethanolamine. See WipfetaL, “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations,” Molecules (2018), 23(7), 1719, which is incorporated herein by reference. In some embodiments, the therapeutic agent is selected from the group consisting of 3% salicylic acid, and 6% benzoic acid, undecylenic alkanolamide, ciclopirox, ciclopirox olamine,BT Ref. 104448-429411 PATENT butenafine hydrochloride, naftifine hydrochloride, nystatin, bifonazole, clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, miconazole, sulconazole, tioconazole, itraconazole, terbinafine, tolciclate, tolnaftate, and tavaborole.

[0088] In some embodiments, the therapeutic agent is useful for treating tinea pedis, tinea cruris, or tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, or Microsporum canis seborrheic dermatitis; cutaneous candidiasis (moniliasis) due to Candida albicans,' tinea (pityriasis) versicolor due to Malassezia furfur, onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes, cutaneous or mucocutaneous mycotic infections due to Candida albicans and other susceptible Candida species; yeast infections; vaginal yeast infections; superficial skin infections due to yeast; Trichophyton tonsurans, blastomycosis; pulmonary and extrapulmonary histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; or aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. In some embodiments, the therapeutic agent is efinaconazole, tavaborole, ciclopirox, ciclopirox olamine, nystatin, clotimazole, miconazole, butenafine hydrochloride, naftifine hydrochloride, luliconazole, and / or itraconazole. Each of these therapeutic agents are indicated for one or more of the above-described diseases or disorders.

[0089] In preferred embodiments, the therapeutic agent is useful for the treatment of onychomycosis. In some embodiments, the therapeutic agent is prescribed by physicians for the off-label treatment of onychomycosis. In more preferred embodiments, the therapeutic agent is FDA approved for the treatment of onychomycosis. In some embodiments, the therapeutic agent is an antifungal that is selected from the group consisting of azoles, allylamines, hydroxypyridinones, and morpholines. By way of non-limiting example, the following agents areBT Ref. 104448-429411 PATENT known to be useful for the treatment of onychomycosis: terbinafine, itraconazole, griseofulvin, ciclopirox, amorolfme, tavaborole, fluconazole, and efinaconazole. In some embodiments, the therapeutic agent is selected from the group consisting of terbinafine, itraconazole, griseofulvin, ciclopirox, amorolfme, tavaborole, fluconazole, and efinaconazole. In some embodiments, the therapeutic agent is tavaborole. In some embodiments, the therapeutic agent is ciclopirox or ciclopirox olamine.

[0090] In more preferred embodiments, the therapeutic agent is an azole antifungal agent. In even more preferred embodiments, the therapeutic agent is a triazole antifungal agent. In even more preferred embodiments, the therapeutic agent is efinaconazole.

[0091] In some embodiments, one or more therapeutic agent is present in the composition in the amount of 0.05% (w / w), 0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), 15% (w / w), 16% (w / w), 17% (w / w), 18% (w / w), 19% (w / w), 20% (w / w), 21% (w / w), 22% (w / w), 23% (w / w), 24% (w / w), 25% (w / w), 26% (w / w), 27% (w / w), 28% (w / w), 29% (w / w), 30% (w / w), 31% (w / w), 32% (w / w), 33% (w / w), 34% (w / w), 35% (w / w), 36% (w / w), 37% (w / w), 38% (w / w), 39% (w / w), 40% (w / w), about any of the aforementioned percentages (e.g., about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38%BT Ref. 104448-429411 PATENT(w / w), about 39% (w / w), or about 40% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., l%-40% (w / w), 2%-35% (w / w), 3%-30% (w / w), 4%-28% (w / w), 5%-25% (w / w), 6%-22% (w / w), 7%-20% (w / w), 8%-l 8% (w / w), 9%-15% (w / w), 10%-12% (w / w), about l%-40% (w / w), about 2%-35% (w / w), about 3%-30% (w / w), about 4%-28% (w / w), about 5%-25% (w / w), about 6%-22% (w / w), about 7%-20% (w / w), about 8%-18% (w / w), about 9%-l 5% (w / w), or about 10%-12% (w / w)).

[0092] In some embodiments, the therapeutic agent is tavaborole and is present in the composition in the amount of 1%- 15% (w / w), 1 %- 10% (w / w), 2%-8% (w / w), 3%-7% (w / w), 4%- 6% (w / w), 5% (w / w), about 1%-15% (w / w), about l%-10% (w / w), about 2%-8% (w / w), about 3%-7% (w / w), about 4%-6% (w / w), or about 5% (w / w).

[0093] In some embodiments, the therapeutic agent is ciclopirox and is present in the composition in the amount of 1%-15% (w / w), 2%-12% (w / w), 3%-10% (w / w), 4%-10% (w / w), 5%-10% (w / w), 6%-9% (w / w), 7%-9% (w / w), 8% (w / w), about 1%-15% (w / w), about 2%-12% (w / w), about 3%-10% (w / w), about 4%-10% (w / w), about 5%-10% (w / w), about 6%-9% (w / w), about 7%-9% (w / w), or about 8% (w / w).

[0094] In some embodiments, the therapeutic agent is ciclopirox and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l% (w / w), about 0.77% (w / w), about 1% (w / w), 0.77% (w / w), or 1% (w / w).

[0095] In some embodiments, the therapeutic agent is ciclopirox olamine and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l% (w / w), about 0.77% (w / w) or 0.77% (w / w).

[0096] In some embodiments, the therapeutic agent is nystatin and is present in the composition in the amount of about 50,000-150,000 USP Nystatin Units, about 75,000-125,000 USP NystatinBT Ref. 104448-429411 PATENTUnits, about 100,000 USP Nystatin Units or 100,000 USP Nystatin Units. See, e.g., U.S. Pharmacopeia entries for nystatin and associated anti-microbial assays for the characterization of Nystatin Units.

[0097] In some embodiments, the therapeutic agent is clotimazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-1.5% (w / w), about 1% (w / w) or 1% (w / w).

[0098] In some embodiments, the therapeutic agent is miconazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.75%-3% (w / w), about l%-2.5% (w / w), about 2% (w / w) or 2% (w / w).

[0099] In some embodiments, the therapeutic agent is butenafine hydrochloride and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%- 1.5% (w / w), about 1% (w / w) or 1% (w / w).

[0100] In some embodiments, the therapeutic agent is naftifine hydrochloride and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.75%-3% (w / w), about l%-2.5% (w / w), about 1% (w / w), about 2% (w / w), 1% (w / w), or 2% (w / w).

[0101] In some embodiments, the therapeutic agent is luliconazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-1.5% (w / w), about 1% (w / w) or 1% (w / w).

[0102] In some embodiments, the therapeutic agent is itraconazole and is present in the amount of about 1 %-40% (w / w), about 5%-20% (w / w), about 8%-l 2% (w / w), about 10% (w / w), or 10% (w / w).

[0103] In preferred embodiments, the therapeutic agent is present in the amount of about 1%- 40% (w / w), about 5%-20% (w / w), about 8%- 12% (w / w), about 10% (w / w), or 10% (w / w) of theBT Ref. 104448-429411 PATENT composition. In more preferred embodiments, the therapeutic agent is efinaconazole and the efinaconazole is present in the composition in the amount of about 1 %-30% (w / w), about 3%-25% (w / w), about 5%-15% (w / w), about 8%-12% (w / w), about 10% (w / w), or 10% (w / w) of the composition. In even more preferred embodiments, the therapeutic agent is efinaconazole and the efinaconazole is present in the composition in the amount of about 10% (w / w) or 10% (w / w).

[0104] In some embodiments, one or more therapeutic agent is present in the composition in the amount of less than 40% (w / w), less than 39% (w / w), less than 38% (w / w), less than 37% (w / w), less than 36% (w / w), less than 35% (w / w), less than 34% (w / w), less than 33% (w / w), less than 32% (w / w), less than 31% (w / w), less than 30% (w / w), less than 29% (w / w), less than 28% (w / w), less than 27% (w / w), less than 26% (w / w), less than 25% (w / w), less than 24% (w / w), less than 23% (w / w), less than 22% (w / w), less than 21% (w / w), less than 20% (w / w), less than 19% (w / w), less than 18% (w / w), less than 17% (w / w), less than 16% (w / w), less than 15% (w / w), less than 14% (w / w), less than 13% (w / w), less than 12% (w / w), less than 11% (w / w), less than 10% (w / w), less than 9% (w / w), less than 8% (w / w), less than 7% (w / w), less than 6% (w / w), less than 5% (w / w), less than 4% (w / w), less than 3% (w / w), less than 2% (w / w), less than 1% (w / w), less than about any of the aforementioned percentages (e.g., less than about 40% (w / w), less than about 39% (w / w), less than about 38% (w / w), less than about 37% (w / w), less than about 36% (w / w), less than about 35% (w / w), less than about 34% (w / w), less than about 33% (w / w), less than about 32% (w / w), less than about 31% (w / w), less than about 30% (w / w), less than about 29% (w / w), less than about 28% (w / w), less than about 27% (w / w), less than about 26% (w / w), less than about 25% (w / w), less than about 24% (w / w), less than about 23% (w / w), less than about 22% (w / w), less than about 21% (w / w), less than about 20% (w / w), less than about 19% (w / w), less than about 18% (w / w), less than about 17% (w / w), less than about 16% (w / w), less than about 15% (w / w),BT Ref. 104448-429411 PATENT less than about 14% (w / w), less than about 13% (w / w), less than about 12% (w / w), less than about 11% (w / w), less than about 10% (w / w), less than about 9% (w / w), less than about 8% (w / w), less than about 7% (w / w), less than about 6% (w / w), less than about 5% (w / w), less than about 4% (w / w), less than about 3% (w / w), less than about 2% (w / w), less than about 1% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 15%-40% (w / w), less than 15%-35% (w / w), less than 15%-30% (w / w), less than 15%-25% (w / w), less than 15%-20% (w / w), less than 14%-20% (w / w), less than 13%-20% (w / w), less than 12%-20% (w / w), less than 11%-20% (w / w), less than 11%-19% (w / w), less than 11%- 18% (w / w), less than 11%-17% (w / w), less than 11%-16% (w / w), less than 11%-15% (w / w), less than 10%- 15% (w / w), less than 5%-l 5% (w / w), less than about 15%-40% (w / w), less than about 15%-35% (w / w), less than about 15%-30% (w / w), less than about 15%-25% (w / w), less than about 15%-20% (w / w), less than about 14%-20% (w / w), less than about 13%-20% (w / w), less than about 12%-20% (w / w), less than about 11%-20% (w / w), less than about 11 %- 19% (w / w), less than about 11%- 18% (w / w), less than about 11%-17% (w / w), less than about 11 %-l 6% (w / w), less than about 11%- 15% (w / w), less than about 10%-l 5% (w / w), or less than about 5%- 15% (w / w)). In preferred embodiments, the therapeutic agent is present in an amount of less than 15% (w / w), less than 10% (w / w), less than 7% (w / w), less than about 15% (w / w), less than about 10% (w / w), or less than about 7% (w / w) of the composition. In more preferred embodiments, the therapeutic agent is efinaconazole and the efinaconazole is present in the composition in the amount of less than 15% (w / w) or less than about 15% (w / w).

[0105] In some embodiments, the amount of one or more therapeutic agent in the composition is limited by the solubility of the agent in the composition. Accordingly, in some embodiments the amount of therapeutic agent in the composition is equal to or less than the limit of solubilityBT Ref. 104448-429411 PATENT for that therapeutic agent in a given volume of the composition. In preferred embodiments, the amount of therapeutic agent in the composition is equal to or less than the limit of solubility for that therapeutic agent in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of therapeutic agent in the composition is less than the limit of solubility for that therapeutic agent in a given volume of the composition or less than the limit of solubility for that therapeutic agent in a given volume of nonvolatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of therapeutic agent in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the therapeutic agent in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular therapeutic agent in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of therapeutic agents and a particular volume of the composition (without therapeutic agent) or a particular volume of non-volatile solvent to be included in the composition and determining whether complete dissolution occurred and / or the saturation point for dissolution of the therapeutic agent in the unit of weight per volume (e.g., mg per mL). Such a process is described herein utilizing efinaconazole as a representative, yet preferred, therapeutic agent for evaluating solubility.

[0106] In some embodiments, the amount of therapeutic agent and non-volatile solvent in the composition is related to one another by a ratio. For example, in some embodiments the ratio by weight of therapeutic agent to non-volatile solvent is 1 : 1, 1 : 1.25, 1 :1.5, 1: 1.75, 1 :2, 1 :2.25, 1 :2.5,1 :2.75, 1 :3, 1:3.25, 1 :3.5, 1 :3.75, 1:4, 1 :4.25, 1 :4.5, 1:4.75, 1 :5, 1 :5.25, 1:5.5, 1 :5.75, 1 :6, 1:6.25,BTRef. 104448-429411 PATENT1:6.5, 1:6.75, 1:7. 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10,1:10.25, 1:10.5, 1:10.75, 1:11, 1:11.25, 1:11.5, 1:11.75, 1:12, 1:12.25, 1:12.5, 1:12.75, 1:13,1:13.25, 1:13.5, 1:13.75, 1:14, 1:14.25, 1:14.5, 1:14.75, 1:15, 1:15.25, 1:15.5, 1:15.75, 1:16,1:16.25, 1:16.5, 1:16.75, 1:17, 1:17.25, 1:17.5, 1:17.75, 1:18, 1:18.25, 1:18.5, 1:18.75, 1:19,1:19.25, 1:19.5, 1:19.75, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, or 1:99. In some embodiments, the ratio by weight of therapeutic agent to nonvolatile solvent is about 1:1, about 1:1.25, about 1:1.5, about 1:1.75, about 1:2, about 1:2.25, about 1:2.5, about 1:2.75, about 1:3, about 1:3.25, about 1:3.5, about 1:3.75, about 1:4, about 1:4.25, about 1:4.5, about 1:4.75, about 1:5, about 1:5.25, about 1:5.5, about 1:5.75, about 1:6, about 1:6.25, about 1:6.5, about 1:6.75, about 1:7, about 1:7.25, about 1:7.5, about 1:7.75, about 1:8, about 1:8.25, about 1:8.5, about 1:8.75, about 1:9, about 1:9.25, about 1:9.5, about 1:9.75, about 1:10, about 1:10.25, about 1:10.5, about 1:10.75, about 1:11, about 1:11.25, about 1:11.5, about 1:11.75, about 1:12, about 1:12.25, about 1:12.5, about 1:12.75, about 1:13, about 1:13.25, about 1:13.5, about 1:13.75, about 1:14, about 1:14.25, about 1:14.5, about 1:14.75, about 1:15, about 1:15.25, about 1:15.5, about 1:15.75, about 1:16, about 1:16.25, about 1:16.5, about 1:16.75, about 1:17, about 1:17.25, about 1:17.5, about 1:17.75, about 1:18, about 1:18.25, about 1:18.5, about 1:18.75, about 1:19, about 1:19.25, about 1:19.5, about 1:19.75, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, or about 1:99. In preferred embodiments, the therapeutic agent is efinaconazole and the ratio by weight of therapeutic agent to non-volatile solvent is about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, about 1:10, about 1:10.5, about 1:11, about 1:11.5, aboutBT Ref. 104448-429411 PATENT1 : 12, about 1 : 12.5, about 1 :13, about 1 : 13.5, about 1 :14, about 1 : 14.5, about 1 : 15, about 1 : 16, about 1 : 17, about 1: 18, about 1 : 19, or about 1 :20. In even more preferred embodiments, the therapeutic agent is efinaconazole and the ratio by weight of therapeutic agent to non-volatile solvent is about 1 :8, about 1 :8.25, about 1:8.5, about 1 :8.75, about 1 :9, about 1 :9.25, about 1 :9.5, about 1:9.75, about 1 : 10, about 1 : 10.25, about 1 :10.5, about 1 : 10.75, about 1 : 11, about 1 : 11.25, about 1 : 11.5, about 1 :11.75, or about 1 : 12.

[0107] In some embodiments, combinations of the aforementioned therapeutic agents are included in the compositions. Each therapeutic agent of the combination may be included in any of the amounts indicated above for the therapeutic agent or the one or more therapeutic agents. Non-Volatile Solvents

[0108] The embodiments described herein contain one or more non-volatile solvents. Nonvolatile solvents are compounds that are liquid at standard temperature and pressure (20° C and 1 atm) and have a boiling point at standard pressure that is greater than the boiling point of water (e g., 100° C at 1 atm). In some embodiments, the non-volatile solvent is an organic solvent. Organic solvents are generally carbon-based and / or sulfur-based substances capable of dissolving or dispersing one or more other substances. In some embodiments, the non-volatile solvent is a solvent that is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure that is greater than or equal to 125° C, 130° C, 135° C, 140° C, 145° C, 150° C, 155° C, 160° C, 165° C, 170° C, 175° C, 180° C, 185° C, 190° C, 195° C, 200° C, 205° C, 210° C, 215° C, 220° C, 225° C, 230° C, 235° C, 240° C, or about any of the aforementioned temperatures (e.g., greater than or equal to about 125° C, about 130° C, about 135° C, about 140° C, about 145° C, about 150° C, about 155° C, about 160° C, about 165° C, about 170° C, about 175° C, about 180° C, about 185° C, about 190° C, about 195° C, about 200° C, about 205° C,BT Ref. 104448-429411 PATENT about 210° C, about 215° C, about 220° C, about 225° C, about 230° C, about 235° C, or about 240° C). In more preferred embodiments, the non-volatile solvent is an organic solvent that is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure that is greater than or equal to 200° C, 205° C, 210° C, 215° C, 220° C, 225° C, 230° C, or 235° C. In even more preferred embodiments, the non-volatile solvent is an organic solvent that is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point that is greater than or equal to 210° C, 225° C, 230° C, or 235° C. Without wishing to be bound by any particular theory, it is believed that non-volatile solvents having a higher boiling point (e.g., greater than or equal to 210° C, 225° C, 230° C, or 235° C) affords a less volatile composition, enhances contact time between therapeutic agent and the application area, and will result in improved drug absorption relative to compositions having lower boiling non-volatile solvents.

[0109] In some embodiments, the non-volatile solvent is a solvent that is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point of between 125° C to 240° C, 130° C to 240° C, 135° C to 240° C, 140° C to 240° C, 145° C to 240° C, 150° C to 240° C, 155° C to 240° C, 160° C to 240° C, 165° C to 240° C, 170° C to 240° C, 175° C to 240° C, 180° C to 240° C, 185° C to 240° C, 190° C to 240° C, 195° C to 240° C, 200° C to 240° C, 205° C to 240° C, 210° C to 240° C, 215° C to 240° C, 220° C to 240° C, 225° C to 240° C, 230° C to 240° C, 235° C to 240° C (inclusive of endpoints), or about any of the aforementioned ranges (e.g., about 125° C to 240° C, about 130° C to 240° C, about 135° C to 240° C, about 140° C to 240° C, about145° C to 240° C, about 150° C to 240° C, about 155° C to 240° C, about 160° C to 240° C, about165° C to 240° C, about 170° C to 240° C, about 175° C to 240° C, about 180° C to 240° C, about185° C to 240° C, about 190° C to 240° C, about 195° C to 240° C, about 200° C to 240° C, about205° C to 240° C, about 210° C to 240° C, about 215° C to 240° C, about 220° C to 240° C, aboutBT Ref. 104448-429411 PATENT225° C to 240° C, about 230° C to 240° C, about 235° C to 240° C (inclusive of endpoints)). In preferred embodiments, the non-volatile solvent is a solvent that is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point of between 200° C to 240° C or about 200° C to 240° C.

[0110] In some embodiments, the non-volatile solvent is a lipophilic compound. In preferred embodiments, the non-volatile solvent is a lipophilic compound that is miscible with acetone, chloroform, ether, and / or vegetable oils. In more preferred embodiments, the non-volatile solvent is a lipophilic compound that is miscible with acetone, chloroform, ether, and vegetable oils. In some embodiments, the lipophilic compound has a Log P value of > 0. In some embodiments, the lipophilic compound has a Log P value of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, about any of the aforementioned values (e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20), a range bounded by any of the aforementioned values or about any of the aforementioned values (e g., about 5-20, about 3-15, about 4-10, or about 10-20), or greater than any of the aforementioned values (e.g., > 1, > 2, > 3, > 4, > 5, > 6, > 7, > 8, > 9, > 10, > 11, > 12, > 13, > 14, >15, > 16, > 17, > 18, > 19, > 20, > about 1, > about 2, > about 3, > about 4, > about 5, > about 6, > about 7, > about 8, > about 9, > about 10, > about 11,> about 12, > about 13, > about 14, > about 15, > about 16, > about 17, > about 18, > about 19, or> about 20). Log P may be determined by measuring the partition of the solvent between an organic solvent (typically octanol) and aqueous buffer and quantifying the amount of compound distributed in the solvent and aqueous buffer. Without wishing to be bound to any particular theory, lipophilic solvents are preferred because lipophilic solvents are believed to facilitate topical penetration through keratinized structures. See, e.g., Park et al., “Effect of Penetration EnhancersBT Ref. 104448-429411 PATENT on Toenail Delivery of Efinaconazole from Hydroalcoholic preparations,” Molecules (2021), Vol. 26, 1650, pages 1-12, discussing the use of lipophilic penetration enhancers such as myristyl lactate and diisopropyl adipate in hydroalcoholic solutions such as the Jublia® formulation.

[0111] In some embodiments, the non-volatile solvent has a hydrophilic-lipophilic balance (“HLB”) of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, about any of the aforementioned numbers (e.g., about 0, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20), or a range bounded by any of the aforementioned numbers or about any of the aforementioned numbers (e.g., 0-20, 0-19, 0-18, 0-17, 0-16, 0-15, 0-14, 0-13, 0- 12, 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 1-19, 2-18, 3-17, 4-16, 5-15, about 0-20, about 0-19, about 0-18, about 0-17, about 0-16, about 0-15, about 0-14, about 0-13, about 0-12, about 0-11, about 0-10, about 0-9, about 0-8, about 0-7, about 0-6, about 0-5, about 0-4, about 0- 3, about 0-2, about 0-1, about 1-19, about 2-18, about 3-17, about 4-16, or about 5-15). See, e.g., Kunieda et al., “Evaluation of the hydrophile-lipophile balance (HLB) of nonionic surfactants. I. Multi surfactant systems,” Journal of Colloid and Interface Science (1985), Vol. 107, Issue 1, pages 107-221. In some embodiments, the non-volatile solvent has an HLB of less than 1, less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, less than 13, less than 14, less than 15, less than 16, less than 17, less than 18, less than 19, less than 20, or less than about any of the aforementioned ranges (e.g., less than about 1 , less than about 2, less than about 3, less than about 4, less than about 5, less than about 6, less than about 7, less than about 8, less than about 9, less than about 10, less than about 11, less than about 12, less than about 13, less than about 14, less than about 15, less than about16, less than about 17, less than about 18, less than about 19, or less than about 20). In preferredBT Ref. 104448-429411 PATENT embodiments, the non-volatile solvent has a hydrophilic-lipophilic balance of less than or equal to 5, less than or equal to 4, less than or equal to 3, less than or equal to 2, less than or equal to 1, or equal to 0. In more preferred embodiments, the non-volatile solvent has a hydrophilic-lipophilic balance of 0.

[0112] Examples of non-volatile solvents include, but are not limited to, acetic acid, anisole, benzyl alcohol, benzyl benzoate, 1 -butanol, butyl acetate, butylene glycol, castor oil, corn oil, cottonseed oil, diethyl phthalate, dimethyl phthalate, dimethyl sulfoxide, dimethyl acetamide, ethyl lactate, ethyl oleate, formic acid, glycerin, isobutyl acetate, isopropyl myristate, isopropyl palmitate, medium chain triglycerides, 3 -methyl- 1 -butanol, 2-methyl-l -propanol, mineral oil, light mineral oil, octyldodecanol, olive oil, peanut oil, 1 -pentanol, polyethylene glycol, propyl acetate, propylene carbonate, propylene glycol, safflower oil, sesame oil, soybean oil, triacetin, tri caprylin, triethyl citrate, triolein, and / or mixtures thereof. A person of ordinary skill in the art will understand the class of compounds that are non-volatile solvents, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are solvents or solubilizing agents and exhibit the properties of non-volatile solvents. In preferred embodiments, the nonvolatile solvent is pharmaceutically acceptable. In some embodiments, the non-volatile solvent is a class 2 and / or a class 3 solvent. See, e.g., “Q3C - Tables and List Guidance for Industry, Revision 3 (June 2017), published by the U.S. Department of Health and Human Services Food and Drug Administration, which is incorporated by reference in its entirety.

[0113] Examples of preferred non-volatile solvents include, but are not limited to, vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, an ester ofBT Ref. 104448-429411 PATENT tocopherols excipient, and / or mixtures thereof. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its discussion of alpha tocopherol, including its nonproprietary names, typical properties, and related substances. Vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol and their esters thereof (such as acetate or succinate esters) each have three chiral centers, giving rise to eight isomeric forms of each molecule. Unless otherwise indicated, references to vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol and their esters thereof encompass both isomerically enriched and racemic forms. In some embodiments, each of these molecules are stereoisomerically enriched (e.g., <7-alpha tocopherol, <7-alpha tocopheryl acetate, or t / -alpha tocopheryl succinate). In more preferred embodiments, each of these molecules are individually a racemic mixture containing roughly equimolar amounts of each of their respective isomers. As used herein, such a mixture is referred to with the adjective “synthetic” (e.g., synthetic vitamin E, a synthetic ester of vitamin E, and / or synthetic vitamin E acetate).

[0114] In some embodiments, the non-volatile solvent is vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, an ester of tocopherols excipient, or mixtures thereof. In some embodiments, the non-volatile solvent is an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, an ester of tocopherols excipient, or mixtures thereof. In some embodiments, the non-volatile solvent is a Ci-Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, is a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, is a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol, is a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of tocopherols excipient, or mixtures thereof. In more preferred embodiments, the non-BT Ref. 104448-429411 PATENT volatile solvent is an acetate ester of vitamin E, an acetate ester of beta tocopherol, an acetate ester of delta tocopherol, an acetate ester of gamma tocopherol, an acetate ester of tocopherols excipient, or mixtures thereof. In even more preferred embodiments, the non-volatile solvent is vitamin E acetate. In some embodiments, the non-volatile solvent is vitamin E.

[0115] In some embodiments, the non-volatile solvent is synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, a synthetic ester of tocopherols excipient, or mixtures thereof. In some embodiments, the non-volatile solvent is a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, a synthetic ester of tocopherols excipient, or mixtures thereof. In some embodiments, the non-volatile solvent is a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, is a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, is a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of tocopherols excipient, or mixtures thereof. In more preferred embodiments, the non-volatile solvent is a synthetic acetate ester of vitamin E, a synthetic acetate ester of beta tocopherol, a synthetic acetate ester of delta tocopherol, a synthetic acetate ester of gamma tocopherol, a synthetic acetate ester of tocopherols excipient, or mixtures thereof. In even more preferred embodiments, the non-volatile solvent is synthetic vitamin E acetate. In some embodiments, the non-volatile solvent is synthetic vitamin E. Synthetic vitamin E acetate is the most preferred nonvolatile solvent.BT Ref. 104448-429411 PATENT

[0116] In some embodiments, the non-volatile solvent is a single solvent. In some embodiments, the non-volatile solvent is a mixture of two or more solvents. In some embodiments, the nonvolatile solvent is a mixture of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solvents, or a range selected from any of the aforementioned integers (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2- 7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10). In some embodiments, the mixture is an isomeric mixture. In some embodiments, the mixture is a stereoisomeric mixture. In some embodiments, the mixture is of different solvent identities (e.g., vitamin E vs. vitamin E acetate being different solvent identities as opposed to tZ-alpha tocopherol vs. t / / -alpha tocopherol which are of the same solvent identity).

[0117] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, and an ester of tocopherols excipient. In some embodiments, the nonvolatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, and a synthetic ester of tocopherols excipient. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, and gammaBT Ref. 104448-429411 PATENT tocopherol. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, and synthetic gamma tocopherol. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, and an ester of gamma tocopherol. In some embodiments, the nonvolatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, is a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a C1-C10, Ci-Cs, C1-C5, C2- C4, or C2 ester of gamma tocopherol. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an acetate ester of vitamin E, an acetate ester of beta tocopherol, an acetate ester of delta tocopherol, an acetate ester of gamma tocopherol, and an acetate ester of tocopherols excipient. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, and a synthetic ester of gamma tocopherol. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2BT Ref. 104448-429411 PATENT ester of delta tocopherol, and a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic acetate ester of vitamin E, a synthetic acetate ester of beta tocopherol, a synthetic acetate ester of delta tocopherol, a synthetic acetate ester of gamma tocopherol, and a synthetic acetate ester of tocopherols excipient. In some embodiments, the nonvolatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is vitamin E, vitamin E acetate, synthetic vitamin E, or synthetic vitamin E acetate. In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is synthetic vitamin E acetate.

[0118] In some embodiments, one or more non-volatile solvents are present in the composition in the amount of 50% (w / w), 55% (w / w), 60% (w / w), 65% (w / w), 70% (w / w), 75% (w / w), 76% (w / w), 77% (w / w), 78% (w / w), 79% (w / w), 80% (w / w), 81% (w / w), 82% (w / w), 83% (w / w), 84% (w / w), 85% (w / w), 86% (w / w), 87% (w / w), 88% (w / w), 89% (w / w), 90% (w / w), 91% (w / w), 92% (w / w), 93% (w / w), 94% (w / w), 95% (w / w), 96% (w / w), 97% (w / w), 98% (w / w), 99% (w / w), about any of the aforementioned percentages (e.g., about 50% (w / w), about 55% (w / w), about 60% (w / w), about 65% (w / w), about 70% (w / w), about 75% (w / w), about 76% (w / w), about 77% (w / w), about 78% (w / w), about 79% (w / w), about 80% (w / w), about 81% (w / w), about 82% (w / w), about 83% (w / w), about 84% (w / w), about 85% (w / w), about 86% (w / w), about 87% (w / w), about 88% (w / w), about 89% (w / w), about 90% (w / w), about 91% (w / w), about 92% (w / w), about 93% (w / w), about 94% (w / w), about 95% (w / w), about 96% (w / w), about 97% (w / w), about 98% (w / w), or about 99% (w / w)), or a range bounded by any of the aforementioned percentages or about any ofBT Ref. 104448-429411 PATENT the aforementioned percentages (e.g., 50%-99% (w / w), 70%-99% (w / w), 75%-99% (w / w), 80%- 99% (w / w), 90%-99% (w / w), 85%-95% (w / w), 80%-95% (w / w), 80%-90% (w / w), 88%-92% (w / w), about 50%-99% (w / w), about 70%-99% (w / w), about 75%-99% (w / w), about 80%-99% (w / w), about 90%-99% (w / w), about 85%-95% (w / w), about 80%-95% (w / w), about 80%-90% (w / w), or about 88%-92% (w / w)). In preferred embodiments, one or more volatile solvents are present in the composition in the amount of about 80%-99% (w / w), about 85%-95% (w / w), about 85%-99% (w / w), about 88%-92% (w / w), about 90%-99% (w / w), about 92%-98% (w / w), about 90% (w / w), about 95% (w / w), 95% (w / w), and / or 90% (w / w).

[0119] In some embodiments, one or more volatile solvents are present in the composition in the amount of greater than 50% (w / w), greater than 55% (w / w), greater than 60% (w / w), greater than 65% (w / w), greater than 70% (w / w), greater than 75% (w / w), greater than 76% (w / w), greater than77% (w / w), greater than 78% (w / w), greater than 79% (w / w), greater than 80% (w / w), greater than81% (w / w), greater than 82% (w / w), greater than 83% (w / w), greater than 84% (w / w), greater than85% (w / w), greater than 86% (w / w), greater than 87% (w / w), greater than 88% (w / w), greater than89% (w / w), greater than 90% (w / w), greater than 91% (w / w), greater than 92% (w / w), greater than93% (w / w), greater than 94% (w / w), greater than 95% (w / w), greater than 96% (w / w), greater than97% (w / w), greater than 98% (w / w), greater than 99% (w / w), about any of the aforementioned percentages (e.g., greater than about 50% (w / w), greater than about 55% (w / w), greater than about 60% (w / w), greater than about 65% (w / w), greater than about 70% (w / w), greater than about 75% (w / w), greater than about 76% (w / w), greater than about 77% (w / w), greater than about 78%(w / w), greater than about 79% (w / w), greater than about 80% (w / w), greater than about 81%(w / w), greater than about 82% (w / w), greater than about 83% (w / w), greater than about 84%(w / w), greater than about 85% (w / w), greater than about 86% (w / w), greater than about 87%BT Ref. 104448-429411 PATENT(w / w), greater than about 88% (w / w), greater than about 89% (w / w), greater than about 90%(w / w), greater than about 91% (w / w), greater than about 92% (w / w), greater than about 93%(w / w), greater than about 94% (w / w), greater than about 95% (w / w), greater than about 96%(w / w), greater than about 97% (w / w), greater than about 98% (w / w), or greater than about 99%(w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., greater than 50%-80% (w / w), greater than 60%-80% (w / w), greater than 70%-80% (w / w), greater than 80%-85% (w / w), greater than 85%-90% (w / w), greater than about 50%-80% (w / w), greater about than 60%-80% (w / w), greater about than 70%-80% (w / w), greater about than 80%-85% (w / w), or greater than about 85%-90% (w / w)).

[0120] In some embodiments, the amount of the non-volatile solvent is greater than or equal to the amount necessary to solubilize the amount of therapeutic agent in the composition. A skilled artisan will readily understand how to determine the amount necessary to solubilize the amount of therapeutic agent in the composition. By way of non-limiting example, this can be determined by measuring different weights of the therapeutic agent and a particular volume of the non-volatile solvent to be included in the composition and determining whether complete dissolution of the therapeutic agent occurred and / or the saturation point for dissolution of the therapeutic agent in the unit of weight per volume (e.g., mg per mL). In some embodiments the amount of non-volatile solvent in the composition is an amount that is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% greater than the amount that is needed to completely dissolve the therapeutic agent in the composition. In some embodiments the amount of non-volatile solvent in the composition is an amount that is at least 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% greater than the amount that is needed to completely dissolve the therapeutic agent in the composition.BT Ref. 104448-429411 PATENT

[0121] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, and an ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition. In more preferred embodiments, at least one of the nonvolatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0122] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol,BT Ref. 104448-429411 PATENT synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, and a synthetic ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition. In more preferred embodiments, at least one of the nonvolatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0123] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, and gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of theBT Ref. 104448-429411 PATENT total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0124] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, and synthetic gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition,BT Ref. 104448-429411 PATENT greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0125] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, and an ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, at least one of the non-volatile solvents is presentBT Ref. 104448-429411 PATENT in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0126] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an Ci-Cio, Ci-Cs, Ci-Cs, C2-C4, or C2 ester of vitamin E, a C1-C10, Ci-Cs, Ci- C5, C2-C4, or C2 ester of beta tocopherol, is a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one ofBT Ref. 104448-429411 PATENT the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0127] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an acetate ester of vitamin E, an acetate ester of beta tocopherol, an acetate ester of delta tocopherol, an acetate ester of gamma tocopherol, and an acetate ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 60%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 65%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 70%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 75%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 80%(w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0128] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from theBT Ref. 104448-429411 PATENT group consisting of a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, and a synthetic ester of gamma tocopherol and at least one of the nonvolatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition. In more preferred embodiments, at least one of the nonvolatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0129] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic Ci-Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, a synthetic C1-C10, Ci-Cs, C1-C5, C2- C4, or C2 ester of delta tocopherol, and a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greaterBT Ref. 104448-429411 PATENT than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0130] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic acetate ester of vitamin E, a synthetic acetate ester of beta tocopherol, a synthetic acetate ester of delta tocopherol, a synthetic acetate ester of gamma tocopherol, and a synthetic acetate ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-BT Ref. 104448-429411 PATENT volatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition. In preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition. In more preferred embodiments, at least one of the nonvolatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0131] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, vitamin E acetate, synthetic vitamin E, or synthetic vitamin E acetate and at least one of the non-volatile solvents is present in the amount of greater than about50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 60%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 65%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 70%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 75%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 80%(w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments,BT Ref. 104448-429411 PATENT at least one of the non-volatile solvents is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, at least one of the non-volatile solvents is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

[0132] In some embodiments, the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is vitamin E acetate and the vitamin E acetate is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition. In preferred embodiments, the vitamin E acetate is present in the amount of greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition. In more preferred embodiments, the vitamin E acetate is present in the amount of greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition. In even more preferred embodiments, the vitamin E acetate is present in the amount of greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.BT Ref. 104448-429411 PATENT

[0133] In some embodiments, combinations of the aforementioned non-volatile solvents are included in the compositions. Each non-volatile solvent of the combination may be included in any of the amounts indicated above for the non-volatile solvent or the one or more non-volatile solvent.Excipients

[0134] The embodiments described herein may optionally contain one or more excipients. Excipients for topical compositions are well-known in the art and include, e.g., emollients, emulsifiers, preservatives, antioxidants, chelating agents, thickeners, humectants, wetting agents, permeation enhancers, buffering agents, solvents, and fragrances. See, e.g., Chang etal., “Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products,” The AAPS Journal (Jan. 2013), vol. 15, pages 41-52, which is incorporated herein by reference in its entirety. Accordingly, some embodiments optionally include one or more of an emollient, an emulsifier, a preservative, an antioxidant, a chelating agent, a thickener, a humectant, a wetting agent, a permeation enhancer, a buffering agent, a pH adjusting agent, a volatile solvent, or a fragrance. As each of these excipients are independently optional, in some embodiments none of these excipients is included. In other embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of these types of excipients are included. In other embodiments, one or more of these types of excipients is excluded. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of these types of excipients is excluded.

[0135] In some embodiments, the composition includes <1%, <0.5%, or <0.1% of an emollient. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of an emulsifier. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a preservative. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of an antioxidant. In someBT Ref. 104448-429411 PATENT embodiments, the composition includes <1%, <0.5%, or <0.1% of a chelating agent. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a thickener. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a humectant. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a wetting agent. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a permeation enhancer. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a buffering agent. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a pH adjusting agent. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a volatile solvent. In some embodiments, the composition includes <1%, <0.5%, or <0.1% of a fragrance.

[0136] In some embodiments, the composition does not include an emollient. In some embodiments, the composition does not include an emulsifier. In some embodiments, the composition does not include a preservative. In some embodiments, the composition does not include an antioxidant. In some embodiments, the composition does not include a chelating agent. In some embodiments, the composition does not include a thickener. In some embodiments, the composition does not include a humectant. In some embodiments, the composition does not include a wetting agent. In some embodiments, the composition does not include a permeation enhancer. In some embodiments, the composition does not include a buffering agent. In some embodiments, the composition does not include a pH adjusting agent. In some embodiments, the composition does not include a volatile solvent. In some embodiments, the composition does not include a fragrance.

[0137] It is entirely plausible that an excipient may be identified in the literature as falling with two or more of the categories of an emollient, an emulsifier, a preservative, an antioxidant, a chelating agent, a thickener, a humectant, a wetting agent, a permeation enhancer, a bufferingBT Ref. 104448-429411 PATENT agent, a pH adjusting agent, a volatile solvent, or a fragrance. Furthermore, excipients may have dual or multiple functionalities that would result in the excipient as falling with two or more of the categories of an emollient, an emulsifier, a preservative, an antioxidant, a chelating agent, a thickener, a humectant, a wetting agent, a permeation enhancer, a buffering agent, a pH adjusting agent, a volatile solvent, or a fragrance. For the purposes of understanding the embodiments described herein and / or any claims, when two or more categories are identified as being included in a composition / embodiment (e.g., a therapeutic agent, a non-volatile solvent, an emollient, an emulsifier, a preservative, an antioxidant, a chelating agent, a thickener, a humectant, a wetting agent, a permeation enhancer, a buffering agent, a pH adjusting agent, a volatile solvent, or a fragrance), it is intended that separate compounds will be present to fulfill the identified categories (i.e., one compound will not fulfill more than one category). As a non-limiting example, if a composition / embodiment is identified as including a therapeutic agent and a preservative, two different compounds are intended to be included in the composition / embodiment despite the fact that a therapeutic agent might function as a preservative and vice versa. As another non-limiting example, if a composition / embodiment is identified as including vitamin E acetate and an antioxidant, two different compounds are intended to be included in the composition / embodiment despite the fact that vitamin E acetate might function as an antioxidant.

[0138] Furthermore, when categorizing a particular compound as a therapeutic agent, a nonvolatile solvent, an emollient, an emulsifier, a preservative, an antioxidant, a chelating agent, a thickener, a humectant, a wetting agent, a permeation enhancer, a buffering agent, a volatile solvent, or a fragrance, a skilled artisan will rely upon the knowledge in the art, this disclosure, and the context of the identification of the particular compound (including, but not limited to, the amount of the particular compound) in understanding the appropriate category. As another non-BT Ref. 104448-429411 PATENT limiting example, a particular compound may be either a therapeutic agent when present at a certain percentage or a preservative when present at a different percentage and the amount of the particular compound in question may guide the skilled artisan to the appropriate categorization.

[0139] In some embodiments, combinations of excipients are included in the compositions. Each excipient of the combination may be included in any of the amounts indicated herein for the excipient or the one or more excipients.Emollients

[0140] The embodiments described herein may optionally contain one or more emollients. Emollients are well-known in the art. For example, they may facilitate skin hydration by providing a protective layer to keep in moisture and prevent and treat skin dryness. They may also smooth and / or soften skin by helping to repair cracks in the skin, which may also help prevent water loss, and relieve dryness, itching, and scaling. They may also act as a lubricating agent in compositions. Compounds that are recognized as emollients or exhibit emollients properties may be optionally included in the compositions described herein.

[0141] Examples of emollients include, but are not limited to, adipate esters such as diisopropyl adipate, glycols such as propylene glycol, lanolin, lanolin alcohols, glycerin, stearates such as glycerol monostearate, ethylene glycol stearates, shea butter, beeswax, dimethicone, cyclomethicone, ceramide, Ceratonia extract, cetostearyl alcohol, cetyl alcohol, petrolatum, oils such as almond oil, canola oil, castor oil, coconut oil, cottonseed oil, mineral oil, mineral oil light, jojoba oil, olive oil, safflower oil, soybean oil, sunflower oil, squalene, paraffin, monostearates, dibutyl sebacate, glycerol behenate, glycerol monooleate, isopropyl myristate, isopropyl palmitate, lecithin, ethyl linoleate, medium chain triglycerides, myristyl alcohol, octyldodecanol, oleyl alcohol, stearyl alcohol, tricaprylin, triolein, waxes such as carnauba wax, cetyl ester wax, xylitol,BT Ref. 104448-429411 PATENT zinc acetate, sterols such as cholesterol, and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are emollients or exhibit properties of emollients, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are emollients or have emollient properties. In some embodiments, one or more of the above identified emollients is optionally included in the composition.

[0142] In preferred embodiments, an emollient is included. In more preferred embodiments, the emollient included in the composition is cholesterol. Cholesterol is the primary lipid component of the nail plate. See Baswan et al. , “Understanding the Formidable Nail Barrier: A Review of the Nail Microstructure, Composition and Diseases,” Mycoses (2017 May), 60(5), pages 284-295, which is incorporated by reference herein in its entirety. Age-related reduction in cholesterol (in the form of cholesterol sulfate) within the nail is associated with onychorrhexis and / or onychoschizia, which contributes to the increased fragility of the nail plate (e.g., brittle nail syndrome and the characteristic ridging or splitting of the nail). Moreover, brittle nails are an adverse effect of certain azole antifungal agents, such as itraconazole, which often exhibit some inhibition of cholesterol biosynthesis and / or cholesterol trafficking (albeit to a lesser extent than their effect on ergosterol biosynthesis). See, e.g., Isono et al., “Itraconazole Inhibits Intracellular Cholesterol Trafficking and Decreases Phosphatidylserine Level in Cervical Cancer Cells,” Anticancer Research (Nov. 2021), 41(11), pages 5477-5480; Kim et al., “Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth,” Cancer Cell (2010), 17(4), pages 388-399. Without wishing to be bound by any particular theory, the inclusion of cholesterol in the composition is believed to improve nail health and / or nail growth, reduce and / or treat onychorrhexis and / or onychoschizia, and avoid brittle nail syndromeBT Ref. 104448-429411 PATENT in subjects. Thus, some embodiments relate to the promotion of nail health and / or nail growth, treatment of onychorrhexis and / or onychoschizia, and / or treatment of brittle nail syndrome. In more preferred embodiments, the promotion of nail health and / or nail growth, treatment of onychorrhexis and / or onychoschizia, and / or treatment of brittle nail syndrome occurs concomitantly with the methods described herein.

[0143] In some embodiments, one or more emollient is present in the composition in the amount of 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.1%- 10% (w / w), 0. l%-5% (w / w), 0.5%-3% (w / w), l%-2% (w / w), about 0.1 %- 10% (w / w), about 0.1%- 5% (w / w), about 0.5%-3% (w / w), or about l%-2% (w / w)). In preferred embodiments, the emollient is present in the amount of about 0. l%-5% (w / w), about 0.5%-3% (w / w), about l%-2% (w / w), about 1% (w / w), or about 2% (w / w) of the composition. In more preferred embodiments, the emollient is present in the amount of about l%-2% (w / w), about 1% (w / w), or about 2% (w / w)BT Ref. 104448-429411 PATENT of the composition. In more preferred embodiments, the emollient is cholesterol and the cholesterol is present in the composition in the amount of about l%-2% (w / w), about 1% (w / w), or about 2% (w / w).

[0144] In some embodiments, one or more emollient is present in composition in the amount of less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 0.1%- 10% (w / w), less than 0. l%-5% (w / w), less than 0.5%-3% (w / w), less than l%-2% (w / w), less thanBT Ref. 104448-429411 PATENT about 0.1 %-l 0% (w / w), less than about 0.1 %-5% (w / w), less than about 0.5%-3% (w / w), or less than about l%-2% (w / w)). In preferred embodiments, the emollient is present in an amount of less than 5% (w / w) or less than about 5% (w / w) of the composition. In more preferred embodiments, the emollient is cholesterol and the cholesterol is present in the composition in the amount of less than 3% (w / w) or less than about 3% (w / w).

[0145] In some embodiments, the amount of one or more emollient in the composition is limited by the solubility of the emollient in the composition. Accordingly, in some embodiments the amount of emollient in the composition is equal to or less than the limit of solubility for that emollient in a given volume of the composition. In preferred embodiments, the amount of emollient in the composition is equal to or less than the limit of solubility for that emollient in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of emollient in the composition is less than the limit of solubility for that emollient in a given volume of the composition or less than the limit of solubility for that emollient in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of emollient in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the emollient in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular emollient in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of emollients and a particular volume of the composition (without emollient) or a particular volume of non-volatile solvent to be included in the composition and determiningBT Ref. 104448-429411 PATENT whether complete dissolution occurred and / or the saturation point for dissolution of the emollient in the unit of weight per volume (e.g., mg per mL).

[0146] In some embodiments, combinations of the aforementioned emollients are included in the compositions. Each emollient of the combination may be included in any of the amounts indicated above for the emollient or the one or more emollients.Emulsifiers

[0147] The embodiments described herein may optionally contain one or more emulsifiers. Emulsifiers are well-known in the art. For example, they are substances that act as a stabilizer for a mixture of two or more liquids that are normally fully immiscible (unmixable or unblendable).

[0148] Examples of emulsifiers include, but are not limited to, natural emulsifying agents (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, propylene glycol monostearate, and polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween® 20], polyoxyethylene sorbitan [Tween® 60], polyoxyethylene sorbitan monooleate [Tween® 80], sorbitan monopalmitate [Span® 40], sorbitan monostearate [Span® 60], sorbitan tristearate [Span® 65], glyceryl monooleate, and sorbitan monooleate [Span® 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj®BT Ref. 104448-429411 PATENT45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij® 30]), and poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, and docusate sodium, and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are emulsifiers or exhibit properties of emulsifiers, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds having emulsifying properties. In some embodiments, one or more of the above identified emulsifiers is optionally included in the composition.

[0149] In some embodiments, one or more emulsifier is present in the composition in the amount of 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w),BT Ref. 104448-429411 PATENT about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.1%- 10% (w / w), 0. l%-5% (w / w), 0.5%-3% (w / w), l%-2% (w / w), about 0.1 %- 10% (w / w), about 0.1%- 5% (w / w), about 0.5%-3% (w / w), or about l%-2% (w / w)). In preferred embodiments, the optional one or more emulsifier is not included in the composition.

[0150] In some embodiments, one or more emulsifier is present in composition in the amount of less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e g., less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of theBT Ref. 104448-429411 PATENT aforementioned percentages or about any of the aforementioned percentages (e g., less than 0.1%- 10% (w / w), less than 0. l%-5% (w / w), less than 0.5%-3% (w / w), less than l%-2% (w / w), less than about 0. l%-10% (w / w), less than about 0. l%-5% (w / w), less than about 0.5%-3% (w / w), or less than about l%-2% (w / w)).

[0151] In some embodiments, the amount of one or more emulsifier in the composition is limited by the solubility of the emulsifier in the composition. Accordingly, in some embodiments the amount of emulsifier in the composition is equal to or less than the limit of solubility for that emulsifier in a given volume of the composition. In preferred embodiments, the amount of emulsifier in the composition is equal to or less than the limit of solubility for that emulsifier in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of emulsifier in the composition is less than the limit of solubility for that emulsifier in a given volume of the composition or less than the limit of solubility for that emulsifier in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of emulsifier in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the emulsifier in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular emulsifier in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of emulsifier and a particular volume of the composition (without emollient) or a particular volume of non-volatile solvent to be included in the composition and determining whetherBT Ref. 104448-429411 PATENT complete dissolution occurred and / or the saturation point for dissolution of the emulsifier in the unit of weight per volume (e.g., mg per mb).

[0152] In some embodiments, combinations of the aforementioned emulsifiers are included in the compositions. Each emulsifier of the combination may be included in any of the amounts indicated above for the emulsifier or the one or more emulsifier.Preservatives

[0153] The embodiments described herein may optionally contain one or more antimicrobial preservatives or combination of compounds that collectively afford antimicrobial preservation. An “antimicrobial preservative” can be any compound or combination of compounds capable of destroying microbes, preventing the multiplication or growth of microbes, or preventing the pathogenic action of microbes.

[0154] Examples of antimicrobial preservatives include, but are not limited to, a paraben compound (e.g., an ester of para-hydroxybenzoic acid such as paraben, methylparaben, ethylparaben, propylparaben, butylparaben, heptylparaben, benzylparaben, isobutylparaben, isopropylparaben, benzylparaben, or their salts), benzalkonium chloride, benzethonium chloride, benzyl alcohol, boric acid or borate, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. A person of ordinary skill in the art will understand the class of compounds that are antimicrobial preservatives or exhibit preservative properties, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are preservatives or haveBT Ref. 104448-429411 PATENT preservative properties. In some embodiments, one or more of the above identified antimicrobial agents is optionally included in the composition.

[0155] In some embodiments, one or more antimicrobial preservative is present in the composition in the amount of 0.00001% (w / w), 0.00005% (w / w), 0.0001% (w / w), 0.0005% (w / w), 0.001% (w / w), 0.005% (w / w), 0.01% (w / w), 0.05% (w / w), 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.00001% (w / w), about 0.00005% (w / w), about 0.0001% (w / w), about 0.0005% (w / w), about 0.001% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.00001%-10% (w / w), 0.0001%-5% (w / w), 0.001%-3% (w / w), 0.01%-2% (w / w), 0.01%-l% (w / w), about 0.00001%-10% (w / w), about 0.0001%-5% (w / w), about 0.001%-3% (w / w), about 0.01%-2% (w / w), about 0.01%-l% (w / w)). In preferred embodiments, the optional one or more preservatives is not included in the composition.BT Ref. 104448-429411 PATENT

[0156] In some embodiments, one or more antimicrobial preservative is present in composition in the amount of less than 0.00005% (w / w), less than 0.0001% (w / w), less than 0.0005% (w / w), less than 0.001% (w / w), less than 0.005% (w / w), less than 0.01% (w / w), less than 0.05% (w / w), less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.00005% (w / w), less than about 0.00005% (w / w), less than about 0.0001% (w / w), less than about 0.0005% (w / w), less than about 0.001% (w / w), less than about 0.005% (w / w), less than about 0.01% (w / w), less than about 0.05% (w / w), less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or aboutBT Ref. 104448-429411 PATENT any of the aforementioned percentages (e.g., less than 0.00005%-10% (w / w), less than 0.0001%- 5% (w / w), less than 0.001%-3% (w / w), less than 0.01%-2% (w / w), less than 0.01%-l% (w / w), less than about 0.00005%- 10% (w / w), less than about 0.0001%-5% (w / w), less than about 0.001%- 3% (w / w), less than about 0.01%-2% (w / w), or less than about 0.01%- 1 % (w / w)).

[0157] In some embodiments, the amount of one or more antimicrobial preservative in the composition is limited by the solubility of the preservative in the composition. Accordingly, in some embodiments the amount of preservative in the composition is equal to or less than the limit of solubility for that preservative in a given volume of the composition. In preferred embodiments, the amount of preservative in the composition is equal to or less than the limit of solubility for that preservative in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of preservative in the composition is less than the limit of solubility for that preservative in a given volume of the composition or less than the limit of solubility for that preservative in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of preservative in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the preservative in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular preservative in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of preservative and a particular volume of the composition (without emollient) or a particular volume of non-volatile solvent to be included in the composition andBT Ref. 104448-429411 PATENT determining whether complete dissolution occurred and / or the saturation point for dissolution of the preservative in the unit of weight per volume (e.g., mg per mL).

[0158] In some embodiments, combinations of the aforementioned preservatives are included in the compositions. Each preservative of the combination may be included in any of the amounts indicated above for the preservative or the one or more preservatives.Antioxidants

[0159] The embodiments described herein may optionally contain one or more antioxidants. An antioxidant can be any compound or combination of compounds capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Antioxidants inhibit oxidation reactions. They do this by being oxidized themselves, so antioxidants are often reducing agents. To the extent that any ingredients identified as included in the embodiments described herein exhibit the function of an antioxidant, e.g., vitamin E, -alpha tocopherol, t / -alpha tocopherol acetate, t / / -alpha tocopheryl acetate, beta tocopherol, delta tocopherol, or gamma tocopherol, an embodiment may optionally contain one or more additional antioxidants or combination of compounds that further functions as an antioxidant.

[0160] Examples of antioxidants include, but are not limited to, butylated hydroxyanisole, butylated hydroxytoluene, vitamin C, vitamin A, lutein, lycopene, retinyl palmitate, potassium metabisulfite, sodium metabisulfite, sodium thiosulfate pentahydrate, 3,4-dihydroxybenzoic acid, propyl gallate, alpha-lipoic acid, ascorbyl palmitate, sodium pyrosulfite, ubiquinone, and selenium. A person of ordinary skill in the art will understand the class of compounds that are antioxidants or exhibit antioxidant properties, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated byBT Ref. 104448-429411 PATENT reference for its identification of compounds having that are antioxidants or have antioxidant properties.

[0161] In some embodiments, one or more antioxidants are present in the composition in the amount of 0.001% (w / w), 0.005% (w / w), 0.01% (w / w), 0.05% (w / w), 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.001% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.001%-10% (w / w), 0.001%- 5% (w / w), 0.001%-3% (w / w), 0.01%-2% (w / w), 0.01%-l% (w / w), about 0.00001%-10% (w / w), about 0.0001%-5% (w / w), about 0.001%-3% (w / w), about 0.01%-2% (w / w), about 0.01%-l% (w / w)). In preferred embodiments, the optional one or more antioxidants is not included in the composition.

[0162] In some embodiments, one or more antioxidants are present in composition in the amount of less than 0.001% (w / w), less than 0.005% (w / w), less than 0.01% (w / w), less than 0.05% (w / w),BT Ref. 104448-429411 PATENT less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.001% (w / w), less than about 0.005% (w / w), less than about 0.01% (w / w), less than about 0.05% (w / w), less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 0.001 %- 10% (w / w), less than 0.001%-5% (w / w), less than 0.001%-3% (w / w), less than 0.01%-2% (w / w), less than 0.01%-1% (w / w), less than about 0.001%-10% (w / w), less than about 0.001%-5% (w / w), less than about 0.001%-3% (w / w), less than about 0.01%-2% (w / w), or less than about 0.01%- 1% (w / w)).BT Ref. 104448-429411 PATENT

[0163] In some embodiments, the amount of one or more antioxidant included in the composition is limited by the solubility of the antioxidant in the composition. Accordingly, in some embodiments the amount of antioxidant in the composition is equal to or less than the limit of solubility for that antioxidant in a given volume of the composition. In preferred embodiments, the amount of antioxidant in the composition is equal to or less than the limit of solubility for that antioxidant in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of antioxidant in the composition is less than the limit of solubility for that antioxidant in a given volume of the composition or less than the limit of solubility for that antioxidant in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of antioxidant in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the antioxidant in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular antioxidant in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of antioxidant and a particular volume of the composition (without emollient) or a particular volume of non-volatile solvent to be included in the composition and determining whether complete dissolution occurred and / or the saturation point for dissolution of the antioxidant in the unit of weight per volume (e g., mg per m ).

[0164] In some embodiments, combinations of the aforementioned antioxidants are included in the compositions. Each antioxidant of the combination may be included in any of the amounts indicated above for the antioxidant or the one or more antioxidants.BT Ref. 104448-429411 PATENTChelating Agents

[0165] The embodiments described herein may optionally contain one or more chelating agents. A “chelating agent” can be any compound or combination of compounds that are capable of forming a complex with a metal ion.

[0166] Examples of chelating agents include, but are not limited to, citric acid, phosphates, a polyaminopolycarboxylic acid or salt thereof such as mono- or polyalkylene polyamine polycarboxylic acids, polyaminoalkane poly carboxy lie acids, polyaminoalkanol polycarboxylic acids, and hydroxyalkylether polyamine polycarboxylic acids, ethylenediaminetetraacetic acid (“ED TA”), ethylene glycol-bis-(b-aminoethylether)-N,N,N',N'-tetraacetic acid (“EGTA”), 1,2- bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (“BAPTA”); ethylene-N,N'-diglycine (“EDDA”), 2,2'-(ethylendiimino)-dibutyric acid (“EBDA”), lauroyl ED TA, dilauroyl EDTA, triethylene tetramine dihydrochloride (“TRIEN”), diethylenetriamin-pentaacetic acid (“DPTA”), triethylenetetramine hexaacetic acid (“TTG”), deferoxamine, Dimercaprol, zinc citrate, penicilamine succimer, Editronate, edetate calcium disodium, desferrioxamine B, dithiocarb sodium, penicillamine, pentetate calcium, a salt of pentetic acid such as a sodium salt, succimer, trientine, nitrilotri acetic acid, trans-diaminocyclohexanetetraacetic acid (“DCTA”), diethylenetriaminepentaacetic acid, bis(aminoethyl) glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, tartaric acid, fumaric acid, and salts thereof (e.g., sodium, potassium, and / or calcium salts of carboxylic acids). A person of ordinary skill in the art will understand the class of compounds that are chelating agents or exhibit the ability to chelate metal ions, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that areBT Ref. 104448-429411 PATENT chelating agents or have the ability to chelate metal ions. In some embodiments, one or more of the above identified chelating agents is optionally included in the composition.

[0167] In some embodiments, one or more chelating agents are present in the composition in the amount of 0.00001% (w / w), 0.00005% (w / w), 0.0001% (w / w), 0.0005% (w / w), 0.001% (w / w), 0.005% (w / w), 0.01% (w / w), 0.05% (w / w), 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.00001% (w / w), about 0.00005% (w / w), about 0.0001% (w / w), about 0.0005% (w / w), about 0.001% (w / w), about 0.005% (w / w), about 0.01% (w / w), about 0.05% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.00001%-10% (w / w), 0.0001%-5% (w / w), 0.001%-3% (w / w), 0.01%-2% (w / w), 0.01%-l% (w / w), about 0.00001%-10% (w / w), about 0.0001%-5% (w / w), about 0.001%-3% (w / w), about 0.01%-2% (w / w), about 0.01%-l% (w / w)). In preferred embodiments, the optional one or more chelating agents is not included in the composition.BT Ref. 104448-429411 PATENT

[0168] In some embodiments, one or more chelating agents are present in the composition in the amount of less than 0.00005% (w / w), less than 0.0001% (w / w), less than 0.0005% (w / w), less than 0.001% (w / w), less than 0.005% (w / w), less than 0.01% (w / w), less than 0.05% (w / w), less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.00005% (w / w), less than about 0.00005% (w / w), less than about 0.0001% (w / w), less than about 0.0005% (w / w), less than about 0.001% (w / w), less than about 0.005% (w / w), less than about 0.01% (w / w), less than about 0.05% (w / w), less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of theBT Ref. 104448-429411 PATENT aforementioned percentages (e.g., less than 0.00005%-l 0% (w / w), less than 0.0001 %-5% (w / w), less than 0.001%-3% (w / w), less than 0.01%-2% (w / w), less than 0.01 %- 1 % (w / w), less than about 0.00005%-10% (w / w), less than about 0.0001%-5% (w / w), less than about 0.001%-3% (w / w), less than about 0.01%-2% (w / w), or less than about 0.01%-1 % (w / w)).

[0169] In some embodiments, the amount of one or more chelating agents included in the composition is limited by the solubility of the chelating agent in the composition. Accordingly, in some embodiments the amount of chelating agent in the composition is equal to or less than the limit of solubility for that chelating agent in a given volume of the composition. In preferred embodiments, the amount of chelating agent in the composition is equal to or less than the limit of solubility for that chelating agent in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of chelating agent in the composition is less than the limit of solubility for that chelating agent in a given volume of the composition or less than the limit of solubility for that chelating agent in a given volume of nonvolatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of chelating agent in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the chelating agent in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular chelating agent in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of chelating agent and a particular volume of the composition (without emollient) or a particular volume of nonvolatile solvent to be included in the composition and determining whether complete dissolutionBT Ref. 104448-429411 PATENT occurred and / or the saturation point for dissolution of the chelating agent in the unit of weight per volume (e.g., mg per mL).

[0170] In some embodiments, combinations of the aforementioned chelating agents are included in the compositions. Each chelating agent of the combination may be included in any of the amounts indicated above for the chelating agent or the one or more chelating agents.Thickeners

[0171] The embodiments described herein may optionally contain one or more thickeners. Thickeners are well-known in the art. For example, they may facilitate the thickening or addition of structure to a formulation, impart physical stability, or increase viscosity. Compounds that are recognized as thickeners or exhibit thickener properties may be optionally included in the compositions described herein.

[0172] Examples of thickeners include, but are not limited to, gums (e.g., xanthan gum and gum tragacanth) and natural polysaccharides (e.g., cellulose, alginic acid, and sodium alginate), mineral thickeners, oils, synthetic polymeric thickeners, acrylic acid or an acrylate (e.g., those available commercially under the trade name Carbopol® and the like), carbomers, carboxypolymethylene, microcrystalline cellulose, modified celluloses (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, or carboxymethylcellulose), maltodextrin, polydextrose, dextrates, alkylgalactomanans, polyvinyl alcohol, poloxamers, polyethylene glycol (“PEG”), stearyl palmitate, PEG- 100 stearate, glyceryl stearate, cetyl alcohol, waxes, titanium dioxide, magnesium aluminum silicate, sodium chloride, bentonite, dimethyl sulfone, and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are thickeners or exhibit properties of thickeners, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated byBT Ref. 104448-429411 PATENT reference for its identification of compounds that are thickeners or have thickener properties. In some embodiments, one or more of the above identified thickeners is optionally included in the composition.

[0173] In some embodiments, one or more thickener is present in the composition in the amount of 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.1%- 10% (w / w), 0. l%-5% (w / w), 0.5%-3% (w / w), l%-2% (w / w), about 0.1 %- 10% (w / w), about 0.1%- 5% (w / w), about 0.5%-3% (w / w), or about l%-2% (w / w)). In preferred embodiments, the optional one or more thickener is not included in the composition.

[0174] In some embodiments, one or more thickener is present in composition in the amount of less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w),BT Ref. 104448-429411 PATENT less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 0.1%- 10% (w / w), less than 0. l%-5% (w / w), less than 0.5%-3% (w / w), less than l%-2% (w / w), less than about 0. l%-10% (w / w), less than about 0. l%-5% (w / w), less than about 0.5%-3% (w / w), or less than about l%-2% (w / w)).

[0175] In some embodiments, the amount of one or more thickener is limited by the solubility of the thickener in the composition. Accordingly, in some embodiments the amount of thickener in the composition is equal to or less than the limit of solubility for that thickener in a given volume of the composition. In preferred embodiments, the amount of thickener in the composition is equal to or less than the limit of solubility for that thickener in a given volume of non-volatile solventBT Ref. 104448-429411 PATENT that is to be included in the composition. In even more preferred embodiments, the amount of thickener in the composition is less than the limit of solubility for that thickener in a given volume of the composition or less than the limit of solubility for that thickener in a given volume of nonvolatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of thickener in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the thickener in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular thickener in any particular composition or nonvolatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of thickener and a particular volume of the composition (without thickener) or a particular volume of non-volatile solvent to be included in the composition and determining whether complete dissolution occurred and / or the saturation point for dissolution of the thickener in the unit of weight per volume (e g., mg per mL).

[0176] In some embodiments, combinations of the aforementioned thickeners are included in the compositions. Each thickener of the combination may be included in any of the amounts indicated above for the thickener or the one or more thickeners.Humectants

[0177] The embodiments described herein may optionally contain one or more humectants. Humectants are well-known in the art. For example, they are capable of reducing or limiting the loss of moisture from a surface. Compounds that are recognized as humectants or exhibit humectant properties may be optionally included in the compositions described herein.BT Ref. 104448-429411 PATENT

[0178] Examples of humectants include, but are not limited to, sodium hyaluronate, glycerin, glycerol, propylene glycol, glyceryl triacetate, a lanolin product (such as PPG-12-PEG 50), polyhydric alcohols (e.g., glycerin, diglycerin, sorbitol, propylene glycol, dipropylene glycol, butylene glycol, hexylene glycol, ethoxylated glucose, 1, 2-hexane diol, hexanetri ol, dipropylene glycol, erythritol, trehalose, diglycerin, xylitol, maltitol, maltose, glucose, fructose, sodium chondroitin sulfate, sodium hyaluronate, sodium adenosin phosphate, sodium lactate, pyrrolidone carbonate, glucosamine, and cyclodextrin), water soluble alkoxylated nonionic polymers (e.g., polyethylene glycols and polypropylene glycols having a molecular weight of up to about 1000, such as those like PEG-200, PEG-400, PEG-600, and PEG- 1000), and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are humectants or exhibit properties of humectants, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are humectants or have humectant properties. In some embodiments, one or more of the above identified humectants is optionally included in the composition.

[0179] In some embodiments, one or more humectant is present in the composition in the amount of 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w),BT Ref. 104448-429411 PATENT about 1 .75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.1%- 10% (w / w), 0. l%-5% (w / w), 0.5%-3% (w / w), l%-2% (w / w), about 0.1 %- 10% (w / w), about 0.1%- 5% (w / w), about 0.5%-3% (w / w), or about l%-2% (w / w)). In preferred embodiments, the optional one or more humectants is not included in the composition.

[0180] In some embodiments, one or more humectant is present in composition in the amount of less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than aboutBT Ref. 104448-429411 PATENT4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e g., less than 0.1%- 10% (w / w), less than 0. l%-5% (w / w), less than 0.5%-3% (w / w), less than l%-2% (w / w), less than about 0. l%-10% (w / w), less than about 0. l%-5% (w / w), less than about 0.5%-3% (w / w), or less than about l%-2% (w / w)).

[0181] In some embodiments, the amount of one or more humectant is limited by the solubility of the humectant in the composition. Accordingly, in some embodiments the amount of humectant in the composition is equal to or less than the limit of solubility for that humectant in a given volume of the composition. In preferred embodiments, the amount of humectant in the composition is equal to or less than the limit of solubility for that humectant in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of humectant in the composition is less than the limit of solubility for that humectant in a given volume of the composition or less than the limit of solubility for that humectant in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of humectant in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the humectant in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular humectant in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of humectantBT Ref. 104448-429411 PATENT and a particular volume of the composition (without humectant) or a particular volume of nonvolatile solvent to be included in the composition and determining whether complete dissolution occurred and / or the saturation point for dissolution of the humectant in the unit of weight per volume (e.g., mg per mL).

[0182] In some embodiments, combinations of the aforementioned humectants are included in the compositions. Each humectant of the combination may be included in any of the amounts indicated above for the humectant or the one or more humectants.Wetting Agents

[0183] The embodiments described herein may optionally contain one or more wetting agents. Wetting agents are well-known in the art and may be referred to as surfactants. For example, wetting agents are often surface-active molecules that reduce the surface tension of water or reduce agglomeration of ingredients in a solution. Compounds that are recognized as wetting agents or exhibit wetting agent properties may be optionally included in the compositions described herein.

[0184] Examples of wetting agents include, but are not limited to, nonionic surfactants (e.g., polyethoxylated sorbitan fatty acid esters (polysorbates such as Polysorbate 80), polyoxytheylene alkyl ethers, polyoxyethylene stearates), ionic surfactants (e.g., docusate sodium, phospholipids, sodium lauryl sulfate), glycerol (glycerin), glycine, propylene glycol, pol oxamer, 1,3 -butanediol, sorbitol, mannitol, trehalose, triacetin, cyclomethicone dimethicone (polydimethylsiloxane), hydrogenated maltose syrup, benzalkonium chloride, cetylpyridinium chloride, polyoxyethylene castor oil derivatives, sorbitan fatty acid esters, tricaprylin, and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are wetting agents or exhibit properties of wetting agents, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by referenceBT Ref. 104448-429411 PATENT for its identification of compounds that are wetting agents or surfactants or have the properties of wetting agents or surfactants. In some embodiments, one or more of the above identified wetting agents is optionally included in the composition.

[0185] In some embodiments, one or more wetting agent is present in the composition in the amount of 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0. l%-10% (w / w), 0. l%-5% (w / w), 0.5%-3% (w / w), l%-2% (w / w), about 0. l%-10% (w / w), about 0. l%-5% (w / w), about 0.5%-3% (w / w), or about l%-2% (w / w)). In preferred embodiments, the optional one or more wetting agents is not included in the composition.

[0186] In some embodiments, one or more wetting agent is present in composition in the amount of less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75%BT Ref. 104448-429411 PATENT(w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5% (w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than 10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 0.1%- 10% (w / w), less than 0. l%-5% (w / w), less than 0.5%-3% (w / w), less than l%-2% (w / w), less than about 0. l%-10% (w / w), less than about 0. l%-5% (w / w), less than about 0.5%-3% (w / w), or less than about l%-2% (w / w)).

[0187] In some embodiments, the amount of one or more wetting agent is limited by the solubility of the wetting agent in the composition. Accordingly, in some embodiments the amount of wetting agent in the composition is equal to or less than the limit of solubility for that wetting agent in a given volume of the composition. In preferred embodiments, the amount of wetting agent in the composition is equal to or less than the limit of solubility for that wetting agent in aBT Ref. 104448-429411 PATENT given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of wetting agent in the composition is less than the limit of solubility for that wetting agent in a given volume of the composition or less than the limit of solubility for that wetting agent in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of wetting agent in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the wetting agent in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular wetting agent in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of wetting agent and a particular volume of the composition (without wetting agent) or a particular volume of non-volatile solvent to be included in the composition and determining whether complete dissolution occurred and / or the saturation point for dissolution of the wetting agent in the unit of weight per volume (e.g., mg per m ).

[0188] In some embodiments, combinations of the aforementioned wetting agents are included in the compositions. Each wetting agent of the combination may be included in any of the amounts indicated above for the wetting agent or the one or more wetting agents.Permeation Enhancers

[0189] The embodiments described herein may optionally contain one or more permeation enhancers. Permeation enhancers are well-known in the art. For example, permeation enhancers may interact with the constituents of skin’s outermost and rate limiting layer stratum comeum (SC), and increase its permeability. Compounds that are recognized as permeation enhancers orBT Ref. 104448-429411 PATENT exhibit permeation enhancer properties may be optionally included in the compositions described herein. Generally, however, permeation enhancers are not included in the compositions described herein because localized action is preferred over less-localized action resulting from over penetration of therapeutic agent or systemic action.

[0190] Examples of permeation enhancers include, but are not limited to, azones such as laurocapran, l-dodecylazacycloheptan-2-one; sulphoxides such as dimethylsulphoxide, DMAC, DMF; pyrrolidones such as 2-pyrrolidone, N-methyl-2 -pyrrolidone; alcohols such as ethanol, 1,2- propandiol or decanol; glycols such as propylene glycol, diethylene glycol, tetraethylene glycol; fatty acids such as oleic acid, lauric acid, sodium lauryl sulfate, myristic acid, isopropyl myristic acid, capric acid; nonionic surfactants such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2- stearyl ether; terpenes; terpenoids; oxazolidinones; urea; ceramide analogs, azone analogs, menthol derivatives, etherified derivatives, esterified derivatives, transkarbams, carbamate salts, TXA derivatives, DDAIP (dodecyl 2-(dimethylamino) propanoate), DDAK, natural essential oils; citric acid esters such as triethyl citrate; hydrophobin polypeptides; alpha-bisabolol; dimethyl isosorbide (Arlasolve® DMI); ethoxy diglycol; 1,2-propandiol; dimethylacetamide; hydroxypropyl betadex; octyldodecanol; and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are permeation enhancers or exhibit properties of permeation enhancers, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are permeation enhancers or have the properties of permeation enhancers. In some embodiments, one or more of the above identified permeation enhancers is optionally included in the composition.BT Ref. 104448-429411 PATENT

[0191] In some embodiments, one or more permeation enhancer is present in the composition in the amount of 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3.75% (w / w), 4% (w / w), 4.25% (w / w), 4.5% (w / w), 4.75% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 3% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w), about 4% (w / w), about 4.25% (w / w), about 4.5% (w / w), about 4.75% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.1%-10% (w / w), 0. l%-5% (w / w), 0.5%-3% (w / w), l%-2% (w / w), about 0. l%-10% (w / w), about 0. l%-5% (w / w), about 0.5%-3% (w / w), or about l%-2% (w / w)). In preferred embodiments, the optional one or more permeation enhancers is not included in the composition.

[0192] In some embodiments, one or more permeation enhancer is present in composition in the amount of less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), less than 3.25% (w / w), less than 3.5% (w / w), less than 3.75% (w / w), less than 4% (w / w), less than 4.25% (w / w), less than 4.5% (w / w), less than 4.75% (w / w), less than 5%BT Ref. 104448-429411 PATENT(w / w), less than 6% (w / w), less than 7% (w / w), less than 8% (w / w), less than 9% (w / w), less than10% (w / w), about any of the aforementioned percentages (e.g., less than about 0.1% (w / w), less than about 0.2% (w / w), less than about 0.3% (w / w), less than about 0.4% (w / w), less than about 0.5% (w / w), less than about 0.6% (w / w), less than about 0.7% (w / w), less than about 0.8% (w / w), less than about 0.9% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), less than about 3% (w / w), less than about 3.25% (w / w), less than about 3.5% (w / w), less than about 3.75% (w / w), less than about 4% (w / w), less than about 4.25% (w / w), less than about 4.5% (w / w), less than about 4.75% (w / w), less than about 5% (w / w), less than about 6% (w / w), less than about 7% (w / w), less than about 8% (w / w), less than about 9% (w / w), or less than about 10% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 0.1%- 10% (w / w), less than 0. l%-5% (w / w), less than 0.5%-3% (w / w), less than l%-2% (w / w), less than about 0. l%-10% (w / w), less than about 0. l%-5% (w / w), less than about 0.5%-3% (w / w), or less than about l%-2% (w / w)).

[0193] In some embodiments, the amount of one or more permeation enhancer is limited by the solubility of the permeation enhancer in the composition. Accordingly, in some embodiments the amount of permeation enhancer in the composition is equal to or less than the limit of solubility for that permeation enhancer in a given volume of the composition. In preferred embodiments, the amount of permeation enhancer in the composition is equal to or less than the limit of solubility for that permeation enhancer in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of permeation enhancer in the composition is less than the limit of solubility for that permeation enhancer in a given volume ofBT Ref. 104448-429411 PATENT the composition or less than the limit of solubility forthat permeation enhancer in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of permeation enhancer in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the permeation enhancer in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular permeation enhancer in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of permeation enhancer and a particular volume of the composition (without humectant) or a particular volume of non-volatile solvent to be included in the composition and determining whether complete dissolution occurred and / or the saturation point for dissolution of the permeation enhancer in the unit of weight per volume (e.g., mg per mL).

[0194] In some embodiments, combinations of the aforementioned permeation enhancers are included in the compositions. Each permeation enhancer of the combination may be included in any of the amounts indicated above for the permeation enhancer or the one or permeation enhancers.Buffering and pH Adjusting Agents

[0195] In general, the compositions described herein are non-aqueous compositions. Accordingly, there is no need to include any buffering and / or pH adjusting agents. Should water be present in a composition, e.g., to create an emulsion or to facilitate formulation as a cream, then the embodiments described herein may optionally contain one or more buffering agents and / or one or more pH adjusting agents. Buffering agents and pH adjusting agents are well-known in the art.BT Ref. 104448-429411 PATENTFor example, buffering agents are often included in compositions to facilitate the maintenance of pH within a desirable range of values. Similarly, pH adjusting agents are often included in compositions to raise or lower the pH of the composition to a desirable value. Compounds that are recognized as buffering agents and / or pH adjusting agents may be optionally included in the compositions described herein.

[0196] Examples of buffering agents include, but are not limited to, acetic acid, adipic acid, ammonia solution, ammonium phosphate, ammonium sulfate, arginine, asparagine, boric acid, calcium carbonate, calcium lactate, tribasic calcium phosphate, citric acid, dibasic potassium phosphate, dibasic sodium phosphate, diethanolamine, glycine, histidine, hydroxyethylpiperazine ethanesulfonic acid, lysine acetate, lysine hydrochloride, maleic acid, malic acid, meglumine, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, potassium metaphosphate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium lactate, triethanolamine, or tromethamine, and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are buffering agents or exhibit properties of buffering agents, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are buffering agents or have the properties of buffering agents. In some embodiments, one or more of the above identified buffering agents is optionally included in the composition. In some embodiments, one or more of the above identified buffering agents is optionally included in the composition and the composition is partially aqueous.

[0197] Examples of pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, aqueous ammonia, diethanolamine, meglumine, sodium citrate, acetic acid,BT Ref. 104448-429411 PATENT adipic acid, ammonium chloride, ascorbic acid, citric acid, fumaric acid, gluconolactone, lactic acid, maleic acid, malic acid, monobasic sodium phosphate, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, calcium hydroxide, monoethanolamine, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, triethanolamine, or tromethamine, and / or combinations thereof. A person of ordinary skill in the art will understand the class of compounds that are pH adjusting agents or exhibit properties of pH adjusting agents, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are pH adjusting agents or have the properties of pH adjusting agents. In some embodiments, one or more of the above identified pH adjusting agents is optionally included in the composition. In some embodiments, the optional pH adjusting agent is hydrochloric acid or sodium hydroxide. In some embodiments, one or more of the above identified pH adjusting agents is optionally included in the composition and the composition is partially aqueous.

[0198] In some embodiments, one or more buffering agents and / or one or more pH adjusting agents is present in the composition in the amount of 0.1% (w / w), 0.15% (w / w), 0.2% (w / w), 0.25% (w / w), 0.3% (w / w), 0.35% (w / w), 0.4% (w / w), 0.45% (w / w), 0.5% (w / w), 0.55% (w / w), 0.6% (w / w), 0.65% (w / w), 0.7% (w / w), 0.75% (w / w), 0.8% (w / w), 0.85% (w / w), 0.9% (w / w), 0.95% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.15% (w / w), about 0.2% (w / w), about 0.25% (w / w), about 0.3% (w / w), about 0.35% (w / w), about 0.4% (w / w), about 0.45% (w / w), about 0.5% (w / w), about 0.55% (w / w), about 0.6% (w / w), about 0.65% (w / w), about 0.7% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.85% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5%BT Ref. 104448-429411 PATENT(w / w), about 1 .75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), or about 3% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0. l%-3% (w / w), 0.1%-2.5% (w / w), 0.25%-2% (w / w),0.25%-l% (w / w), about 0. l%-3% (w / w), about 0.1%-2.5% (w / w), about 0.25%-2% (w / w), or about 0.25%-l% (w / w)). In preferred embodiments, one or more buffering agents and / or one or more pH adjusting agents (in addition to any ingredient(s) already identified as included in an embodiment that also exhibits the function of a buffering agent and / or pH adjusting agents) is present in the composition in the amount of about 0.3%-2% (w / w). In preferred embodiments, the optional one or more buffering agents and / or one or more pH adjusting agents is not included in the composition.

[0199] In some embodiments, one or more buffering agents and / or one or more pH adjusting agents is present in the composition in the amount of less than 0.1% (w / w), less than 0.15% (w / w), less than 0.2% (w / w), less than 0.25% (w / w), less than 0.3% (w / w), less than 0.35% (w / w), less than 0.4% (w / w), less than 0.45% (w / w), less than 0.5% (w / w), less than 0.55% (w / w), less than 0.6% (w / w), less than 0.65% (w / w), less than 0.7% (w / w), less than 0.75% (w / w), less than 0.8% (w / w), less than 0.85% (w / w), less than 0.9% (w / w), less than 0.95% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), about any of the aforementioned percentages (e.g., less than about 0.1% (w / w), less than about 0.15% (w / w), less than about 0.2% (w / w), less than about 0.25% (w / w), less than about 0.3% (w / w), less than about 0.35% (w / w), less than about 0.4% (w / w), less than about 0.45% (w / w), less than about 0.5% (w / w), less than about 0.55% (w / w), less than about 0.6% (w / w), less than about 0.65% (w / w), less than about 0.7% (w / w), less than about 0.75% (w / w), less than about 0.8% (w / w), less thanBT Ref. 104448-429411 PATENT about 0.85% (w / w), less than about 0.9% (w / w), less than about 0.95% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), or less than about 3% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 2%-3% (w / w), less than 2%-2.5% (w / w), less than 1.5%-2% (w / w), less than 0.75%- 1% (w / w), less than about 2%- 3% (w / w), less than about 2%-2.5% (w / w), less than about 1.5%-2% (w / w), or less than about 0.75%-l% (w / w)). In preferred embodiments, one or more buffering agents and / or one or more pH adjusting agents (in addition to any ingredient(s) already identified as included in an embodiment that also exhibits the function of a buffering agent and / or pH adjusting agents) is present in the composition in the amount of less than about 2%-3% (w / w).

[0200] In some embodiments, the amount of one or more buffering agents and / or one or more pH adjusting agents is limited by the solubility of the buffering agent and / or pH adjusting agent in the composition. Accordingly, in some embodiments the amount of buffering agent and / or pH adjusting agent in the composition is equal to or less than the limit of solubility for that buffering agent and / or pH adjusting agent in a given volume of the composition. In preferred embodiments, the amount of buffering agent and / or pH adjusting agent in the composition is equal to or less than the limit of solubility for that buffering agent and / or pH adjusting agent in a given volume of nonvolatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of buffering agent and / or pH adjusting agent in the composition is less than the limit of solubility for that buffering agent and / or pH adjusting agent in a given volume of the composition or less than the limit of solubility for that buffering agent and / or pH adjusting agent in a given volume of non-volatile solvent that is to be included in the composition. By way ofBT Ref. 104448-429411 PATENT non-limiting example, in some embodiments the amount of buffering agent and / or pH adjusting agent in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the buffering agent and / or pH adjusting agent in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular buffering agent and / or pH adjusting agent in any particular composition or non-volatile solvent that is to be included in the composition. By way of nonlimiting example, this can be determined by measuring different weights of buffering agent and / or pH adjusting agent and a particular volume of the composition (without buffering agent and / or pH adjusting agent) or a particular volume of non-volatile solvent to be included in the composition and determining whether complete dissolution occurred and / or the saturation point for dissolution of the buffering agent and / or pH adjusting agent in the unit of weight per volume (e.g., mg per mL).

[0201] In some embodiments, combinations of the aforementioned buffering and / or pH adjusting agents are included in the compositions. Each buffering and / or pH adjusting agent of the combination may be included in any of the amounts indicated above for the buffering and / or pH adjusting agents or the one or more buffering and / or pH adjusting agent.Volatile Solvents

[0202] The embodiments described herein may optionally contain one or more volatile solvents in addition to the non-volatile solvents previously described. However, it is preferred that compositions do not include volatile solvents or do not include substantial amounts (e.g., greater than 20%). Volatile solvents are compounds that are liquid at standard temperature and pressure (20° C and 1 atm) and have a boiling point that is less than or equal to the boiling point of waterBT Ref. 104448-429411 PATENT(e g., 100° C at 1 atm). Thus, for any given solvent, it is either a non-volatile solvent as previously described or a volatile solvent as described herein. Volatile solvents are well-known in the art.For example, volatile solvents may be included to dissolve other substances that are present in the composition. Compounds that are recognized as volatile solvents or exhibit the properties of a volatile solvent may be optionally included in the compositions described herein.

[0203] Examples of volatile solvents include, but are not limited to, acetone, 2-butanol, 2- methyl-2-propanol, tert-butyl methyl ether, ethanol, ethyl acetate, ethyl formate, ethyl ether, n- heptane, 1 -propanol, isopropanol, isopropyl acetate, methyl acetate, methyl ethyl ketone, pentane, triethylamine, and water. A person of ordinary skill in the art will understand the class of compounds that are volatile solvents, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which is incorporated by reference for its identification of compounds that are solvents or solubilizing agents and exhibit the properties of volatile solvents. In some embodiments, one or more of the above identified volatile solvents is optionally included in the composition. In preferred embodiments, the optional volatile solvent is pharmaceutically acceptable. In more preferred embodiments, the optional volatile solvent is a class 2 and / or a class 3 solvent. See, e.g., “Q3C - Tables and List Guidance for Industry, Revision 3 (June 2017), published by the U.S. Department of Health and Human Services Food and Drug Administration, which is incorporated by reference in its entirety.

[0204] In some embodiments, one or more volatile solvents are present in the composition in the amount of 0.05% (w / w), 0.1% (w / w), 0.5% (w / w), 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), 15% (w / w), 16% (w / w), 17% (w / w), 18% (w / w), 19% (w / w), 20% (w / w), 21% (w / w), 22% (w / w), 23% (w / w), 24% (w / w), 25% (w / w), 26% (w / w), 27% (w / w), 28% (w / w), 29%BT Ref. 104448-429411 PATENT(w / w), 30% (w / w), 31% (w / w), 32% (w / w), 33% (w / w), 34% (w / w), 35% (w / w), 36% (w / w), 37% (w / w), 38% (w / w), 39% (w / w), 40% (w / w), 41% (w / w), 42% (w / w), 43% (w / w), 44% (w / w), 45% (w / w), 46% (w / w), 47% (w / w), 48% (w / w), 49% (w / w), 50% (w / w), about any of the aforementioned percentages (e.g., about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 1 %-50% (w / w), 2%-40% (w / w), 3%-30% (w / w), 4%-28% (w / w), 5%-25% (w / w), 6%-22% (w / w), 7%-20% (w / w), 8%-l 8% (w / w), 9%-15% (w / w), 10%-12% (w / w), about l%-50% (w / w), about 2%-40% (w / w), about 3%-30% (w / w), about 4%-28% (w / w), about 5%-25% (w / w), about 6%-22% (w / w), about 7%-20% (w / w), about 8%-18% (w / w), about 9%-15% (w / w), or about 10%-12% (w / w)). In preferred embodiments, the optional one or more volatile solvents is not included in the composition.

[0205] In some embodiments, one or more volatile solvents are present in the composition in the amount of less than 50% (w / w), less than 49% (w / w), less than 48% (w / w), less than 47% (w / w), less than 46% (w / w), less than 45% (w / w), less than 44% (w / w), less than 43% (w / w), less thanBT Ref. 104448-429411 PATENT42% (w / w), less than 41% (w / w), less than 40% (w / w), less than 39% (w / w), less than 38% (w / w), less than 37% (w / w), less than 36% (w / w), less than 35% (w / w), less than 34% (w / w), less than 33% (w / w), less than 32% (w / w), less than 31% (w / w), less than 30% (w / w), less than 29% (w / w), less than 28% (w / w), less than 27% (w / w), less than 26% (w / w), less than 25% (w / w), less than 24% (w / w), less than 23% (w / w), less than 22% (w / w), less than 21% (w / w), less than 20% (w / w), less than 19% (w / w), less than 18% (w / w), less than 17% (w / w), less than 16% (w / w), less than 15% (w / w), less than 14% (w / w), less than 13% (w / w), less than 12% (w / w), less than ll% (w / w), less than 10% (w / w), less than 9% (w / w), less than 8% (w / w), less than 7% (w / w), less than 6% (w / w), less than 5% (w / w), less than 4% (w / w), less than 3% (w / w), less than 2% (w / w), less than 1% (w / w), less than about any of the aforementioned percentages (e.g., less than about 50% (w / w), less than about 49% (w / w), less than about 48% (w / w), less than about 47% (w / w), less than about 46% (w / w), less than about 45% (w / w), less than about 44% (w / w), less than about 43% (w / w), less than about 42% (w / w), less than about 41% (w / w), less than about 40% (w / w), less than about 39% (w / w), less than about 38% (w / w), less than about 37% (w / w), less than about 36% (w / w), less than about 35% (w / w), less than about 34% (w / w), less than about 33% (w / w), less than about 32% (w / w), less than about 31% (w / w), less than about 30% (w / w), less than about 29% (w / w), less than about 28% (w / w), less than about 27% (w / w), less than about 26% (w / w), less than about 25% (w / w), less than about 24% (w / w), less than about 23% (w / w), less than about 22% (w / w), less than about 21% (w / w), less than about 20% (w / w), less than about 19% (w / w), less than about 18% (w / w), less than about 17% (w / w), less than about 16% (w / w), less than about 15% (w / w), less than about 14% (w / w), less than about 13% (w / w), less than about 12% (w / w), less than about 11% (w / w), less than about 10% (w / w), less than about 9% (w / w), less than about 8% (w / w), less than about 7% (w / w), less than about 6% (w / w), less than about 5% (w / w), less than about 4%BTRef. 104448-429411 PATENT(w / w), less than about 3% (w / w), less than about 2% (w / w), less than about 1% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 10%-50% (w / w), less than 15%-40% (w / w), less than 15%-35% (w / w), less than 15%-30% (w / w), less than 15%-25% (w / w), less than 15%-20% (w / w), less than 14%-20% (w / w), less than 13%-20% (w / w), less than 12%-20% (w / w), less than 11%-20% (w / w), less than 11%- 19% (w / w), less than 11%-18% (w / w), less than 11%-17% (w / w), less than 11%-16% (w / w), less than 11%-15% (w / w), less than 10%-l 5% (w / w), less than 5%-l 5% (w / w), less than about 15%- 40% (w / w), less than about 15%-35% (w / w), less than about 15%-30% (w / w), less than about 15%-25% (w / w), less than about 15%-20% (w / w), less than about 14%-20% (w / w), less than about 13%-20% (w / w), less than about 12%-20% (w / w), less than about 11%-20% (w / w), less than about 11%-19% (w / w), less than about 11%- 18% (w / w), less than about 11%-17% (w / w), less than about 11%-16% (w / w), less than about 11%-15% (w / w), less than about 10%-15% (w / w), or less than about 5%-l 5% (w / w)).

[0206] In some embodiments, the amount of volatile solvent and non-volatile solvent in the composition is related to one another by a ratio. For example, in some embodiments the ratio by weight of volatile solvent to non-volatile solvent is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1:4.75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7. 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10, 1:10.25, 1:10.5, 1:10.75, 1:11, 1:11.25, 1:11.5, 1:11.75, 1:12, 1:12.25, 1:12.5, 1:12.75, 1:13,1:13.25, 1:13.5, 1:13.75, 1:14, 1:14.25, 1:14.5, 1:14.75, 1:15, 1:15.25, 1:15.5, 1:15.75, 1:16,1:16.25, 1:16.5, 1:16.75, 1:17, 1:17.25, 1:17.5, 1:17.75, 1:18, 1:18.25, 1:18.5, 1:18.75, 1:19,1:19.25, 1:19.5, 1:19.75, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80,1:85, 1:90, 1:95, or 1:99.BTRef. 104448-429411 PATENT

[0207] In some embodiments, the ratio by weight of volatile solvent to non-volatile solvent is about 1:1, about 1:1.25, about 1:1.5, about 1:1.75, about 1:2, about 1:2.25, about 1:2.5, about1:2.75, about 1:3, about 1:3.25, about 1:3.5, about 1:3.75, about 1:4, about 1:4.25, about 1:4.5, about 1:4.75, about 1:5, about 1:5.25, about 1:5.5, about 1:5.75, about 1:6, about 1:6.25, about1:6.5, about 1:6.75, about 1:7, about 1:7.25, about 1:7.5, about 1:7.75, about 1:8, about 1:8.25, about 1:8.5, about 1:8.75, about 1:9, about 1:9.25, about 1:9.5, about 1:9.75, about 1:10, about1:10.25, about 1:10.5, about 1:10.75, about 1:11, about 1:11.25, about 1:11.5, about 1:11.75, about 1:12, about 1:12.25, about 1:12.5, about 1:12.75, about 1:13, about 1:13.25, about 1:13.5, about 1:13.75, about 1:14, about 1:14.25, about 1:14.5, about 1:14.75, about 1:15, about 1:15.25, about 1:15.5, about 1:15.75, about 1:16, about 1:16.25, about 1:16.5, about 1:16.75, about 1:17, about 1:17.25, about 1:17.5, about 1:17.75, about 1:18, about 1:18.25, about 1:18.5, about 1:18.75, about 1:19, about 1:19.25, about 1:19.5, about 1:19.75, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, or about 1:99.

[0208] In some embodiments, the ratio by weight of volatile solvent to non-volatile solvent is less than 1:1, less than 1:1.25, less than 1:1.5, less than 1:1.75, less than 1:2, less than 1:2.25, less than 1:2.5, less than 1:2.75, less than 1:3, less than 1:3.25, less than 1:3.5, less than 1:3.75, less than 1:4, less than 1:4.25, less than 1:4.5, less than 1:4.75, less than 1:5, less than 1:5.25, less than 1:5.5, less than 1:5.75, less than 1:6, less than 1:6.25, less than 1:6.5, less than 1:6.75, less than 1 :7, less than 1 :7.25, less than 1 :7.5, less than 1 :7.75, less than 1 :8, less than 1 :8.25, less than 1 :8.5, less than 1 :8.75, less than 1 :9, less than 1 :9.25, less than 1 :9.5, less than 1 :9.75, less than 1:10, less than 1:10.25, less than 1:10.5, less than 1:10.75, less than 1:11, less than 1:11.25, less than 1:11.5, less than 1:11.75, less than 1:12, less than 1:12.25, less than 1:12.5, less than 1:12.75, less thanBTRef. 104448-429411 PATENT1:13, less than 1 : 13.25, less than 1 : 13.5, less than 1 : 13.75, less than 1:14, less than 1 : 14.25, less than 1:14.5, less than 1:14.75, less than 1:15, less than 1:15.25, less than 1:15.5, less than 1:15.75, less than 1:16, less than 1:16.25, less than 1:16.5, less than 1:16.75, less than 1:17, less than 1:17.25, less than 1:17.5, less than 1:17.75, less than 1:18, less than 1:18.25, less than 1:18.5, less than 1:18.75, less than 1:19, less than 1:19.25, less than 1:19.5, less than 1:19.75, less than 1:20, less than 1 :25, less than 1 :30, less than 1 :35, less than 1 :40, less than 1 :45, less than 1 :50, less than 1:55, less than 1:60, less than 1:65, less than 1:70, less than 1:75, less than 1:80, less than 1:85, less than 1:90, less than 1:95, less than 1:99, or less than about any of the aforementioned ratios (e.g., less than about 1:1, less than about 1:10, less than about 1 :20, less than about 1 :25, less than about 1:30, less than about 1:35, less than about 1:40, less than about 1:50, less than about 1:60, less than about 1:70, less than about 1:80, less than about 1:90, or less than about 1:99).

[0209] In some embodiments, the ratio by weight of volatile solvent to non-volatile solvent is greater than 1:1, greater than 1:1.25, greater than 1:1.5, greater than 1:1.75, greater than 1:2, greater than 1:2.25, greater than 1:2.5, greater than 1:2.75, greater than 1:3, greater than 1:3.25, greater than 1:3.5, greater than 1:3.75, greater than 1:4, greater than 1:4.25, greater than 1:4.5, greater than 1:4.75, greater than 1:5, greater than 1:5.25, greater than 1:5.5, greater than 1:5.75, greater than 1:6, greater than 1:6.25, greaterthan 1:6.5, greaterthan 1:6.75, greater than 1:7, greaterthan 1:7.25, greater than 1:7.5, greater than 1:7.75, greater than 1:8, greater than 1:8.25, greater than 1:8.5, greaterthan 1:8.75, greaterthan 1:9, greaterthan 1:9.25, greaterthan 1:9.5, greater than 1:9.75, greater than 1:10, greater than 1 : 10.25, greater than 1:10.5, greater than 1 : 10.75, greater than 1:11, greater than 1:11.25, greater than 1:11.5, greater than 1:11.75, greater than 1:12, greater than 1:12.25, greaterthan 1:12.5, greaterthan 1:12.75, greaterthan 1:13, greaterthan 1:13.25, greater than 1:13.5, greater than 1:13.75, greater than 1:14, greater than 1:14.25, greater than 1:14.5,BTRef. 104448-429411 PATENT greater than 1:14.75, greater than 1:15, greater than 1:15.25, greater than 1:15.5, greater than 1:15.75, greater than 1:16, greater than 1:16.25, greater than 1:16.5, greater than 1:16.75, greater than 1:17, greater than 1:17.25, greater than 1:17.5, greater than 1:17.75, greater than 1:18, greater than 1:18.25, greater than 1:18.5, greater than 1:18.75, greater than 1:19, greater than 1:19.25, greater than 1:19.5, greater than 1:19.75, greater than 1:20, greater than 1:25, greater than 1:30, greater than 1:35, greater than 1:40, greater than 1:45, greater than 1:50, greater than 1:55, greater than 1:60, greater than 1:65, greater than 1:70, greater than 1:75, greater than 1:80, greater than 1:85, greater than 1:90, greater than 1:95, greater than 1:99, or greater than about any of the aforementioned ratios (e.g., greater than about 1:1, greater than about 1:10, greater than about 1 :20, greater than about 1 :25, greater than about 1 :30, greater than about 1 :35, greater than about 1 :40, greater than about 1 :50, greater than about 1 :60, greater than about 1 :70, greater than about 1 :80, greater than about 1 :90, or greater than about 1 :99).

[0210] In some embodiments, combinations of the aforementioned volatile solvents are included in the compositions. Each volatile solvent of the combination may be included in any of the amounts indicated above for the volatile solvent or the one or more volatile solvent.Fragrances

[0211] The embodiments described herein may optionally contain one or more perfumes, fragrances, or fragrance compounds. Perfumes, fragrances and fragrance compounds are well- known in the art. See, e.g., “Perfume and Flavor Chemicals (Aroma Chemicals),” Steffen Arctander, published by the author, 1969, which is incorporated by reference for its identification of perfumes, fragrances, and fragrance compounds. Compounds that are recognized as perfumes, fragrances, or fragrance compounds may be optionally included in the compositions described herein.BT Ref. 104448-429411 PATENT

[0212] Examples of perfumes, fragrances, or fragrance compounds include, but are not limited to, alicyclic esters, aliphatic esters, cyclic esters, aromatic esters, alicyclic ethers, cyclic ethers, aromatic ethers, primary alcohols, tertiary alcohols, aromatic alcohols, cyclic alcohols, aliphatic aldehyde, cyclic aldehydes, aliphatic primary aldehyde, aromatic aldehydes, tertiary aldehydes, aliphatic ketones, aromatic ketones, cyclic ketones, macrocyclic ketones, aliphatic nitrile, aromatic nitrile, cyclic nitrile, 1,2-benzopyrone, anethole, benzaldehyde, decyl aldehyde, benzyl acetate, benzyl alcohol, benzyl formate, benzyl propionate, iso-bornyl acetate, camphene, cis-citral (neral), citronellal, citronellol, citronellyl acetate, paracymene, decanal, dihydrolinalool, dihydromyrcenol, methyl benzyl carbinyl acetate, dimethyl benzyl carbinyl acetate, dimethyl phenyl carbinol, eucalyptol, helional, geranial, geraniol, geranyl acetate, geranyl nitrile, cis-3- hexenyl acetate, dihydrocitronellal, d-limonene, linalool, linalool oxide, tetra-hydro linalool, alpha-methyl ionone, methyl nonyl acetaldehyde, methyl phenyl carbinyl acetate, laevo-menthyl acetate, menthone, iso-menthone, myrcene, myrcenyl acetate, myrcenol, nerol, neryl acetate, nonyl acetate, phenyl ethyl alcohol, phenyl acetaldehyde, alpha-pinene, beta-pinene, gamma-terpinene, terpineol, alpha-terpineol, beta-terpineol, terpinyl acetate, vertenex (para- tertiary butyl cyclohexyl acetate), gamma-methyl ionone, undecalactone, undecylenic aldehyde, alpha-damascone, beta- damascone, amyl acetate, lemon oil, orange oil, hexyl cinnamic aldehyde, alpha-amylcinnamic aldehyde, p-anis aldehyde, cinnamic aldehyde, cuminic aldehyde, p-t-butyl-alpha- methyldihydrocinnamaldehyde, 4-hydroxy-3-methoxycinnamaldehyde, 2-phenyl-3-(2- furyl)prop-2-enal, vanillin isobutyrate, ethyl vanillin, ethyl vanillin acetate, vanillin acetate, cyclamen aldehyde, heptanal, lauryl aldehyde, nonanal, octanal, phenyl propyl aldehyde, vanillin, salycil aldehyde, cytral, 2, 4-dihydroxy-3 -methylbenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, 5-methyl salicylic aldehydes, 4-nitrobenzaldehyde, o-nitrobenzaldehyde, 5-ethyl-2-BT Ref. 104448-429411 PATENT thiophenecarbaldehyde, 5-methyl-2-thiophenecarboxaldehyde, 2-thiophenecarb aldehyde, as aronaldehyde, 5-(hydroxymethyl)-2-furaldehyde, 2-benzofurancarboxaldehyde, 2- benzofurancarboxaldehyde, 4-ethoxy-3 -methoxybenzaldehyde, protocatechualdehyde, heliotropine, 2,3,4-trimethoxybenz aldehyde, 3,4,5-trimethoxybenzaldehyde, 2,8-dithianon-4-3 n- 4-carboxaldehyde, sorbinaldehyde, 2,4-heptadienal, 2,4-decadienal, 2,4-nonadienal, (E,E)-,2,4- octadien-l-al, 2,4-octadienal, 2,4-dodec adienal, 4-undecadienal, 2,4-tridec adien-l-al, 2-trans-4- cis-7-cis-tridecatrienal, piperonylidene propionaldehyde, 2-methyl-3-(2-furyl)acrolein, 2,4- pentadienal, 2-furfurylidene butyraldehyde, 3-(2-furyl)acrolein, pyruvaldehyde, ethanedial, menthol, 3-buten-2-one, 3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-l-yl), 4-(2,6,6- trimethylcyclohen-l-en-l-yl)but-3-en-2-one, 3-buten-2-one, 4-(2,6,6-trimethyl-2-cyclohexen-l- yl)-, (E)-, menthyl lactate, isomenthyl acetate, isomenthyl propionate, isomenthyl isobutyrate, camphor, p-menthane, cresol, tetra hydromyrcenol, cytronellol, cytronellyil derivatives, geranyl derivatives, linalyl acetate, mugetanol, eugenol, jasmal, pinanol, cedrene, beta pinene, cineole, nonadi enol, ethylhexanal, octanol acetate, methyl furfural, terpinene, thujene, amylacetate, benzylacetate, di-hydrocumarin, di -hydromyrcenyl acetate, isoamylacetate, para-cymene, triethyl acetate, para-cresol, ethyl acetate, benzyl-benzoate, isopropyl myristate, methyl abietate, and / or combinations thereof. In some embodiments, the perfume, fragrance, or fragrance compound is selected to afford a scent such as lavender, violet, rose, jasmine, pine, woody, floral, fruity, lemon, lime, apple, peach, raspberry, strawberry, banana, plum, apricot, vanilla, pear, eucalyptus, aromatic, aldehydic, tutti frutti, oriental, sweet, amber, Paola, Muguet, Citron (lime) ella, and / or a combination thereof. A person of ordinary skill in the art will understand the class of compounds that are perfumes, fragrances, or fragrance compounds, as their identity and properties are readily discerned from the literature. See, e.g, Handbook of Pharmaceutical Excipients, which isBT Ref. 104448-429411 PATENT incorporated by reference for its identification of compounds that are perfumes, fragrances, or fragrance compounds. In some embodiments, one or more of the above identified perfumes, fragrances, or fragrance compounds is optionally included in the composition.

[0213] In some embodiments, one or more perfume, fragrance, or fragrance compound is present in the composition in the amount of 0.1% (w / w), 0.15% (w / w), 0.2% (w / w), 0.25% (w / w), 0.3% (w / w), 0.35% (w / w), 0.4% (w / w), 0.45% (w / w), 0.5% (w / w), 0.55% (w / w), 0.6% (w / w), 0.65% (w / w), 0.7% (w / w), 0.75% (w / w), 0.8% (w / w), 0.85% (w / w), 0.9% (w / w), 0.95% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), about any of the aforementioned percentages (e.g., about 0.1% (w / w), about 0.15% (w / w), about 0.2% (w / w), about 0.25% (w / w), about 0.3% (w / w), about 0.35% (w / w), about 0.4% (w / w), about 0.45% (w / w), about 0.5% (w / w), about 0.55% (w / w), about 0.6% (w / w), about 0.65% (w / w), about 0.7% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.85% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.5% (w / w), about 1.75% (w / w), about 2% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), or about 3% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.1%-3% (w / w), 0.1%-2.5% (w / w), 0.25%-2% (w / w), 0.25%-l% (w / w), about 0.1%-3% (w / w), about 0.1%-2.5% (w / w), about 0.25%-2% (w / w), or about 0.25%-l% (w / w)). In some embodiments, one or more perfume, fragrance, or fragrance compound is present in the composition in the amount of about 0.25%-l% (w / w). In preferred embodiments, the optional one or more perfume, fragrance, or fragrance compound is not included in the composition.

[0214] In some embodiments, one or more perfume, fragrance, or fragrance compound is present in the composition in the amount of less than 0.1% (w / w), less than 0.15% (w / w), less than 0.2%BT Ref. 104448-429411 PATENT(w / w), less than 0.25% (w / w), less than 0.3% (w / w), less than 0.35% (w / w), less than 0.4% (w / w), less than 0.45% (w / w), less than 0.5% (w / w), less than 0.55% (w / w), less than 0.6% (w / w), less than 0.65% (w / w), less than 0.7% (w / w), less than 0.75% (w / w), less than 0.8% (w / w), less than 0.85% (w / w), less than 0.9% (w / w), less than 0.95% (w / w), less than 1% (w / w), less than 1.25% (w / w), less than 1.5% (w / w), less than 1.75% (w / w), less than 2% (w / w), less than 2.25% (w / w), less than 2.5% (w / w), less than 2.75% (w / w), less than 3% (w / w), about any of the aforementioned percentages (e.g., less than about 0.1% (w / w), less than about 0.15% (w / w), less than about 0.2% (w / w), less than about 0.25% (w / w), less than about 0.3% (w / w), less than about 0.35% (w / w), less than about 0.4% (w / w), less than about 0.45% (w / w), less than about 0.5% (w / w), less than about 0.55% (w / w), less than about 0.6% (w / w), less than about 0.65% (w / w), less than about 0.7% (w / w), less than about 0.75% (w / w), less than about 0.8% (w / w), less than about 0.85% (w / w), less than about 0.9% (w / w), less than about 0.95% (w / w), less than about 1% (w / w), less than about 1.25% (w / w), less than about 1.5% (w / w), less than about 1.75% (w / w), less than about 2% (w / w), less than about 2.25% (w / w), less than about 2.5% (w / w), less than about 2.75% (w / w), or less than about 3% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 2%-3% (w / w), less than 2%-2.5% (w / w), less than 1.5%-2% (w / w), less than 0.75%-l% (w / w), less than about 2%-3% (w / w), less than about 2%-2.5% (w / w), less than about 1.5%-2% (w / w), or less than about 0.75%-l% (w / w)). In preferred embodiments, one or more perfume, fragrance, or fragrance compound (in addition to any ingredient(s) already identified as included in an embodiment that also exhibits the function of a perfume, fragrance, or fragrance compound) is present in the composition in the amount of less than about 2%-3% (w / w).BT Ref. 104448-429411 PATENT

[0215] In some embodiments, the amount of one or more perfume, fragrance, or fragrance compound is limited by the solubility of the perfume, fragrance, or fragrance compound in the composition. Accordingly, in some embodiments the amount of perfume, fragrance, or fragrance compound in the composition is equal to or less than the limit of solubility for that perfume, fragrance, or fragrance compound in a given volume of the composition. In preferred embodiments, the amount of perfume, fragrance, or fragrance compound in the composition is equal to or less than the limit of solubility for that perfume, fragrance, or fragrance compound in a given volume of non-volatile solvent that is to be included in the composition. In even more preferred embodiments, the amount of perfume, fragrance, or fragrance compound in the composition is less than the limit of solubility for that perfume, fragrance, or fragrance compound in a given volume of the composition or less than the limit of solubility for that perfume, fragrance, or fragrance compound in a given volume of non-volatile solvent that is to be included in the composition. By way of non-limiting example, in some embodiments the amount of perfume, fragrance, or fragrance compound in the composition is 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the limit of solubility of the perfume, fragrance, or fragrance compound in a given volume of the composition or a given volume of non-volatile solvent that is to be included in the composition. A skilled artisan will readily understand how to determine the limit of solubility of any particular perfume, fragrance, or fragrance compound in any particular composition or non-volatile solvent that is to be included in the composition. By way of non-limiting example, this can be determined by measuring different weights of perfume, fragrance, or fragrance compound and a particular volume of the composition (without perfume, fragrance, or fragrance compound) or a particular volume of nonvolatile solvent to be included in the composition and determining whether complete dissolutionBT Ref. 104448-429411 PATENT occurred and / or the saturation point for dissolution of the perfume, fragrance, or fragrance compound in the unit of weight per volume (e.g., mg per mL).

[0216] In some embodiments, combinations of the aforementioned fragrances are included in the compositions. Each fragrance of the combination may be included in any of the amounts indicated above for the fragrance or the one or more fragrance.Topical Cream

[0217] Some embodiments relate to a topical cream. A topical cream may include one or more of the following: a therapeutic agent, non-volatile solvent, permeation enhancer, emollient, surfactant, humectant, emulsifier, thickener, buffering agent or pH adjuster, antimicrobial agent or preservative, and vehicle. In some embodiments, the topical cream includes one or more of the following: efinaconazole as a therapeutic agent, vitamin E acetate as a non-volatile solvent, cholesterol as a first permeation enhancer, isopropyl myristate as an emollient, polysorbate 80 as a surfactant, propylene glycol as a humectant, glyceryl stearate as an emulsifier, a carbomer as a thickener, triethanolamine as a buffering agent or pH adjuster, phenoxyethanol as an antimicrobial agent or preservative, and water as a vehicle.

[0218] In preferred embodiments, the topical cream includes one or more of the following: efinaconazole as a therapeutic agent in the amount of about 1-2.5% (w / w), vitamin E acetate as a non-volatile solvent in the amount of about 5-30% (w / w), cholesterol as a first permeation enhancer in the amount of about 0.1-1% (w / w), isopropyl myristate as an emollient in the amount of about 1 -5% (w / w), polysorbate 80 as a surfactant in the amount of about 1 -5% (w / w), propylene glycol as a humectant in the amount of about 2-10% (w / w), glyceryl stearate as an emulsifier in the amount of about 1-5% (w / w), a carbomer as a thickener in the amount of about 0.1-1% (w / w), triethanolamine as a buffering agent or pH adjuster in an amount sufficient to achieve the desiredBT Ref. 104448-429411 PATENT pH, phenoxyethanol as an antimicrobial agent or preservative in the amount of about 0.1-1% (w / w), and water as a vehicle in a quantity sufficient to total the constituents at 100%.

[0219] In preferred embodiments, the topical cream includes one or more of the following: efinaconazole as a therapeutic agent in the amount of about 1% (w / w), vitamin E acetate as a nonvolatile solvent in the amount of about 10% (w / w), cholesterol as a first permeation enhancer in the amount of about 0.5% (w / w), isopropyl myristate as an emollient in the amount of about 3% (w / w), polysorbate 80 as a surfactant in the amount of about 2% (w / w), propylene glycol as a humectant in the amount of about 5% (w / w), glyceryl stearate as an emulsifier in the amount of about 3% (w / w), a carbomer as a thickener in the amount of about 0.5% (w / w), triethanolamine as a buffering agent or pH adjuster in an amount sufficient to achieve the desired pH, phenoxyethanol as an antimicrobial agent or preservative in the amount of about 0.5% (w / w), and water as a vehicle in a quantity sufficient to total the constituents at 100%.

[0220] In some embodiments, the topical cream includes one or more of the following: efinaconazole as a therapeutic agent, vitamin E acetate as a non-volatile solvent, dimethyl isosorbide as a first permeation enhancer, squalane as an emollient, PEG-100 stearate as an emulsifier, stearic acid as a emulsifier, butylene glycol as a humectant, xanthan gum as a thickener, lactic acid as a buffering agent or pH adjuster, phenoxyethanol as an antimicrobial agent or preservative, and water as a vehicle.

[0221] In preferred embodiments, the topical cream includes one or more of the following: efinaconazole as a therapeutic agent in the amount of about 1-2.5% (w / w), vitamin E acetate as a non-volatile solvent in the amount of about 5-30% (w / w), dimethyl isosorbide as a first permeation enhancer in the amount of about 1-5% (w / w), squalane as an emollient in the amount of about 1- 5% (w / w), PEG-100 stearate as an emulsifier in the amount of about 1-5% (w / w), stearic acid as aBT Ref. 104448-429411 PATENT emulsifier in the amount of about 1-5% (w / w), butylene glycol as a humectant in the amount of about 1-5% (w / w), xanthan gum as a thickener in the amount of about 0.1-1% (w / w), lactic acid as a buffering agent or pH adjuster in the amount of about 0.1-1% (w / w), phenoxyethanol as an antimicrobial agent or preservative in the amount of about 0.1-2% (w / w), and water as a vehicle in a quantity sufficient to total the constituents at 100%.

[0222] In preferred embodiments, the topical cream includes one or more of the following: efinaconazole as a therapeutic agent in the amount of about 1% (w / w), vitamin E acetate as a nonvolatile solvent in the amount of about 10% (w / w), dimethyl isosorbide as a first permeation enhancer in the amount of about 3% (w / w), squalane as an emollient in the amount of about 4% (w / w), PEG-100 stearate as an emulsifier in the amount of about 3% (w / w), stearic acid as a emulsifier in the amount of about 2% (w / w), butylene glycol as a humectant in the amount of about 3% (w / w), xanthan gum as a thickener in the amount of about 0.3% (w / w), lactic acid as a buffering agent or pH adjuster in the amount of about 0.8% (w / w), phenoxyethanol as an antimicrobial agent or preservative in the amount of about 1% (w / w), and water as a vehicle in a quantity sufficient to total the constituents at 100%.Ophthalmic Ointment

[0223] Some embodiments relate to an ophthalmic ointment. An ophthalmic ointment may include one or more of the following: a therapeutic agent, a non-volatile solvent, a base or occlusive agent, a lubricant or spreadability enhancer, a surfactant, or a permeation enhancer. In some embodiments, the ophthalmic ointment includes one or more of the following: efinaconazole as the therapeutic agent, vitamin E acetate as the non-volatile solvent, white petrolatum as the base or occlusive agent, mineral oil as the lubricant or spreadability enhancer, polysorbate 80 as the surfactant, and cholesterol as the permeation enhancer.BT Ref. 104448-429411 PATENT

[0224] In preferred embodiments, the ophthalmic ointment includes one or more of the following: efinaconazole as the therapeutic agent in the amount of about 1-2.5% (w / w), vitamin E acetate as the non-volatile solvent in the amount of about 5-30% (w / w), white petrolatum as the base or occlusive agent in the amount of about 50-90% (w / w), mineral oil as the lubricant or spreadability enhancer in the amount of about 5-30% (w / w), polysorbate 80 as the surfactant in the amount of about 0.1-1% (w / w), and cholesterol as the permeation enhancer in the amount of about 0.1-1% (w / w).

[0225] In more preferred embodiments, the ophthalmic ointment includes one or more of the following: efinaconazole as the therapeutic agent in the amount of about 1% (w / w), vitamin E acetate as the non-volatile solvent in the amount of about 10% (w / w), white petrolatum as the base or occlusive agent in the amount of about 70% (w / w), mineral oil as the lubricant or spreadability enhancer in the amount of about 18% (w / w), polysorbate 80 as the surfactant in the amount of about 0.5% (w / w), and cholesterol as the permeation enhancer in the amount of about 0.5% (w / w). Ophthalmic Cream

[0226] Some embodiments relate to an ophthalmic cream. An ophthalmic cream may include one or more of the following: a therapeutic agent, a non-volatile solvent, a humectant, an emollient, a hydrating agent, an anti-inflammatory agent, a skin soother, a moisturizer, a thickener, a surfactant, a chelating agent, a preservative, and a vehicle. In some embodiments, the ophthalmic cream includes one or more of the following: efinaconazole as the therapeutic agent, vitamin E acetate as the non-volatile solvent, glycerin as the humectant, dimethicone as the first emollient, squalane as the second emollient, sodium hyaluronate as the hydrating agent, niacinamide as the anti-inflammatory agent, allantioin as the skin soother, panthenol as the moisturizer,BT Ref. 104448-429411 PATENT hydroxyethylcellulose as the thickener, polysorbate 80 as the surfactant, disodium EDTA as the chelating agent, phenoxyethanol as the preservative, and water as the vehicle.

[0227] In preferred embodiments, the ophthalmic cream includes one or more of the following: efinaconazole as the therapeutic agent in the amount of about 1-2.5% (w / w), vitamin E acetate as the non-volatile solvent in the amount of about 5-30% (w / w), glycerin as the humectant in the amount of about 1-5% (w / w), dimethicone as the first emollient in the amount of about 1-5% (w / w), squalane as the second emollient in the amount of about 1-5% (w / w), sodium hyaluronate as the hydrating agent in the amount of about 0.01-1% (w / w), niacinamide as the antiinflammatory agent in the amount of about 0.1-2% (w / w), allantioin as the skin soother in the amount of about 0.1-2% (w / w), panthenol as the moisturizer in the amount of about 0.1-2% (w / w), hydroxyethylcellulose as the thickener in the amount of about 0.1-2% (w / w), polysorbate 80 as the surfactant in the amount of about 1-5% (w / w), di sodium EDTA as the chelating agent in the amount of about 0.01-1% (w / w), phenoxyethanol as the preservative in the amount of about 0.01-1% (w / w), and water as the vehicle in a quantity sufficient to afford 100% for all constituents.

[0228] In more preferred embodiments, the ophthalmic cream includes one or more of the following: efinaconazole as the therapeutic agent in the amount of about 1% (w / w), vitamin E acetate as the non-volatile solvent in the amount of about 10% (w / w), glycerin as the humectant in the amount of about 3% (w / w), dimethicone as the first emollient in the amount of about 1.5% (w / w), squalane as the second emollient in the amount of about 2% (w / w), sodium hyaluronate as the hydrating agent in the amount of about 0.1% (w / w), niacinamide as the anti-inflammatory agent in the amount of about 0.3% (w / w), allantioin as the skin soother in the amount of about 0.3% (w / w), panthenol as the moisturizer in the amount of about 0.5% (w / w), hydroxy ethylcellulose as the thickener in the amount of about 0.8% (w / w), polysorbate 80 as theBT Ref. 104448-429411 PATENT surfactant in the amount of about 1% (w / w), disodium EDTA as the chelating agent in the amount of about 0.05% (w / w), phenoxyethanol as the preservative in the amount of about 0.5% (w / w), and water as the vehicle in a quantity sufficient to afford 100% for all constituents.Ophthalmic Emulsion

[0229] Some embodiments relate to an ophthalmic emulsion. An ophthalmic emulsion may include one or more of the following: a therapeutic agent, a non-volatile solvent, an oil phase, a surfactant, a thickener, a humectant, a buffering agent or pH adjuster, a chelating agent, a mucoadhesive polymer, and water. In some embodiments, the ophthalmic emulsion includes one or more of the following: efinaconazole as the therapeutic agent, vitamin E acetate as the nonvolatile solvent, castor oil as the oil phase, polysorbate 80 as the surfactant, a carbomer as the thickener, glycerin as the humectant, sodium hydroxide or hydrochloric acid buffering agent or pH adjuster, disodium EDTA as the chelating agent, polycarbophil as the mucoadhesive polymer, and water.

[0230] In some embodiments, the ophthalmic emulsion includes one or more of the following: efinaconazole as the therapeutic agent in the amount of about 1-2.5% (w / w), vitamin E acetate as the non-volatile solvent in the amount of about 5-30% (w / w), castor oil as the oil phase in the amount of about 1-5% (w / w), polysorbate 80 as the surfactant in the amount of about 0.5-5% (w / w), a carbomer as the thickener in the amount of about 0.01-1% (w / w), glycerin as the humectant in the amount of about 1-5% (w / w), sodium hydroxide or hydrochloric acid buffering agent or pH adjuster in an amount sufficient to obtain the desired pH, disodium EDTA as the chelating agent in the amount of about 0.01-1% (w / w), polycarbophil as the mucoadhesive polymer in the amount of about 0.01-1% (w / w), and water in a quantity sufficient to afford 100% for all constituents.BT Ref. 104448-429411 PATENT

[0231] In preferred embodiments, the ophthalmic emulsion includes one or more of the following: efinaconazole as the therapeutic agent in the amount of about 1% (w / w), vitamin E acetate as the non-volatile solvent in the amount of about 10% (w / w), castor oil as the oil phase in the amount of about 1.25% (w / w), polysorbate 80 as the surfactant in the amount of about 1% (w / w), a carbomer as the thickener in the amount of about 0.05% (w / w), glycerin as the humectant in the amount of about 2.2% (w / w), sodium hydroxide or hydrochloric acid buffering agent or pH adjuster in an amount sufficient to obtain the desired pH (approximately 6.5-7.0), disodium EDTA as the chelating agent in the amount of about 0.05% (w / w), polycarbophil as the mucoadhesive polymer in the amount of about 0.1-0.2% (w / w), and water in a quantity sufficient to afford 100% for all constituents.Treatment Methods

[0232] Described herein are methods for treating a subject having a disease or disorder by administering any of the afore-described compositions. The compositions are generally applied by a subject or healthcare professional to a treatment area (e g., an affected area). Atopical route of application is preferred, as this route avoids systemic side effects caused by the therapeutic agent.

[0233] Any therapeutic agent is preferably administered such that a pharmaceutically effective amount of the therapeutic agent contacts the affected cells of the body. The dose administered to a subject, particularly a human, in the context of the methods is preferably sufficient to effect a therapeutic response in the subject over a reasonable period of time. The dose will be determined by the strength of the particular therapeutic agent employed, the condition of the subject, the body weight of the subject to be treated, and / or, when applicable, knowledge regarding pharmaceutically effective amounts of the therapeutic agent from approved uses. The existence, nature, and extentBT Ref. 104448-429411 PATENT of any adverse side effects that might accompany the administration of a particular therapeutic agent also will determine the size of the dose and the particular route of administration employed with a particular subject. The skilled artisan will appreciate that certain factors can influence the dosage required to effectively treat a subject, including but not limited to the identity of the disease or disorder, the identity of the therapeutic agent, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, the presence of other diseases or disorders, the age of the subject, the weight of the subject, and / or the sex of the subject. It will also be appreciated that the effective dosage used for treatment can increase or decrease over the course of a particular treatment. Changes in dosage can result and become apparent from the results of diagnostic assays for the disease or disorder or therapeutic agent. Thus, the dosage can vary widely, but it can be determined by a skilled artisan using standard methods such as conducting a safety and / or dose escalation study or knowledge in the art regarding the therapeutic agent, including standards set by regulatory authorities or clinicians.

[0234] For example, some embodiments relate to a method for treating a subject having a disease or disorder amenable to topical treatment comprising, consisting of, or consisting essentially of: topically administering to the subject any of the afore-described compositions. Some embodiments relate to a method for treating a subject having a disease or disorder of the nail, nail bed, skin and / or eye, comprising, consisting of, or consisting essentially of: topically administering to the subject the composition any of the afore-described compositions. Additional embodiments relate to a method for treating a subject having a disease or disorder of the nail and / or nail bed comprising, consisting of, or consisting essentially of: topically administering to the subject any of the afore-described compositions. Other embodiments relate to a method for treating a subject having a disease or disorder of the skin comprising, consisting of, or consisting essentially of:BT Ref. 104448-429411 PATENT topically administering to the subject any of the afore-described compositions. Other embodiments relate to a method for treating a subject having a disease or disorder of the eye comprising, consisting of, or consisting essentially of: topically administering to the subject any of the afore-described compositions. Still yet, some embodiments relate to a method for treating a subject having a fungal disease or disorder comprising, consisting of, or consisting essentially of: topically administering to the subject any of the afore-described compositions. Some embodiments relate to a method for treating a subject having a fungal skin infection comprising, consisting of, or consisting essentially of: topically administering to the subject any of the afore- described compositions. Some embodiments relate to a method for treating a subject having tinea pedis, tinea cruris, or tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, or Microsporum canis; seborrheic dermatitis; cutaneous candidiasis (moniliasis) due to Candida albicans,' tinea (pityriasis) versicolor due to Malassezia furfur, onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes, cutaneous or mucocutaneous mycotic infections due to Candida albicans and other susceptible Candida species; yeast infections; vaginal yeast infections; superficial skin infections due to yeast; Trichophyton tonsurans,' blastomycosis; pulmonary and extrapulmonary histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; or Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy., comprising, consisting of, or consisting essentially of: topically administering to the subject any of the afore-described compositions.

[0235] In some embodiments, a bandage may be utilized to cover the treated area (or a portion thereof) to reduce evaporation of the composition. In other embodiments, a bandage may be utilized to cover the treated area (or a portion thereof) to afford more continuous delivery of theBT Ref. 104448-429411 PATENT therapeutic agent. Examples of suitable bandages include crepe bandages (e.g., woven elasticated bandages commonly made of cotton), conforming bandages (e.g., that conform closely to the body’s contours and are generally stretchy), cohesive bandages (e.g., bandages that are designed to stick to themselves), open wove bandages, and adhesive bandages. In some embodiments, the subject applies a bandage after application of the composition. In some embodiments, the subject applies a bandage after each application of the composition. In some embodiments, the bandage is impregnated with the composition. In such instances, application of the impregnated bandage to the site of treatment constitutes administration of the composition.

[0236] Preferred embodiments relate to a method for treating a subject having onychomychosis, comprising, consisting of, or consisting essentially of: topically administering to a nail of the subject a pharmaceutically effective amount of any of the afore-described compositions. Other preferred embodiments relate to a method for treating a subject having onychomychosis or fungal keratitis, comprising, consisting of, or consisting essentially of: topically or intraocularly administering to an eye of the subject a pharmaceutically effective amount of any of the afore- described compositions. Typically treatment of onychomycosis in the context of the methods described here includes treatment of Tinea unguium.

[0237] In addition to the treatment of onychomycosis, the methods provided herein can be used for other suitable purposes including the inhibition of fungal lanosterol 14 a-demethylase and / or ergosterol biosynthesis. For example, the methods can be applied to inhibit the growth of and / or to eradicate a microorganism, such as a dermatophyte, for example a dermatophyte of the Tricophyton, Microsporum, and Epidermophyton species and / or a yeast (e.g., a yeast of the Malassezia species or Candida species). In certain embodiments, the methods can be employed to inhibit and / or eradicate microorganisms selected from Trichophyton mentagrophytes,BT Ref. 104448-429411 PATENTTrichophyton rubrum, Candida albicans Trichophyton tonsurans, Trichophyton verrucosum,Trichophyton schoenleinii, Epidermophyton floccosum, Scopulari opsis brevicaulis, Acremonium spp., Fusarium spp., Candida par apsilosis, Candida krusei, Candida tropicalis, and Microsporum canis.

[0238] In some embodiments, the subj ect is a human. The human subj ect may be an adult human or a juvenile human. In some embodiments, the subject is immunocompromised. However, in other embodiments, the subject is not immunocompromised.

[0239] In some embodiments, the disease or disorder is a disease or disorder of the nail, nail bed skin, and / or eye. In some embodiments, the disease or disorder is a skin infection. In preferred embodiments, the disease or disorder is a microbial infection. In more preferred embodiments, the disease or disorder is onychomychosis and / or or fungal keratitis. In even more preferred embodiments, the disease or disorder is caused by dermatophytes, yeasts, and / or molds. Yet still, in some embodiments, the disease or disorder is caused by Trichophyton rubrum, Trichophyton mentagophytes, or both Trichophyton rubrum and Trichophyton mentagophytes . In some embodiments, the disease or disorder is caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, Candida albicans, Malassezia furfur, or Trichophyton tonsurans. In some embodiments, the disease or disorder is tinea pedis, tinea cruris, tinea corporis, seborrheic dermatitis, tinea versicolor, blastomycosis, histoplasmosis, or aspergillosis. In some embodiments, the disease or disorder is tinea pedis, tinea cruris, or tinea corporis.

[0240] In some embodiments, the composition is repeatedly administered in an amount and for a time sufficient to ameliorate the signs or symptoms of the disease or disorder. For example, in some embodiments the composition is administered for 1 week, 2 weeks, 3 weeks, 4 weeks, 5BT Ref. 104448-429411 PATENT weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, about any of the aforementioned time periods (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, or about 60 weeks) or a range bounded by any of the aforementioned time periods or about any of the aforementioned time periods (e.g., 1-60 weeks, 10-55 weeks, 12-48 weeks, 12-24 weeks, about 1- 60 weeks, about 10-55 weeks, about 12-48 weeks, or about 12-24 weeks). In preferred embodiments, the composition is administered for about 60 weeks, about 48 weeks, about 36 weeks, about 24 weeks, or about 12 weeks. In more preferred embodiments, the composition is administered for 12 weeks.BT Ref. 104448-429411 PATENT

[0241] In some embodiments the composition is administered for less than 1 week, less than 2 weeks, less than 3 weeks, less than 4 weeks, less than 5 weeks, less than 6 weeks, less than 7 weeks, less than 8 weeks, less than 9 weeks, less than 10 weeks, less than 11 weeks, less than 12 weeks, less than 13 weeks, less than 14 weeks, less than 15 weeks, less than 16 weeks, less than 17 weeks, less than 18 weeks, less than 19 weeks, less than 20 weeks, less than 21 weeks, less than 22 weeks, less than 23 weeks, less than 24 weeks, less than 25 weeks, less than 26 weeks, less than 27 weeks, less than 28 weeks, less than 29 weeks, less than 30 weeks, less than 31 weeks, less than 32 weeks, less than 33 weeks, less than 34 weeks, less than 35 weeks, less than 36 weeks, less than 37 weeks, less than 38 weeks, less than 39 weeks, less than 40 weeks, less than 41 weeks, less than 42 weeks, less than 43 weeks, less than 44 weeks, less than 45 weeks, less than 46 weeks, less than 47 weeks, less than 48 weeks, less than 49 weeks, less than 50 weeks, less than 51 weeks, less than 52 weeks, less than 53 weeks, less than 54 weeks, less than 55 weeks, less than 56 weeks, less than 57 weeks, less than 58 weeks, less than 59 weeks, less than 60 weeks, about any of the aforementioned time periods (e g., less than about 1 week, less than about 2 weeks, less than about 3 weeks, less than about 4 weeks, less than about 5 weeks, less than about 6 weeks, less than about 7 weeks, less than about 8 weeks, less than about 9 weeks, less than about 10 weeks, less than about 11 weeks, less than about 12 weeks, less than about 13 weeks, less than about 14 weeks, less than about 15 weeks, less than about 16 weeks, less than about 17 weeks, less than about 18 weeks, less than about 19 weeks, less than about 20 weeks, less than about 21 weeks, less than about 22 weeks, less than about 23 weeks, less than about 24 weeks, less than about 25 weeks, less than about 26 weeks, less than about 27 weeks, less than about 28 weeks, less than about 29 weeks, less than about 30 weeks, less than about 31 weeks, less than about 32 weeks, less than about 33 weeks, less than about 34 weeks, less than about 35 weeks, less than about 36 weeks, less than about 37BT Ref. 104448-429411 PATENT weeks, less than about 38 weeks, less than about 39 weeks, less than about 40 weeks, less than about 41 weeks, less than about 42 weeks, less than about 43 weeks, less than about 44 weeks, less than about 45 weeks, less than about 46 weeks, less than about 47 weeks, less than about 48 weeks, less than about 49 weeks, less than about 50 weeks, less than about 51 weeks, less than about 52 weeks, less than about 53 weeks, less than about 54 weeks, less than about 55 weeks, less than about 56 weeks, less than about 57 weeks, less than about 58 weeks, less than about 59 weeks, or less than about 60 weeks) or a range bounded by any of the aforementioned time periods or about any of the aforementioned time periods (e.g., less than 24-60 weeks, less than 36-60 weeks, less than 48-60 weeks, less than 40-50 weeks, less than about 24-60 weeks, less than about 36-60 weeks, less than about 48-60 weeks, or less than about 40-50 weeks). In preferred embodiments, the composition is administered for less than about 60 weeks, less than about 48 weeks, less than about 36 weeks, less than about 24 weeks, or less than about 14 weeks. In more preferred embodiments, the composition is administered for less than 14 weeks. In even more preferred embodiments, the duration of treatment is for not more than 12 weeks.

[0242] In some embodiments, the composition is administered 1 time daily, 2 times daily, 3 times daily, 4 times daily, 5 times daily, or 6 times daily to an area in need of treatment (e.g., an affected area). In preferred embodiments, the composition is administered 1-2 times daily (e.g., morning and evening). In more preferred embodiments, the composition is administered once daily.

[0243] In some embodiments, the area in need of treatment (e.g., an affected area) is the subject’s nail, nail fold, nail bed, cuticle, hyponychium, skin, nail plate, eye and / or cornea. In some embodiments, the area in need of treatment (e.g., an affected area) is a fingernail of the subject. In some embodiments, the area in need of treatment (e.g., an affected area) is the cornea of the subject.BT Ref. 104448-429411 PATENTIn more preferred embodiments, the area in need of treatment (e.g., an affected area) is a toenail of the subject. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4- 7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10 nails are in need of treatment.

[0244] In some embodiments, the area in need of treatment is partially covered by the administration of the composition. In preferred embodiments, the area in need of treatment is completely covered by the administration of the composition. In some embodiments, the composition is administered to each toenail or toenail bed of the subject. In preferred embodiments, the composition is administered to each affected toenail or toenail bed of the subject. In some embodiments, the subject administers the composition only to affected toes and / or fingers.

[0245] In some embodiments, the composition is administered to the eye of a subject. For example, a subject may be suffering from fungal keratitis and / or a fungal infection of the eye. In such embodiments, a composition suitable for ophthalmic administration may be utilized. In some embodiments, the composition is administered to each eye of the subject. In some embodiments, the composition is administered to the subject’s cornea. In more preferred embodiments, the composition is administered to each of the subject’s corneas. In more preferred embodiments, the composition is administered to each affected eye of the subject. In even more preferred embodiments, the composition is administered to each of the subject’s affected corneas. Administration to the eye and / or cornea may be by topical administration and / or intraocular administration. Intraocular administration is preferably performed by injection.

[0246] In some embodiments, the average amount of therapeutic agent delivered to each cm2of the affected area is 0.1 mg / cm2, 0.15 mg / cm2, 0.2 mg / cm2, 0.25 mg / cm2, 0.3 mg / cm2, 0.35 mg / cm2,BT Ref. 104448-429411 PATENT0.4 mg / cm2, 0.45 mg / cm2, 0.5 mg / cm2, 0.55 mg / cm2, 0.6 mg / cm2, 0.65 mg / cm2, 0.7 mg / cm2, 0.75 mg / cm2, about any of the aforementioned amounts (e.g., about 0.1 mg / cm2, about 0.15 mg / cm2, about 0.2 mg / cm2, about 0.25 mg / cm2, about 0.3 mg / cm2, about 0.35 mg / cm2, about 0.4 mg / cm2, about 0.45 mg / cm2, about 0.5 mg / cm2, about 0.55 mg / cm2, about 0.6 mg / cm2, about 0.65 mg / cm2, about 0.7 mg / cm2, or about 0.75 mg / cm2), or a range bounded by any of the aforementioned amounts or about any of the aforementioned amounts (e.g., 0.1-0.75 mg / cm2, 0.15-0.7 mg / cm2, 0.2-0.65 mg / cm2, 0.3-0.6 mg / cm2, 0.35-0.55 mg / cm2, 0.4-0.5 mg / cm2, about 0.1-0.75 mg / cm2, about 0.15-0.7 mg / cm2, about 0.2-0.65 mg / cm2, about 0.3-0.6 mg / cm2, about 0.35-0.55 mg / cm2, or about 0.4-0.5 mg / cm2). In preferred embodiments, the average amount of therapeutic agent delivered to each cm2of the affected area is about 0.15 mg / cm2to about 0.45 mg / cm2.

[0247] In some embodiments, the administration of the composition to the affected area results in the formation of a film. In some embodiments, the film is a solid film. However, in preferred embodiments, the administration of the composition to the affected area does not result in the formation of a solid film.

[0248] In some embodiments, the affected area is initially debrided prior to the first administration of the composition. In some embodiments, the affected area is debrided one or more times during the treatment period (e.g., the period of time beginning with the first administration of the composition until the last administration of the composition). In some embodiments, the affected area is debrided daily during the treatment period. However, in preferred embodiments, the affected area is not debrided initially. In more preferred embodiments, the affected area is not debrided during the treatment period.

[0249] In some embodiments, the method is performed with occluding or partially occluding the nail, nail associated tissue, or the affected area. However, in preferred embodiments, the methodBT Ref. 104448-429411 PATENT is performed without occluding or partially occluding the nail, nail associated tissue, or the affected area. In some embodiments, the composition is not administered in an occluded or semi-occluded manner. Those of skill the art will appreciate the advantages provided by embodiments disclosed herein, including the absence of requirements for burdensome techniques such as occlusion and debridement. In general, debridement by mechanically reducing or otherwise reducing nail thickness to remove onychomycotic or potentially affected areas, usually through repeated application, can be avoided. Thus, for example, some embodiments can be characterized by not requiring a step of scraping, aggressive clipping, and / or filing the nail down, all of which are examples of possible mechanical debridement strategies not necessarily practiced in connection with some methods provided herein.

[0250] In some embodiments, the method is performed without removing (intentionally and / or unintentionally) the administered composition from the affected area. Removal of an antionychomycosis compositions are regularly practiced in connection with previously described topical therapies for the condition. Removal can be by simple mechanical wiping or any other cleaning of the surface / area that was contacted with the composition and / or by contacting the treated area with a chemical agent that removes the therapeutic agent. Some embodiments involve methods in which no form of removal is required as part of the treatment regimen. For example, in some embodiments the subject avoids cleaning the affected area after daily administration of the composition. In such methods, the composition is allowed to stay on the treatment area without any kind of active removal on the part of the patient or other individual. As a result, therapeutic agent will often remain in the affected area for the majority of the treatment period, including up to the entirety of the treatment period. In some embodiments, the subject covers the affected area to avoid removing the administered composition from the affected area. One manner of covering,BT Ref. 104448-429411 PATENT particularly for an affected fingernail or toenail, is to apply an adhesive bandage (e.g., a Band- Aid®) or tape (e.g., medical tape and / or waterproof tape) after daily administration.

[0251] In some embodiments, the subject waits 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, about any of the aforementioned time periods (e.g., about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, or about 20 minutes), or a range bounded by any of the aforementioned time periods or about any of the aforementioned time periods (e.g., 1-20, 2-19, 3-18, 4-17, 5-16, 6-15, 7-14, 8-13, 9-12, 10-11, about 1-20, about 2-19, about 3-18, about 4-17, about 5-16, about 6-15, about 7-14, about 8-13, about 9-12, or about 10-11) before administering the composition if the treatment area was previously in contact with water. In preferred embodiments, the subject waits for a period of time sufficient to allow the affected area to dry prior to administering the composition if the treatment area was previously in contact with water.

[0252] In some embodiments, the subject waits at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, at least 10 minutes, at least 11 minutes, at least 12 minutes, at least 13 minutes, at least 14 minutes, at least 15 minutes, at least 16 minutes, at least 17 minutes, at least 18 minutes, at least 19 minutes, at least 20 minutes, about any of the aforementioned time periods (e.g., at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least aboutBT Ref. 104448-429411 PATENT8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, or at least about 20 minutes), or a range bounded by any of the aforementioned time periods or about any of the aforementioned time periods (e.g., at least 1-20, at least 2-19, at least 3-18, at least 4-17, at least 5-16, at least 6-15, at least 7-14, at least 8-13, at least 9-12, at least 10- 11, at least about 1-20, at least about 2-19, at least about 3-18, at least about 4-17, at least about 5- 16, at least about 6-15, at least about 7-14, at least about 8-13, at least about 9-12, or at least about 10-11) before administering the composition if the treatment area was previously in contact with water. In preferred embodiments, the subject waits at least 10 minutes before administering the composition if the treatment area was previously in contact with water.

[0253] In some embodiments, the subject waits 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, about any of the aforementioned time periods (e.g., about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, or about 20 minutes), or a range bounded by any of the aforementioned time periods or about any of the aforementioned time periods (e.g., 1 -20, 2-19, 3-18, 4-17, 5-16, 6-15, 7-14, 8-13, 9-12, 10-11, about 1-20, about 2-19, about 3-18, about 4-17, about 5-16, about 6-15, about 7-14, about 8-13, about 9-12, or about 10-11) to administer the composition after showering, bathing, or washing the treatment area. In preferred embodiments, the subject waits for a period of timeBT Ref. 104448-429411 PATENT sufficient to allow the affected area to dry prior to administering the composition after showering, bathing, or washing the treatment area.

[0254] In some embodiments, the subject waits at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, at least 10 minutes, at least 11 minutes, at least 12 minutes, at least 13 minutes, at least 14 minutes, at least 15 minutes, at least 16 minutes, at least 17 minutes, at least 18 minutes, at least 19 minutes, at least 20 minutes, about any of the aforementioned time periods (e.g., at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 min...

Claims

1. BT Ref. 104448-429411 PATENTWHAT IS CLAIMED IS:

1. A composition for topical treatment comprising: a therapeutic agent, a non-volatile organic solvent in the amount of greater than or equal to about 50% (w / w), and optionally an emollient.

2. The composition of claim 1, wherein the composition is formulated as a solution, a cream, a gel, a lotion, a shampoo, a suspension, an emulsion, a nail lacquer, an ointment, a lozenge, a capsule, a suppository, or a vaginal insert.

3. The composition of any of claims 1-2, wherein the therapeutic agent is an antimicrobial agent.

4. The composition of any of claims 1-3, wherein the therapeutic agent is an antifungal agent.

5. The composition of any of claims 1-4, wherein the therapeutic agent is useful for treating a skin infection caused by dermatophytes, yeasts, or molds.

6. The composition of any of claims 1-5, wherein the therapeutic agent is a therapeutic agent approved by a regulatory authority for topical treatment.

7. The composition of any of claims 1-6, wherein the therapeutic agent is a therapeutic agent approved by the FDA for topical treatment.

8. The composition of any of claims 1-7, wherein the therapeutic agent is selected from the group consisting of: salicylic acid, benzoic acid, undecylenic alkanolamide, ciclopirox, butenafine, naftifine, nystatin, bifonazole, clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, miconazole, sulconazole, tioconazole, itraconazole, terbinafine, tolciclate, tolnaftate, tavaborole, and pharmaceutically acceptable salts thereof.BT Ref. 104448-429411 PATENT9. The composition of any of claims 1-8, wherein the therapeutic agent is selected from the group consisting of: 3% salicylic acid, and 6% benzoic acid, undecylenic alkanolamide, ciclopirox, ciclopirox olamine, butenafine hydrochloride, naftifine hydrochloride, nystatin, bifonazole, clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, miconazole, sulconazole, tioconazole, itraconazole, terbinafine, tolciclate, tolnaftate, and tavaborole.

10. The composition of any of claims 1-9, wherein the therapeutic agent is useful for treating tinea pedis, tinea cruris, or tinea corporis due to Trichophyton rubruin, Trichophyton mentagrophytes, Epidermophyton floccosum, or Microsporum canis, seborrheic dermatitis; fungal keratitis cutaneous candidiasis (moniliasis) due to Candida albicans,' tinea (pityriasis) versicolor due to Malassezia furfur, onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes, cutaneous or mucocutaneous mycotic infections due to Candida albicans and other susceptible Candida species; yeast infections; vaginal yeast infections; superficial skin infections due to yeast; Trichophyton tonsurans,' blastomycosis; pulmonary and extrapulmonary histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; or aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

11. The composition of any of claims 1-10, wherein the therapeutic agent is useful for treating onychomycosis.

12. The composition of any of claims 1-11, wherein the therapeutic agent is approved by a regulatory authority for treating onychomycosis.

13. The composition of any of claims 1-12, wherein the therapeutic agent is approved by the FDA for treating onychomycosis.BT Ref. 104448-429411 PATENT14. The composition of any of claims 1-13, wherein the therapeutic agent is an antifungal agent that is selected from the group consisting of azoles, allylamines, hydroxypyridinones, morpholines, and oxaboroles.

15. The composition of any of claims 1-14, wherein the therapeutic agent is an antifungal agent that is selected from the group consisting of: terbinafine, itraconazole, griseofulvin, ciclopirox, amorolfme, tavaborole, fluconazole, and efinaconazole.

16. The composition of any of claims 1-15, wherein the therapeutic agent is an antifungal agent that is selected from the group consisting of: terbinafine, itraconazole, cicloprox, cicloprox olamine, tavaborole, and efinaconazole.

17. The composition of any of claims 1-16, wherein the therapeutic agent is an azole antifungal agent that is a triazole antifungal agent.

18. The composition of any of claims 1-17, wherein the therapeutic agent is efinaconazole.

19. The composition of any of claims 1-18, wherein the therapeutic agent is tavaborole.

20. The composition of any of claims 1-19, wherein the therapeutic agent is ciclopirox or ciclopirox olamine.

21. The composition of any of claims 1-20, wherein the therapeutic agent is nystatin.

22. The composition of any of claims 1-21, wherein the therapeutic agent is clotimazole.

23. The composition of any of claims 1-22, wherein the therapeutic agent is miconazole.

24. The composition of any of claims 1-23, wherein the therapeutic agent is butenafine hydrochloride.BT Ref. 104448-429411 PATENT25. The composition of any of claims 1 -24, wherein the therapeutic agent is naftifine hydrochloride.

26. The composition of any of claims 1-25, wherein the therapeutic agent is luliconazole.

27. The composition of any of claims 1-26, wherein the therapeutic agent is itraconazole.

28. The composition of any of claims 1-27, wherein the therapeutic agent is present in the amount of about l%-40% (w / w), about 5%-20% (w / w), about 8%-12% (w / w), about 10% (w / w), or 10% (w / w).

29. The composition of any of claims 1-28, wherein the therapeutic agent is efinaconazole and is present in the composition in the amount of about l%-30% (w / w), 3%-20% (w / w), about 5%-l 5% (w / w), about 8%-12% (w / w), about 10% (w / w), or 10% (w / w).

30. The composition of any of claims 1-29, wherein the therapeutic agent is tavaborole and is present in the composition in the amount of about 1%-15% (w / w), about l%-10% (w / w), about 2%-8% (w / w), about 5% (w / w), or 5% (w / w).

31. The composition of any of claims 1-30, wherein the therapeutic agent is ciclopirox and is present in the composition in the amount of about 1%-15% (w / w), about 2%-12% (w / w), about 3%-10% (w / w), about 5%-10% (w / w), about 8% (w / w), or 8% (w / w).

32. The composition of any of claims 1-31, wherein the therapeutic agent is ciclopirox and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l% (w / w), about 0.77% (w / w), about 1% (w / w), 0.77% (w / w), or 1% (w / w).BT Ref. 104448-429411 PATENT33. The composition of any of claims 1-32, wherein the therapeutic agent is ciclopirox olamine and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l% (w / w), about 0.77% (w / w) or 0.77% (w / w).

34. The composition of any of claims 1-33, wherein the therapeutic agent is nystatin and is present in the composition in the amount of about 50,000-150,000 USP Nystatin Units, about 75,000-125,000 USP Nystatin Units, about 100,000 USP Nystatin Units or 100,000 USP Nystatin Units.

35. The composition of any of claims 1-34, wherein the therapeutic agent is clotimazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-1.5% (w / w), about 1% (w / w) or 1% (w / w).

36. The composition of any of claims 1-35, wherein the therapeutic agent is miconazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.75%-3% (w / w), about l%-2.5% (w / w), about 2% (w / w) or 2% (w / w).

37. The composition of any of claims 1-36, wherein the therapeutic agent is butenafme hydrochloride and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-l .5% (w / w), about 1% (w / w) or 1% (w / w).

38. The composition of any of claims 1-37, wherein the therapeutic agent is naftifine hydrochloride and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.75%-3% (w / w), about l%-2.5% (w / w), about 1% (w / w), about 2% (w / w), 1% (w / w), or 2% (w / w).

39. The composition of any of claims 1-38, wherein the therapeutic agent is luliconazole and is present in the composition in the amount of about 0.5%-5% (w / w), about 0.6%-2% (w / w), about 0.7%-1.5% (w / w), about 1% (w / w) or 1% (w / w).BTRef. 104448-429411 PATENT40. The composition of any of claims 1-39, wherein the therapeutic agent is itraconazole and is present in the amount of about l%-40% (w / w), about 5%-20% (w / w), about 8%-12% (w / w), about 10% (w / w), or 10% (w / w).

41. The composition of any of claims 1-40, wherein the ratio by weight of the therapeutic agent to the non-volatile solvent is about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, about 1:10, about 1:10.5, about 1:11, about 1:11.5, about 1:12, about 1:12.5, about 1:13, about 1:13.5, about 1:14, about 1:14.5, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, or about 1:99.

42. The composition of any of claims 1-41, wherein the composition comprises about l%-20% (w / w) therapeutic agent and about 80%-99% (w / w) non-volatile solvent, about 5%-l 5% (w / w) therapeutic agent and about 85%-95% (w / w) non-volatile solvent, 8%-12% (w / w) therapeutic agent and about 88%-92% (w / w) non-volatile solvent, about 10% (w / w) therapeutic agent and about 90% (w / w) non-volatile solvent, 10% (w / w) therapeutic agent and 90% (w / w) non-volatile solvent.

43. The composition of any of claims 1-42, wherein the composition comprises about 1%-15% (w / w) therapeutic agent and about 85%-99% (w / w) non-volatile solvent, about l%-10% (w / w) therapeutic agent and about 90%-99% (w / w) non-volatile solvent, about 2%-8% (w / w) therapeutic agent and about 92%-98% (w / w) non-volatile solvent, about 5% (w / w) therapeutic agent and about 95% (w / w) non-volatile solvent, or 5% (w / w) therapeutic agent and 95% (w / w) non-volatile solvent.BT Ref. 104448-429411 PATENT44. The composition of any of claims 1 -43, wherein the non-volatile solvent is an organic solvent.

45. The composition of any of claims 1-44, wherein the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure that is greater than or equal to 125° C, 130° C, 135° C, 140° C, 145° C, 150° C, 155° C, 160° C, 165° C, 170° C, 175° C, 180° C, 185° C, 190° C, 195° C, 200° C, 205° C, 210° C, 215° C, 220° C, 225° C, 230° C, or 235° C.

46. The composition of any of claims 1-45, wherein the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure that is greater than or equal to 200° C, 205° C, 210° C, 215° C, 220° C, 225° C, 230° C, or 235° C.

47. The composition of any of claims 1-46, wherein the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure that is greater than or equal to 225° C, 230° C, or 235° C.

48. The composition of any of claims 1-47, wherein the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and has a boiling point at standard pressure of between about 200° C to 240° C.

49. The composition of any of claims 1-48, wherein the non-volatile solvent is a liquid at standard temperature and pressure (20° C and 1 atm) and begins to decay at about 240° C at standard pressure.

50. The composition of any of claims 1-49, wherein the non-volatile solvent is a lipophilic compound.BT Ref. 104448-429411 PATENT51. The composition of any of claims 1-50, wherein the non-volatile solvent is a lipophilic compound that is miscible with acetone, chloroform, ether, and vegetable oils.

52. The composition of any of claims 1-51, wherein the non-volatile solvent has a hydrophilic-lipophilic balance of less than or equal to 5, less than or equal to 4, less than or equal to 3, less than or equal to 2, less than or equal to 1, or equal to 0.

53. The composition of any of claims 1-52, wherein the non-volatile solvent is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, an ester of tocopherols excipient, and mixtures thereof.

54. The composition of any of claims 1-53, wherein the non-volatile solvent is a Ci- Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, or tocopherols excipient.

55. The composition of any of claims 1-54, wherein the non-volatile solvent is an acetate ester of vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, or tocopherols excipient.

56. The composition of any of claims 1-55, wherein the non-volatile solvent is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, a synthetic ester of tocopherols excipient, and mixtures thereof.

57. The composition of any of claims 1-56, wherein the non-volatile solvent is a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, or tocopherols excipient.BT Ref. 104448-429411 PATENT58. The composition of any of claims 1-57, wherein the non-volatile solvent is a synthetic Ci-Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E.

59. The composition of any of claims 1-58, wherein the non-volatile solvent is vitamin E.

60. The composition of any of claims 1-59, wherein the non-volatile solvent is synthetic vitamin E.

61. The composition of any of claims 1-60, wherein the non-volatile solvent is vitamin E acetate.

62. The composition of any of claims 1-61, wherein the non-volatile solvent is synthetic vitamin E acetate.

63. The composition of any of claims 1-62, wherein the non-volatile solvent is a single solvent.

64. The composition of any of claims 1-63, wherein the non-volatile solvent is a mixture of two or more solvents.

65. The composition of any of claims 1-64, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, and an ester of tocopherols excipient.

66. The composition of any of claims 1-65, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic betaBT Ref. 104448-429411 PATENT tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherols excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, and a synthetic ester of tocopherols excipient.

67. The composition of any of claims 1-66, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, and gamma tocopherol.

68. The composition of any of claims 1-67, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, and synthetic gamma tocopherol.

69. The composition of any of claims 1-68, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, and an ester of gamma tocopherol.

70. The composition of any of claims 1-69, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an Ci-Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, is a C1-C10, Ci- Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol.BT Ref. 104448-429411 PATENT71. The composition of any of claims 1-70, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an acetate ester of vitamin E, an acetate ester of beta tocopherol, an acetate ester of delta tocopherol, an acetate ester of gamma tocopherol, and an acetate ester of tocopherols excipient.

72. The composition of any of claims 1-71, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, and a synthetic ester of gamma tocopherol.

73. The composition of any of claims 1-72, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic Ci-Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a synthetic C1-C10, Ci- Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol.

74. The composition of any of claims 1-73, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic acetate ester of vitamin E, a synthetic acetate ester of beta tocopherol, a synthetic acetate ester of delta tocopherol, a synthetic acetate ester of gamma tocopherol, a synthetic acetate ester of tocopherols excipient.

75. The composition of any of claims 1-74, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of twoBT Ref. 104448-429411 PATENT or more solvents is vitamin E, vitamin E acetate, synthetic vitamin E, or synthetic vitamin E acetate.

76. The composition of any of claims 1-75, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is synthetic vitamin E acetate.

77. The composition of any of claims 1-76, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, gamma tocopherol, tocopherols excipient, an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, an ester of gamma tocopherol, and an ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 60%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 65%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 70%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 75%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 80%(w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

78. The composition of any of claims 1-77, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, synthetic gamma tocopherol, synthetic tocopherolsBT Ref. 104448-429411 PATENT excipient, a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, a synthetic ester of gamma tocopherol, and a synthetic ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 60%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 65%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 70%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 75%(w / w) of the total amount of non-volatile solvents in the composition, greater than about 80%(w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85%(w / w) of the total amount of non-volatile solvents in the composition.

79. The composition of any of claims 1-78, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, beta tocopherol, delta tocopherol, and gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in theBT Ref. 104448-429411 PATENT composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

80. The composition of any of claims 1-79, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: synthetic vitamin E, synthetic beta tocopherol, synthetic delta tocopherol, and synthetic gamma tocopherol and at least one of the nonvolatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition.

81. The composition of any of claims 1-80, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an ester of vitamin E, an ester of beta tocopherol, an ester of delta tocopherol, and an ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-BT Ref. 104448-429411 PATENT volatile solvents in the composition, greater than about 70% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 75% (w / w) of the total amount of nonvolatile solvents in the composition, greater than about 80% (w / w) of the total amount of nonvolatile solvents in the composition, or greater than about 85% (w / w) of the total amount of nonvolatile solvents in the composition.

82. The composition of any of claims 1-81, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an Ci-Cio, Ci-Cs, C1-C5, C2-C4, or C2 ester of vitamin E, a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, is a C1-C10, Ci- Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

83. The composition of any of claims 1-82, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: an acetate ester of vitamin E, an acetate ester of beta tocopherol, an acetate ester of delta tocopherol, an acetate ester of gamma tocopherol,BT Ref. 104448-429411 PATENT and an acetate ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

84. The composition of any of claims 1-83, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic ester of vitamin E, a synthetic ester of beta tocopherol, a synthetic ester of delta tocopherol, and a synthetic ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.BT Ref. 104448-429411 PATENT85. The composition of any of claims 1-84, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic Ci-Cio, Ci-Cs, Ci-Cs, C2-C4, or C2 ester of vitamin E, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of beta tocopherol, a synthetic C1-C10, Ci-Cs, C1-C5, C2-C4, or C2 ester of delta tocopherol, and a synthetic C1-C10, Ci- Cs, C1-C5, C2-C4, or C2 ester of gamma tocopherol and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

86. The composition of any of claims 1-85, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: a synthetic acetate ester of vitamin E, a synthetic acetate ester of beta tocopherol, a synthetic acetate ester of delta tocopherol, a synthetic acetate ester of gamma tocopherol, and a synthetic acetate ester of tocopherols excipient and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the totalBT Ref. 104448-429411 PATENT amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

87. The composition of any of claims 1-86, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is selected from the group consisting of: vitamin E, vitamin E acetate, synthetic vitamin E, or synthetic vitamin E acetate and at least one of the non-volatile solvents is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

88. The composition of any of claims 1-87, wherein the non-volatile solvent is a mixture of two or more solvents and at least one of the non-volatile solvents in the mixture of two or more solvents is vitamin E acetate and the vitamin E acetate is present in the amount of greater than about 50% (w / w) of the total amount of non-volatile solvents in the composition, greater thanBT Ref. 104448-429411 PATENT about 55% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 60% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 65% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 70% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 75% (w / w) of the total amount of non-volatile solvents in the composition, greater than about 80% (w / w) of the total amount of non-volatile solvents in the composition, or greater than about 85% (w / w) of the total amount of non-volatile solvents in the composition.

89. The composition of any of claims 1-88, wherein the non-volatile solvent is present in the amount of greater than about 50% (w / w), greater than about 55% (w / w), greater than about 60% (w / w), greater than about 65% (w / w), greater than about 70% (w / w), greater than about 75% (w / w), greater than about 80% (w / w), or greater than about 85% (w / w).

90. The composition of any of claims 1-89, wherein the non-volatile solvent is present in the amount of about 50% (w / w), about 55% (w / w), about 60% (w / w), about 65% (w / w), about 70% (w / w), about 75% (w / w), about 80% (w / w), about 85% (w / w), about 90% (w / w), or about 95% (w / w).

91. The composition of any of claims 1-90, wherein the emollient is present.

92. The composition of any of claims 1-91, wherein the emollient is selected from the group consisting of: adipate esters, glycols, lanolin, lanolin alcohols, glycerin, stearates, shea butter, beeswax, dimethicone, cyclomethicone, diisopropyl adipate, ceramide, Ceratonia extract, cetostearyl alcohol, cetyl alcohol, petrolatum, oils, paraffin, dibutyl sebacate, glycerol behenate, glycerol monooleate, isopropyl myristate, isopropyl palmitate, lecithin, ethyl linoleate, medium chain triglycerides, myristyl alcohol, octyl dodecanol, oleyl alcohol, stearyl alcohol, tricaprylin, triolein, waxes, and sterols.BT Ref. 104448-429411 PATENT93. The composition of any of claims 1-92, wherein the emollient is selected from the group consisting of: diisopropyl adipate, propylene glycol, lanolin, lanolin alcohols, glycerin, glycerol monostearate, ethylene glycol stearates, shea butter, beeswax, dimethicone, cyclomethicone, ceramide, Ceratonia extract, cetostearyl alcohol, cetyl alcohol, petrolatum, almond oil, canola oil, castor oil, coconut oil, cottonseed oil, mineral oil, mineral oil light, jojoba oil, olive oil, safflower oil, soybean oil, sunflower oil, squalene, paraffin, monostearates, dibutyl sebacate, glycerol behenate, glycerol monooleate, isopropyl myristate, isopropyl palmitate, lecithin, ethyl linoleate, medium chain triglycerides, myristyl alcohol, octyldodecanol, oleyl alcohol, stearyl alcohol, tricaprylin, triolein, carnauba wax, cetyl ester wax, xylitol, zinc acetate, and cholesterol94. The composition of any of claims 1-93, wherein the emollient is cholesterol.

95. The composition of any of claims 1-94, wherein the emollient is present in the amount of about 0. l%-5% (w / w), about 0.5%-3% (w / w), about l%-2% (w / w), about 1% (w / w), or about 2% (w / w).

96. The composition of any of claims 1-95, wherein the composition does not further include any emollient or additional emollient.

97. The composition of any of claims 1-96, wherein the composition does not further include any emulsifier or additional emulsifier.

98. The composition of any of claims 1-97, wherein the composition does not further include any preservative or additional preservative.

99. The composition of any of claims 1-98, wherein the composition does not further include any antioxidant or additional antioxidant.BT Ref. 104448-429411 PATENT100. The composition of any of claims 1 -99, wherein the composition does not further include any chelating agent or additional chelating agent.

101. The composition of any of claims 1-100, wherein the composition does not further include any thickener or additional thickener.

102. The composition of any of claims 1-101, wherein the composition does not further include any humectant or additional humectant.

103. The composition of any of claims 1-102, wherein the composition does not further include any wetting agent or additional wetting agent.

104. The composition of any of claims 1-103, wherein the composition does not further include any permeation enhancer or additional permeation enhancer.

105. The composition of any of claims 1-104, wherein the composition does not further include any buffering agent or additional buffering agent.

106. The composition of any of claims 1-105, wherein the composition does not further include any pH adjusting agent or additional pH adjusting agent.

107. The composition of any of claims 1-106, wherein the composition does not further include any volatile solvent or additional volatile solvent.

108. The composition of any of claims 1-107, wherein the composition does not further include any additional non-volatile solvent.

109. The composition of any of claims 1-108, wherein the composition does not further include any fragrances, perfumes, or fragrance compounds.

110. The composition of any of claims 1-109, wherein the composition does not further include any additional therapeutic agent.BT Ref. 104448-429411 PATENT111. The composition of any of claims 1-110, wherein the composition does not include any additional ingredients that were liquid before incorporation into the composition.

112. The composition of any of claims 1-111, wherein the composition does not include any additional ingredients that were solid before incorporation into the composition.

113. The composition of any of claims 1-112, wherein the composition does not further include one or more of an additional alcohol, citric acid, butylated hydroxytoluene, Cl 2- 15 alkyl lactate, cyclomethicone, diisopropyl adipate, disodium edetate, or water.

114. The composition of any of claims 1-113, wherein the composition does not include any polymeric film forming compounds.

115. The composition of any of claims 1-114, wherein the composition is suitable for topical application to a subject in need of treatment.

116. The composition of any of claims 1-115, wherein the composition is formulated as a solution.

117. The composition of any of claims 1-116, wherein the composition is formulated for delivery of the therapeutic agent to the nail or nail bed of a subject.

118. The composition of any of claims 1-117, wherein the surface tension of the composition is about 40 dynes / cm or less, about 35 dynes / cm or less, about 30 dynes / cm or less, or about 25 dynes / cm or less.

119. The composition of any of claims 1-118, wherein the composition includes one or more emulsifiers.

120. The composition of any of claims 1-119, wherein the composition includes one or more preservatives.BT Ref. 104448-429411 PATENT121 . The composition of any of claims 1 -120, wherein the composition includes one or more antioxidants.

122. The composition of any of claims 1 -121, wherein the composition includes one or more chelating agents.

123. The composition of any of claims 1 -122, wherein the composition includes one or more thickeners.

124. The composition of any of claims 1 -123, wherein the composition includes one or more humectants.

125. The composition of any of claims 1 -124, wherein the composition includes one or more wetting agents.

126. The composition of any of claims 1 -125, wherein the composition includes one or more permeation enhancers.

127. The composition of any of claims 1 -126, wherein the composition includes one or more buffering agents.

128. The composition of any of claims 1 -127, wherein the composition includes one or more pH adjusting agents.

129. The composition of any of claims 1 -128, wherein the composition includes one or more volatile solvents.

130. The composition of any of claims 1 -129, wherein the composition includes two or more non-volatile solvents.

131. The composition of any of claims 1 -130, wherein the composition includes two or more therapeutic agents.BT Ref. 104448-429411 PATENT132. The composition of any of claims 1-131, wherein the composition includes one or more fragrances, perfumes, or fragrance compounds.

133. A method for treating a subject having a disease or disorder amenable to topical treatment comprising: topically administering to the subject the composition of any of claims 1- 132.

134. A method for treating a subject having a disease or disorder of the nail, nail bed, and / or skin comprising: topically administering to the subject the composition of any of claims 1- 132.

135. A method for treating a subject having a disease or disorder of the nail and / or nail bed comprising: topically administering to the subject the composition of any of claims 1-132.

136. Amethod for treating a subject having a disease or disorder of the skin comprising: topically administering to the subject the composition of any of claims 1-132.

137. A method for treating a subject having a fungal disease or disorder comprising: topically administering to the subject the composition of any of claims 1-132.

138. Amethod for treating a subject having a fungal skin infection comprising: topically administering to the subject the composition of any of claims 1-132.

139. A method for treating a subject having onychomychosis, comprising: topically administering to a nail of the subject a pharmaceutically effective amount of the composition of any of claims 1-132.

140. A method for treating a subject having tinea pedis, tinea cruris, or tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epider ophyton flocco um, or Microsporum canis; seborrheic dermatitis; cutaneous candidiasis (moniliasis) due to Candida albicans,' tinea (pityriasis) versicolor due to Malassezia furfur,' onychomycosis due toBT Ref. 104448-429411 PATENTTrichophyton rubrum or Trichophyton mentagrophytes, cutaneous or mucocutaneous mycotic infections due to Candida albicans and other susceptible Candida species; yeast infections; vaginal yeast infections; superficial skin infections due to yeast; Trichophyton tonsurans, blastomycosis; pulmonary and extrapulmonary histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; or Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy., comprising: topically administering to the subject a pharmaceutically effective amount of the composition of any of claims 1-132.

141. The method of any of claims 133-140, wherein the subject is a human.

142. The method of any of claims 133-141, wherein the subject is an adult human.

143. The method of any of claims 133-142, wherein the subject is a juvenile human.

144. The method of any of claims 133-143, wherein the subject is immunocompromised.

145. The method of any of claims 133-144, wherein the subject is not immunocompromi sed .

146. The method of claim 133-145, wherein the disease or disorder is a disease or disorder of the nail.

147. The method of any of claims 133-146, wherein the disease or disorder is a disease or disorder of the nail bed.

148. The method of any of claims 133-147, wherein the disease or disorder is a disease or disorder is a fungal infection.

149. The method of any of claims 133-148, wherein the disease or disorder is a disease or disorder is a skin infection.BT Ref. 104448-429411 PATENT150. The method of any of claims 133-149, wherein the disease or disorder is onychomychosis.

151. The method of any of claims 133-150, wherein the disease or disorder is caused by dermatophytes, yeasts, and / or molds.

152. The method of any of claims 133-151, wherein the disease or disorder is caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsponim canis, Candida albicans, Malassezia furfur, or Trichophyton tonsurans.

153. The method of any of claims 133-152, wherein the disease or disorder is caused by a fungus selected from the group consisting of: Trichophyton rubrum, Trichophyton mentagophytes, and both Trichophyton rubrum and Trichophyton mentagophytes.

154. The method of any of claims 133-153, wherein the disease or disorder is tinea pedis, tinea cruris, tinea corporis, seborrheic dermatitis, tinea versicolor, blastomycosis, histoplasmosis, or aspergillosis.

155. The method of any of claims 133-154, wherein the disease or disorder is tinea pedis, tinea cruris, or tinea corporis.

156. The method of any of claims 133-155, wherein the treatment of the subject includes topically administering to the subject the composition of any of any of claims 1-132.

157. The method of any of claims 133-156, wherein the administration of the composition is repeated in an amount and for a time sufficient to ameliorate the signs or symptoms of the disease or disorder.

158. The method of any of claims 133-157, wherein the composition is administered for about 60 weeks, about 48 weeks, about 36 weeks, about 24 weeks, or about 12 weeks.BT Ref. 104448-429411 PATENT159. The method of any of claims 133-158, wherein the composition is administered for about 48 weeks.

160. The method of any of claims 133-159, wherein the composition is administered for about 36 weeks.

161. The method of any of claims 133-160, wherein the composition is administered for about 24 weeks.

162. The method of any of claims 133-161, wherein the composition is administered for about 12 weeks.

163. The method of any of claims 133-162, wherein the composition is administered 1- 4 times daily to the affected area.

164. The method of any of claims 133-163, wherein the composition is administered once daily to the affected area.

165. The method of any of claims 133-164, wherein the affected area is the subject’s nail, nail fold, nail bed, cuticle, hyponychium, skin, and / or nail plate.

166. The method of any of claims 133-165, wherein the affected area is a toenail.

167. The method of any of claims 133-166, wherein the affected area is completely covered by the administration.

168. The method of any of claims 133-167, wherein the composition is administered to each affected area of the subject.

169. The method of any of claims 133-168, wherein the composition is administered to each nail or nail bed of the subject.

170. The method of any of claims 133-169, wherein the composition is administered to each toenail or toenail bed of the subject.BT Ref. 104448-429411 PATENT171. The method of any of claims 133-170, wherein the subject administers the composition only to affected toes and / or fingers.

172. The method of any of claims 133-171, wherein the average amount of therapeutic agent delivered to each cm2of the affected area is about 0.15 mg / cm2to about 0.45 mg / cm2.

173. The method of any of claims 133-172, wherein the administration to the surface of a nail or nail bed does not form a solid film.

174. The method of any of claims 133-173, wherein the affected area is not debrided initially or during the treatment period.

175. The method of any of claims 133-174, wherein the composition is not removed from the treatment area during the treatment period.

176. The method of any of claims 133-175, wherein the method is performed without occluding or partially occluding the nail, nail associated tissue, or affected area.

177. The method of any of claims 133-176, wherein the method is performed with occluding or partially occluding the nail, nail associated tissue, or affected area.

178. The method of any of claims 133-177, wherein the subject waits at least 10 minutes before administering the composition if the treatment area was previously in contact with water.

179. The method of any of claims 133-178, wherein the subject waits at least 10 minutes to administer the composition after showering, bathing, or washing the treatment area180. The method of any of claims 133-179, wherein the subject avoids pedicures, the use of nail polish, and / or cosmetic nail products during the treatment period.

181. The method of any of claims 133-180, wherein the method includes a step of cleaning the affected area prior to administering the composition.BT Ref. 104448-429411 PATENT182. The method of any of claims 133-181, wherein the subject cleans the affected area prior to treatment and waits for at least 10 minutes before administering the composition if the cleaning includes wetting the affected area with water.

183. The method of any of claims 133-182, wherein the method comprises cutting nails once every two weeks or more frequently.

184. The method of any of claims 133-183, wherein the method does not comprise cutting nails more often than every two weeks.

185. The method of any of claims 133-184, wherein the composition is not administered in an occluded or semi-occluded manner.

186. The method of any of claims 133-185, wherein the method comprises spreading the composition throughout the treatment area with an applicator.

187. The method of any of claims 133-186, wherein the method comprises administering the composition from a container that is in fluid communication with an applicator, loading the applicator, and applying the composition with the applicator.

188. The method of any of claims 133-187, wherein the composition is in a container that is suitable for storing the composition for pharmaceutical use that comprises an applicator that is capable of dispensing a pharmaceutically effective dose of the composition and spreading an approximately uniform amount of the composition to the treatment area by manual action after loading, loading the applicator with the dose of the composition, and administering the composition to the treatment area to be treated by manual spreading.

189. The method of any of claims 133-188, wherein the method comprises manually loading the applicator with the dose of the composition.BT Ref. 104448-429411 PATENT190. The method of any of claims 133-189, wherein the container is a squeeze sensitive container and the applicator is a flow through applicator that delivers the composition to the treatment area when a user applies sufficient pressure on the container.

191. The method of any of claims 133-190, wherein the volume of the composition contained in the applicator is about 75 to about 150 microliters.

192. The method of any of claims 133-191, wherein performance of the method in a subject population results in a mycological cure rate of at least about 40%, a clinical efficacy rate of at least about 20%, a complete cure rate of at least about 10%, or a combination of any or all thereof.

193. The method of any of claims 133-192, wherein the method of treatment results in a complete cure for the subject or a subject population.

194. The method of any of claims 133-193, wherein the method of treatment results in a mycological cure for the subject or a subject population.

195. The method of any of claims 133-194, wherein the method of treatment results in an almost complete cure for the subject or a subject population.

196. The method of any of claims 133-195, wherein the method of treatment results in clinical efficacy for the subject or a subject population.

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