WO2020231800A1

WO2020231800A1 - Topical antifungal formulation

Info

Publication number: WO2020231800A1
Application number: PCT/US2020/032078
Authority: WO
Inventors: Edward Kisak; John Newsam; Avadhesh KUSHWAHA; Mehul Shah; Lalatendu Panigrahi; K. Balakrishna PATRO
Original assignee: Encube Ethicals Private Limited
Priority date: 2019-05-10
Filing date: 2020-05-08
Publication date: 2020-11-19

Abstract

A topical antifungal formulation may include an active, such as efinaconazole, a monohydric alcohol, such as ethanol, a glycol, such as propylene glycol and at least one excipient. The topical antifungal formulation may be used to topically treat onychomycosis in a subject suffering therefrom, by providing effective transungual penetration of the active.

Description

TOPICAL ANTIFUNGAL FORMULATION

CROSS-REFERENCE

This application claims priority to U.S. Patent Application 62/979,737 filed May

10, 2019.

BACKGROUND

1. FIELD

The present subject matter relates generally to antifungal formulations, and more specifically to topical antifungal formulations comprising efinaconazole.

2. DESCRIPTION OF THE RELATED ART

Fungal infections of the nail and surrounding skin are not only unsightly and socially embarrassing, but in extreme cases can be very painful or even result in loss of the nail. Fungal infections are caused by dermatophytes (i.e., fungi), which infect the nail and surrounding skin on an animal and can cause inflammation, discoloration, and/or loss of the nail. Dermatophyte infections (i.e., fungal infections) can have a variety of different causes, including poor hygiene and unsanitary living conditions.

Onychomycosis (i.e., tinea unguium) is a disease often caused by fungi that affects the nail beds of fingernails and toenails, causing discoloration and irregular growth of the affected nails. Onychomycosis usually begins at the corner of the nail as a yellowish discoloration, and then spreads, separating the nail from its bed distally, resulting in irregular nail dystrophy. Individuals can contract such a condition through exposure to the afflicting fungi in the environment, particularly when subject to unsanitary conditions or compromised immune systems.

Accordingly, many topical antifungal formulations have previously been developed in an attempt to decrease or eliminate microbes, in particular dermatophytes, from the nails of an infected mammal, and to decrease or eliminate infection, irritation, discoloration and/or loss of the nail associated with such dermatophyte infections.

Existing topical antifungal formulations suffer from inefficient transungual or transdermal penetration of the actives into the site of infection, or unpleasant side-effects of ingrown nails or application site dermatitis, vesicles or pain, for example. Thus, a composition comprising efinaconazole having a formulation solving the aforementioned problems is desired.

SUMMARY

According to an embodiment of the present subject matter, there are provided topical antifungal formulations for effective topical delivery of one or more antifungal agents, and particularly efinaconazole (referred to alternatively as “the Active”). These topical formulation may comprise:

(i) efinaconazole,

(ii) a monohydric alcohol,

(iii) a glycol and

(iv) at least one excipient selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycol 300 (PEG-300), diisopropyl adipate, lauric diethanolamide, hexylene glycol, octyldodecanol, oleic acid, PEG-7 methyl ether, polypropylene glycol, laureth-4, lauryl lactate, sodium lauryl sulfate, dipropylene glycol, glyceryl monooleate, cocamide diethanolamine (DEA), urea, oleyl alcohol, propylene glycol monolaurate, 2-amino-2methyl-l -propanol, myristyl alcohol, ethyl oleate, isostearic acid, isopropyl myristate, diethyl sebacate, castor oil, caprylic/capric triglyceride, lactic acid, diethylene glycol, 02-15 alkyl lactate, benzyl alcohol, levulinic acid, polysorbate 80, propylene carbonate, oleyl oleate, cholesterol, lecithin, cetyl alcohol, dexpenthanol, polyglyceryl-3 oleate, polysorbate 20, polysorbate 60, polysorbate 40, glyceryl riconoleate, sorbitan monolaurate, dimethyl sulfoxide, dimethyl isosorbide, isostearyl alcohol, olive oil, steareth-20, polypropylene glycol (15) (PPG- 15) stearyl ether, limonene, lanolin, alpha- terpineol, squalene, ethyl lactate, isopropyl palmitate, ammonium acetate, tricaprylin, PEG 40 castor oil, monolaurin, sodium docusate, glyceryl ricinoleate, glyceryl stearate methyl salicylate and combinations thereof.

One embodiment of the present subject matter relates to a formulation comprising:

(i) efinaconazole,

(ii) ethanol,

(iii) propylene glycol and

(iv) at least one excipient selected from the group above.

Another embodiment of the present subject matter relates to a formulation comprising:

(i) efinaconazole,

(ii) ethanol and (iii) at least one excipient selected from the group consisting of propylene glycol, glyceryl monooleate, dimethyl isosorbide, isopropyl myristate, caprylic/capric triglyceride, diethylene glycol monoethyl ether isostearyl alcohol and combinations thereof.

A further embodiment of the present subject matter relates to a method for treating onychomycosis in a subject suffering from onychomycosis, said method comprising the topical administration to said subject of a therapeutically effective amount of the topical formulation, preferably to a nail of the subject suffering from onychomycosis.

These and other features of the present subject matter will become readily apparent upon further review of the following specification.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows exemplary efinaconazole penetration across shed snake skin of select formulations having an ethanol, propylene glycol, isopropyl myristate and limonene vehicle (Efin 119). Increased penetration enhancement was seen with the addition of cholesterol (Efin 146) and sodium lauryl sulfate (Efin F143) compared to the base vehicle and Jublia®.

Fig. 2 shows (A) transungual penetration, (B) flux and (C) ungual delivery results of human cadaver nail testing of exemplary formulation EncuJubF46 compared to Jublia®.

Fig. 3 shows (A) transungual penetration and (B) ungual delivery results of human cadaver nail testing of exemplary formulation Efin F166 compared to Jublia®.

Fig. 4 shows (A) transungual penetration and (B) ungual delivery results of human cadaver nail testing of exemplary formulation Efin F167 compared to Jublia®.

Similar reference characters denote corresponding features consistently throughout the attached drawings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Definitions:

As used herein, the terms "administering", "administration", and like terms refer to any method which, in sound medical or cosmetic practice, delivers the composition to a subject in such a manner as to provide a positive effect on a dermatological disorder, condition, or appearance. The compositions are preferably administered such that they cover the entire area to be treated. "Direct administration" refers to any method which, in sound medical or cosmetic practice, delivers the composition to a subject without the use of another composition, delivery agent, or device. "Indirect administration" refers to any method which, in sound medical or cosmetic practice, delivers the composition to a subject with the use of at least one other composition, delivery agent, or device.

As used herein, the phrases an "effective amount" or a "therapeutically effective amount" of an active agent or ingredient, or pharmaceutically active agent or ingredient, which are synonymous herein, refer to an amount of the pharmaceutically active agent sufficient enough to have a positive effect on the area of application. Accordingly, these amounts are sufficient to modify the skin disorder, condition, or appearance to be treated but low enough to avoid serious side effects, within the scope of sound medical or dermatological advice. A therapeutically effective amount of the pharmaceutically active agent will cause a substantial relief of symptoms when applied repeatedly over time. Effective amounts of the pharmaceutically active agent will vary with the particular condition or conditions being treated, the severity of the condition, the duration of the treatment, the specific components of the composition being used, and like factors. As used herein, a "treatment" or "treating" of a skin or nail disease, disorder, or condition encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or the delay, prevention, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured. A useful topical formulation herein needs only to reduce the severity of a skin or nail disease, disorder, or condition, reduce the severity of symptoms associated therewith, provide improvement to a subject's quality of life, or delay, prevent, or inhibit the onset of a skin or nail disease, disorder, or condition.

It is noted that, as used in the present application including this specification and the claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise.

Throughout the application, descriptions of various embodiments use “comprising” language; however, it will be understood by one of skill in the art, that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of’ or“consisting of.”

Further, it is noted that, as used in the present application including this specification and the claims, the range of values, such as concentration ranges, percentage ranges, or ratio ranges, is understood such 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 described subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and such embodiments are also encompassed within the present subject matter, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the present subject matter.

Further, for purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and the claims, are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and the claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Unless defined otherwise, all other technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the present subject matter pertains.

The topical antifungal formulation according to an embodiment of the present subject matter may comprise:

(i) efinaconazole,

(ii) a monohydric alcohol,

(iii) a glycol, and

(iv) at least one excipient selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycol 300 (PEG-300), diisopropyl adipate, lauric diethanolamide, hexylene glycol, octyldodecanol, oleic acid, PEG-7 methyl ether, polypropylene glycol, laureth-4, lauryl lactate, sodium lauryl sulfate, dipropylene glycol, glyceryl monooleate, cocamide diethanolamine (DEA), urea, oleyl alcohol, propylene glycol monolaurate, 2-amino-2methyl-l -propanol, myristyl alcohol, ethyl oleate, isostearic acid, isopropyl myristate, diethyl sebacate, castor oil, caprylic/capric triglyceride, lactic acid, diethylene glycol, 02-15 alkyl lactate, benzyl alcohol, levulinic acid, polysorbate 80, propylene carbonate, oleyl oleate, cholesterol, lecithin, cetyl alcohol, dexpenthanol, polyglyceryl-3 oleate, polysorbate 20, polysorbate 60, polysorbate 40, glyceryl riconoleate, sorbitan monolaurate, dimethyl sulfoxide, dimethyl isosorbide, isostearyl alcohol, olive oil, steareth-20, polypropylene glycol (15) (PPG- 15) stearyl ether, limonene, lanolin, alpha- terpineol, squalene, ethyl lactate, isopropyl palmitate, ammonium acetate, tricaprylin, PEG 40 castor oil, monolaurin, sodium docusate, glyceryl ricinoleate, glyceryl stearate methyl salicylate and combinations thereof. In one embodiment the monohydric alcohol is ethanol and the glycol is propylene glycol. Other monohydric alcohols and/or glycols may further be useful herein.

The at least one excipient of the topical formulation may be selected from the group consisting of diethylene glycol monoethyl ether, PEG-300, diisopropyl adipate, lauric diethanolamide, hexylene glycol, octyldodecanol, oleic acid, PEG-7 methyl ether, polypropylene glycol, laureth-4, lauryl lactate, sodium lauryl sulfate, glyceryl monooleate, cocamide DEA, urea, lactic acid, diethylene glycol, Cl 2- 15 alkyl lactate, benzyl alcohol, levulinic acid, polysorbate 80, propylene carbonate and combinations thereof. The topical formulation may further comprise a neutral copolymer, by way of non-limiting example selected from the group consisting of poly(ethyl acrylate-co-methyl methacrylate), poly(methacylic acid-co-methyl methacrylate and combinations thereof. In another embodiment, the at least one excipient of the topical formulation may be selected from the group consisting of octyldodecanol, oleic acid, sodium lauryl sulfate, dipropylene glycol, oleyl alcohol, myristyl alcohol, ethyl oleate, isostearic acid, isopropyl myristate, diethyl sebacate, caprylic/capric triglyceride, Cl 2- 15 alkyl lactate, oleyl oleate, cholesterol combined with isopropyl myristate, cetyl alcohol, polyglyceryl-3 oleate, polysorbate 40, isostearyl alcohol, olive oil, PPG- 15 stearyl ether, limonene, squalene, isopropyl palmitate, tricaprylin, glyceryl stearate and combinations thereof.

In some embodiments, the at least one excipient of the topical formulation may include a first excipient and a second excipient, wherein the first excipient is isopropyl myristate and the second excipient is selected from the group consisting of isopropyl palmitate, ethyl oleate, squalene, limonene, caprylic/capric triglyceride, PPG- 15 stearyl ether, isostearyl alcohol, octyldodecanol, oleyl oleate, glyceryl monooleate, sodium lauryl sulfate, C12-15 alkyl lactate, polyglyceryl-3 oleate, cetyl alcohol, oleyl alcohol, polysorbate 60, oleic acid, diethyl sebacate, myristyl alcohol, cholesterol, sodium docusate, glyceryl ricinoleate, tricaprylin, glyceryl stearate, diethylene glycol monoethyl ether and combinations thereof. In one embodiment, the second excipient is caprylic/capric triglyceride.

In another embodiment, the at least one excipient further includes a third excipient of diethylene glycol monoethyl ether; and the topical formulation further comprises a fourth excipient selected from the group consisting of urea, sodium lauryl sulfate and poly(methacylic acid-co-methyl methacrylate) and combinations thereof. Alternatively, the second excipient may be limonene and the at least one excipient may further comprise a third excipient selected from the group consisting of isopropyl palmitate, caprylic/capric triglyceride, oleyl oleate, sodium lauryl sulfate, polyglyceryl-3 oleate, diethyl sebacate, myristyl alcohol, cholesterol, sodium docusate, cholesterol and combinations thereof. IN an embodiment, the third excipient is cholesterol.

In one embodiment, the ethanol may be present in an amount about 30-60 wt/wt%, 35-45 wt/wt%, or any range having endpoints of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 and 60 wt/wt%. Likewise, the propylene glycol may be present in an amount about 5-20 wt/wt%, 10-18 wt/wt%, or any range having endpoints of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 wt/wt%. The isopropyl myristate may be present in an amount about 10-30 wt/wt%, 20-30%, or any range having endpoints of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 wt/wt%. The limonene may be present in an amount about 0- 10 wt/wt%, 5-10 wt/wt%, or any range having endpoints of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 wt/wt%. Similarly, the cholesterol may be present in an amount about 0-10 wt/wt%, 5-10 wt/wt%, or any range having endpoints of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 wt/wt%. The active may be present in an amount from 1-20 wt/wt%, 5-15 wt/wt%, or any range having endpoints of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 wt/wt%. Finally, the at least one excipient may further comprise a fourth excipient selected from the group consisting of sodium docusate, sodium lauryl sulfate, diethyl sebacate, polyglyceryl-3 oleate and combinations thereof.

In another embodiment of the present subject matter, the topical formulation may comprise:

(i) efinaconazole,

(ii) ethanol and (iii) at least one excipient selected from the group consisting of propylene glycol, glyceryl monooleate, dimethyl isosorbide, isopropyl myristate, caprylic/capric triglyceride, diethylene glycol monoethyl ether isostearyl alcohol and combinations thereof. The topical formulation may comprise least two of the excipients, including dimethyl isosorbide. The at least one excipient may particularly include isopropyl myristate, caprylic/capric triglyceride and diethylene glycol monoethyl ether. More particularly, the isopropyl myristate may be present in an amount of about 5-10 wt/wt%, the caprylic/capric triglyceride may be present in an amount of about 5-20 wt/wt% and the diethylene glycol monoethyl ether may be present in an amount of about 5-20 wt/wt%.

Well-known carriers used to formulate other topical therapeutic compositions for administration to humans will be useful in these compositions. Examples of these components that are well known to those of skill in the art are described in The Merck Index, Thirteenth Edition, Budavari et ak, Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the“Inactive Ingredient Guide”, U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, January 1996, the contents of which are hereby incorporated by reference in their entirety. Examples of such useful pharmaceutically acceptable excipients, carriers and diluents include purified water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO, which are among those preferred for use herein.

These additional other inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990) and Remington’s Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, Pa. (1990), both of which are incorporated by reference herein in their entirety.

In one embodiment, the present compositions are formulated as a nail product, lacquer, enamel, gel paint, lotion, cream, ointment, gel, suspension, emulsion, foam, aerosol, or other pharmaceutically acceptable topical dosage form. In an embodiment, the composition is formulated as a nail product. As contemplated herein, certain specific excipients may be selected to maximize penetration enhancement of the efinaconazole active agent.

Yet another embodiment of the present subject matter includes methods for treating a subject, such as a mammal, suffering from onychomycosis, said method comprising the topical administration to said subject of a therapeutically effective amount of one or more of the topical formulations according to the above embodiments. Specifically, the topical administration is to a nail of the subject suffering from onychomycosis.

To be effective, the route of administration for the topical formulations used in the present methods and pharmaceutical compositions must readily affect the target areas. In particular, onychomycosis is known to affect toe or fingernails.

In this regard, the compositions described herein can be used in methods for temporarily or permanently reducing, inhibiting, treating, ameliorating, or prophylactically treating nail and surrounding skin fungal infections, as well as skin or tissue diseases or disorders. These methods can be achieved by topically applying the present compositions to the nail and surrounding skin of a subject, such as a mammal. In the alternative, these methods can be achieved by topically applying the present compositions to skin or tissue of a subject, such as a mammal. In this regard, the present compositions can be used in methods for preventing, inhibiting, or prophylactic ally treating a dermatophyte infection.

The present compositions are effective when applied to a subject either directly or indirectly. In an embodiment, the present compositions are directly applied to the area of nail and/or surrounding skin to be treated. In an alternative embodiment, the present compositions are indirectly applied to the area of skin to be treated. Such indirect application can occur via, for example, an article of clothing, a sock, or a bandage. In this regard, the article of clothing, sock, or bandage can be absorbent or non-absorbent.

In an embodiment, the administration of the present compositions reduces the number of fungi, preferably pathogenic fungi, on the nail and/or skin of the mammal to which it is applied. The fungi that can be acted on by the present topical compositions are selected from the group consisting of bacteria, funguses, molds, viruses, and combinations thereof.

For example, non-limiting examples of Trichophyton sp. treatable herein are those selected from the group consisting of T. rubrum, T. mentagrophytes, T. tonsurans, T. violaceum, and combinations thereof.

Several specific nail and/or skin disorders may be treated according to the present methods. Exemplary among these disorders are onychomycosis, tinea unguium and nonspecific fungal infections of the nail, and combinations thereof. Other nail and surrounding skin disorders known to those of ordinary skill in the art as effectively treatable by a topical composition are further contemplated as within the scope of the present subject matter.

Combination therapy In another embodiment, the present compositions may be used in combination with an additional (separate) dosage form to enhance their effectiveness in treating an ungual (or subungual) disorder. In this regard, the present compositions may be administered as part of a regimen additionally including any other pharmaceutical and/or pharmaceutical dosage form known in the art as effective for the treatment of an ungual, subungual and/or dermatological disorder. This additional dosage form may be applied or taken at the same time as the present compositions, i.e., concomitantly. Alternatively, one of the present compositions and the additional dosage form can be administered in the morning and the other can be administered in the evening.

In an embodiment, the present composition is administered as a combination with a separate oral composition containing an antifungal agent.

Dosage

Appropriate dosage levels for the efinaconazole, contemplated in the compositions and methods herein are well known to those of ordinary skill in the art and are selected to maximize the treatment of fungal skin infections and the above-mentioned nail and skin conditions. Dosage levels on the order of about 0.001 mg to about 5,000 mg per kilogram body weight of the efinaconazole are known to be useful in the treatment of the diseases, disorders, and conditions contemplated herein. Typically, this effective amount of the efinaconazole will generally comprise from about 0.001 mg to about 100 mg per kilogram of subject body weight per day. Moreover, it will be understood that this dosage of ingredients can be administered in a single or multiple dosage units to provide the desired therapeutic effect. It is understood, however, that a specific dose level for any particular subject will vary depending upon a variety of factors, including the age, body weight, general health, sex and diet of the subject; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; and the form of administration. One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation .

The following examples illustrate the above embodiments without limitation. All amounts are given by percent by weight based upon 100 percent by weight of total composition, unless noted otherwise.

Example 1

Exemplary topical formulations

Topical formulations were prepared as listed in Tables 1-29. All formulations prepared are free-flowing homogeneous solutions. Formulations with Eudragit (an exemplary neutral polymer) present are free-flowing, but are thicker in viscosity than the other solution formulations. These formulations are all single-phase homogeneous solutions and were systematically prepared by adding all the ingredients together, including the Active, and sonicating until all the ingredients were dissolved and fully dispersed.

Tables 1-21 outline the formulations tested on shed snake skin focused on delivering equivalent or more efinaconazole into and through the nail as compared to existing topical efinaconazole product, Jublia® (alternatively referred to as the standard). Tables 22-29 outline the results of formulations tested on human cadaver nails for both the enhanced delivery formulations and for the equivalent delivery formulations in comparison to Jublia®. All excipients in the exemplary formulations are listed in the FDA Inactive Ingredient Database (“HD”).

Table 1: Formulations EfinFl -EfinF7 tested in a permeation study across snake skin.

The results in table 1 show flux testing of a spectrum of formulations EfinFl-EfinF7.

Table 2: Formulations EfinFl l-EfmF20 prepared and tested in a permeation study across snake skin.

The results in table 2 show flux testing of a spectrum of formulations emphasizing pure solvents with 1% efinaconazole at two time points.

Table 3: Formulations EfinFl l-EfmF19 prepared and tested in a permeation study across snake skin; sat

=saturation.

Table 3 shows results of testing pure solvents with efinaconazole at saturation limits. Transcutol P (Efinl l) delivered the most efinaconazole.

Table 4: Formulations EfinF21 -EfmF29 prepared and tested in a permeation study across snake skin.

Table 4 shows results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle with Eudragit NE 30D. Octyldodecanol (Efin29) was noted as a penetration enhancer. Table 5: Formulations EfmF30-EfmF38 prepared and tested in a permeation study across snake skin.

Table 5 shows results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle with Eudragit NE 30D. Oleic acid (EfinF31) enhanced delivery over the chassis (Efin30), but performance was less than Jublia®.

Table 6: Formulations EfinF39-EfmF47 prepared and tested in a permeation study across snake skin.

Table 6 includes results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle with Eudragit NE 30D. Urea (EfinF40) enhanced delivery over the chassis (Efin39).

Table 7: Formulations EfinF48-EfmF56 prepared and tested in a permeation study across snake skin.

Table 7 includes results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle. Isopropyl palmitate (EfinF53) was the penetration enhancer of most interest.

Table 8: Formulations EfinF57-EfmF65 prepared and tested in a permeation study across snake skin.

Table 8 includes results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle. Dipropylene glycol (EfinF59) was the penetration enhancer of most interest in this study.

Table 9: Formulations EfinF66-EfmF76 prepared and tested in a permeation study across snake skin.

Table 9 includes results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle. Ethyl oleate (EfinF71) and isopropyl myristate (EfinF73) were the two stand outs in this study.

Table 10: Formulations EfmF66-EfinF86 prepared and tested in a permeation study across snake skin.

Table 10 includes results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle. A combination of cholesterol with isopropyl myristate (EfinF85) performed the best in this study. Table 11: Formulations EfinF66 and EfinF87-EfinF94 prepared and tested in a permeation study across snake skin.

Table 11 includes results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle. Some enhancement was seen over the EfinF66 base formulation.

Table 12: Formulations EfinF66 and EfinF95-EfinF104 prepared and tested in a permeation study across snake skin.

Table 12 includes results of snake skin screening of an exemplary formulation with an ethanol and propylene glycol vehicle. Isostearyl alcohol (EfinF97) and squalene (EfinF104) performed the best of these formulations in the exemplary study at improving efinaconazole penetration.

Table 13: Formulations EfinF66 and EfinF105-EfinFl 14 prepared and tested in a permeation study across snake skin.

Table 13 includes results of multiplexed snake skin studies of exemplary formulations with an ethanol and propylene glycol vehicle. Isopropyl palmitate + isopropyl myristate (EfinF106), ethyl oleate + isopropyl myristate (EfinF108) and isopropyl palmitate + ethyl oleate (EfinFl 11) demonstrated particularly good enhancement.

Table 14: Formulations EfinF66 and EfinFl 15-EfinF124 prepared and tested in a permeation study across snake skin.

Table 14 includes results of multiplexed snake skin of exemplary formulations with an ethanol, propylene glycol and isopropyl myristate vehicle (EfinFl 15). Isopropyl myristate was added to the base vehicle due to its repeated functionality in increasing flux. Increased enhancement was seen with the addition of limonene (EfinFl 19) and oleyl oleate

(EfinFl 24).

Table 15: Formulations EfinFl 15 and EfmF125-EfinF134 prepared and tested in a permeation study across snake skin.

Table 15 includes results of multiplexed snake skin penetration of exemplary formulations with an ethanol, propylene glycol and isopropyl myristate vehicle (EfinF115).

Table 16: Formulations EncuFl 15 and EncuF135-EncuF139 prepared and tested in a permeation study across snake skin.

Table 16 includes results of multiplexed snake skin penetration of exemplary formulations with an ethanol, propylene glycol and isopropyl myristate vehicle (EfinFl 15). Increased penetration enhancement was seen with the addition of cholesterol (EfinF135) and tricaprylin (EfinF138).

Table 17: Formulations EfinFl 15, EfinFl 19 and EfmF140-EfmF149 prepared and tested in a permeation study across snake skin.

Table 17 includes results of multiplexed snake skin penetration of an exemplary formulation with an ethanol, propylene glycol, isopropyl myristate and limonene vehicle (EfinFl 19). Increased penetration enhancement was seen with the addition of cholesterol

(EfinFl 46) and sodium lauryl sulfate (EfinFl 43).

Table 18: Formulations EfinFl 19 and EfmF150-EfinF156 prepared and tested in a permeation study across snake skin.

Table 18 includes results of multiplexed snake skin penetration of exemplary formulations with an ethanol, propylene glycol, isopropyl myristate, limonene and cholesterol vehicle (EfinF150). A small additional penetration enhancement was seen with the inclusion of polyglyceryl-3-oleate (EfinF155).

Table 19: Formulations EncuJubFl-EncuJubF6 prepared and tested in a permeation study across snake skin.

Table 19 includes shows snake skin penetration study results of select formulations EncuJubFl-EncuJubF6 compared to Jublia®. Isopropyl myristate (present in EncuJubF6) was identified as a penetration enhancer.

Table 20: Formulations EncuJubF7-EncuJubF14 prepared and tested in a permeation study across snake skin.

Table 20 includes snake skin penetration study results of select formulations EncuJubF7-EncuJubF14 compared to Jublia®. Cyclomethicone (which was present in EncuJubFl - F6) is absent from these formulations.

Table 21: Formulations EncuJubF16-EncuJubF27 prepared and tested in a permeation study across snake skin.

Table 21 includes snake skin penetration results of select formulations EncuJubF16-EncuJubF27 compared to Jublia®. Formulations tested comprised the following ingredients: ethanol, propylene glycol, Capmul GMO, isopropyl myristate, Crodamol GTCC, Transcutol P and isostearyl alcohol.

Table 22: Results of EncuJubF24 prepared and tested in a permeation study across human cadaver nails.

Table 23: Results of EncuJubF26 prepared and tested in a permeation study across human cadaver nails.

Table 24: Results of EfinF143 and EfmF146 prepared and tested in a permeation study across human cadaver nails.

Table 24 includes ungual and transungual penetration results of human nail screening of select formulations compared to Jublia®.

Table 25: Formulation EfinF165 prepared and tested in a permeation study across human cadaver nails.

Table 26: Formulation EfinF166 prepared and tested in a permeation study across human cadaver nails.

Table 27: Formulation EncuJubF167 prepared and tested in a permeation study across human cadaver nails.

Tables 25-27 show transungual penetration results of human nail screening of select formulations compared to Jublia®. EfinF165 showed an approximate 20% increase in delivery into the nail and statistically equivalent flux across the nail relative to Jublia®. EfinF165 was altered with the addition of Eudragit S100 to form formulation EfinF166. As shown in Figs. 3A-3B, EfinF166 showed an approximate 3X increase in delivery of efinaconazole into the nail and statistically equivalent flux across the nail. The film forming polymer appears to significantly increase delivery of the base formulation when applied on human cadaver nails for multiple days. EfinF166 altered with the addition of Urea forms formulation EfinF167. As shown in Figs. 4A-4B, EfinF167 showed an approximate 2.5X increased in delivery into the nail and approximately 2X increased flux across the nail.

Table 28: Formulation EncuJubF45 prepared and tested in a permeation study across human cadaver nails.

Table 29: Formulation EncuJubF46 prepared and tested in a permeation study across human cadaver nails.

Example 2

Efinaconazole transdermal and transungual delivery by exemplary topical formulations Two types of assays were performed to evaluate transungual or transdermal delivery of efinaconazole by the exemplary topical formulations relative to Jublia®.

Snake skin assay: Experimentally prepared topical formulations were tested using shed snake skin - a keratinized substrate which enables rapid screening of transungual formulations.

Human Nail flux studies : Select experimentally prepared topical formulations were tested for permeation across human cadaver nails.

Delivered concentrations of efinaconazole across a snake skin substrate for the exemplary topical formulations detailed in comparison to Jublia® are shown in Tables 1-21 as the delivered concentration ± standard error according to the snake skin assay.

Based on the results of flux studies across snake skin, the enhancement ratio (“ER”) of the formulations was calculation by dividing the flux of the formulation with the excipient in question by the flux of the base vehicle. These ER values are shown in Tables 30

33.

Table 30: Enhancement Ratio of adding an excipient to a base ethanol/propylene glycol chassis.

Table 31: Enhancement Ratio of adding an excipient to a base ethanol/propylene glycol/Eudragit NE 30D chassis.

Table 32: Enhancement Ratio of adding an excipient to a base ethanol/propylene glycol/isopropyl myristate chassis.

Table 33: Enhancement Ratio of adding an excipient to a base ethanol/propylene glycol/isopropyl

myristate/limonene chassis.

Results of further studies testing exemplary topical formulations further tested on human cadaver nails versus Jublia®. The results of these studies are shown in Tables 22-29, with particular examples further illustrated in Figs. 1-2.

The density, spreadability and surface tension of select equivalent formulations were also determined. These measurements were compared to in-house measurements for Jublia® for these physical characteristics. Results are shown in Tables 34 and 35.

Table 34: Measurements of density and surface tension for prospective equivalent formulations. The 24 hr flux % values are calculated versus Jublia® based on the results of the permeation study across snake skin.

Table 35: Spreadability of prospective topical formulations; diameter spread in cm.

Example 3

Experimental details of Snake Skin and Human Nail Flux assays

Two types of assays were performed to evaluate transungual or periungual delivery of efinaconazole in the exemplary topical formulations.

Human Nail flux assay: Select experimentally prepared topical formulations were tested for permeation across human cadaver nails.

Material and Equipment used in all assays:

The following equipment and materials were used during the course of the permeation studies:

2

1.) Diffusion Cells. ~60 diffusion cells with 3.3ml receptor volume and a 0.55cm receptor fluid exposure surface area were used.

2.) Nail adapters. Teflon nail adapters with a 0.5cm diameter orifice were mounted onto diffusion cells for cadaver nail studies 3.) Stirring Dry Block Heaters. Reacti-Therm #18823 stirring dry block heaters were used to maintain the receptor fluid at 32 ± 0.5°C with constant stirring throughout the studies.

4.) The analysis was carried out with an Agilent 1200 HPLC unit with a Waters

MS/MS detector, ID#: (TM-EQ-0890 or an Agilent 1100 HPLC (TM-EQ-089).

5.) Analytical balance. Ohaus AV3102C, AV213C and EX224 models.

Table 36: Materials used

Receptor Fluid Preparation: The receptor fluid (the“Receptor Fluid”) consisted of phosphate buffered saline (“PBS”), sourced from Quality Biologicals with 0.01wt% NaN3 added as a preservative and 2 wt% h y dro x y p o p y 1 - b - c y c 1 ode x t i n (“HPBCD”). The PBS was supplied as a 10X concentrate and was diluted to IX concentration prior to the study by volumetrically adding distilled water at a ratio of 9: 1 by volume. The HPBCD was added as a solubilizing agent for efinaconazole in the receptor fluid. With the addition of HPBCD, the solubility of efinaconazole in the Receptor Fluid was measured to be -1.65 mg/ml and was determined to be sufficient to maintain sink conditions throughout the study. After mixing, the Receptor Fluid was degassed and filtered through a 0.2pm membrane under vacuum; the Receptor Fluid, so filtered, was stirred for an additional 20 minutes under vacuum.

Experimental Protocols:

Snake skin assay protocol:

Shed Snake skin was prepared as follows :

1. The shed snake skin was soaked in a room temperature water bath containing ~ 1 liter of distilled water for 30 minutes.

2. The snake skin was removed from the water bath, tapped dry, then sprayed with fresh distilled water to rinse off any remaining debris.

3. The snake skin was gently stretched to inspect for visible damage. A piece of the skin large enough to accommodate the number of cells for the study was then cut from an undamaged portion of the skin

4. The cut skin piece was placed on a paper towel, stretched and reexamined for any damage. Any damaged area was removed. The skin was then air dried overnight

5. The skin was inspected the following day for any holes; these areas were avoided.

6. The dried skin was then cut into 1.8 x 1.8cm square skin pieces - one for each formulation tested.

2

Glass FDCs with a 3.3ml receiver volume and 0.55 cm diffusional area were prepared as follows:

1. Receptor wells were filled with degassed Receptor Fluid using a pipette. 2. A 6 mm by 3 mm diameter Teflon coated magnetic stir bar was introduced into each receptor well.

3. A skin piece was centered on each receptor compartment.

4. The donor and receptor well compartments were aligned and clamped together with a pinch clamp, ensuring that the skin pieces were centered between both donor and receptor wells.

5. Additional Receptor Fluid was added as necessary. Air bubbles in the receptor well, if any, were removed by tilting the FDC assembly such that the air escapes along the sample port. Receptor wells were filled with approximately 3.3 ml of Receptor Fluid.

6. The assembled FDCs were placed into stirring dry block heaters which were preheated to 32°C. The Receptor Fluid was continuously agitated via the magnetic stir bar.

7. After 10 minutes, the surface of the skin in each FDC was examined. If the snake skin appeared wet or showed signs of leakage the cell was discarded.

After the cells were assembled, a sample of the exemplary formulation, positive control or standard was then applied to the skin. A one-time dosing regimen was used in which the sample were applied in 10 pi doses using a Nichryo positive displacement pipettor. Once the sample was applied to the snake skin, it was gently spread across the surface using the blunt end of a glass rod. Assuming the formulations were prepared at a default 10 wt/wt% efinaconazole and had a specific gravity of ~ 0.85 (the target density) the approximate efinaconazole dose applied per cell was 1545.5 pg/cm . Each sample was applied in a minimum of five-fold replicates. Using a graduated Hamilton type injector syringe, a 300 mΐ aliquot was extracted from the sampling port of each FDC at the desired timepoints (default of 24 hours). If there were multiple timepoints, fresh Receptor Fluid was added to each receptor well to replace the volume of fluid extracted. Each extracted aliquot was introduced into a well in a 96-well plate.

Extractions were stored in a refrigerator at 2-8°C prior to HPLC analysis. Extractions were typically analyzed within 24 hours of collection and were stored a maximum of 1 week prior to analysis.

Human Nail flux study protocol:

Human cadaver nails were prepared as follows:

1. Human cadaver nails were allowed to equilibrate to room temperature.

2. The human cadaver nails were submerged in PBS for 15 minutes.

3. Any excess tissue from the nails was removed using forceps. The nails were then rinsed off with PBS and tapped dry.

Glass FDCs with a 3.3ml receiver volume and 0.20 cm2 diffusional area were assembled as follows:

1. The receptor wells were filled with degassed Receptor Fluid using a pipette.

2. A 6 mm by 3 mm diameter Teflon coated magnetic stir bar was introduced into each receptor well.

3. The nails were rested on a silicon gasket, with the gasket in turn centered on a nail adapter receiving plate. All pieces were then sandwiched together by placing the nail adapter donor plate on top of the nail. The pieces were held together by applying thin beads of a cyanoacrylate glue between each layer. 4. After the nail adapter was assembled and glued, the pieces were pressed together with pressure for 5 minutes to ensure the gluing process was complete.

5. The nail adapter assembly was then glued to the receptor chamber of the diffusion cell using a cyanoacrylate glue. This consisted of applying a thin bead of glue to the receptor chamber flange and pressing the nail adapter assembly on the receptor chamber for 5 minutes.

6. After the entire cell was assembled, an aliquot of PBS was then added to the donor chamber. The cell was then allowed to sit undisturbed for 24 hours. After 24 hours, the cell was checked to see if there was any leakage. Cells that showed leakage were discarded.

7. The remaining cells were then divided equally between the formulations to be tested. Additional Receptor Fluid was added if necessary. Air bubbles in the receptor well, if any, was removed by tilting the FDC assembly such that the air escaped along the sample port. Receptor wells were filled with approximately 3.3 ml of Receptor Fluid.

8. The assembled FDCs were then placed into stirring dry block heaters which were preheated to 32°C. The Receptor Fluid was continuously agitated via the magnetic stir bars during the course of the study.

After the cells were assembled, a sample of the exemplary formulation, positive control or standard was then applied to the skin. A multi-day dosing regimen was used in which the samples were applied in 5 pi doses using a Nichryo positive displacement pipettor every day. From day 2 onward, the surface of the nail was first washed with PBS and wiped clean with a cotton swab prior to applying the next 5 mΐ dose. Assuming the formulations were prepared at a default 10 wt/wt% efinaconazole and had a specific gravity of ~ 0.85 (the target density) the approximate efinaconazole dose applied per cell per day was 2165 pg/cm . Each sample was applied in a minimum of three-fold replicates.

Using a graduated Hamilton type injector syringe, a 300 pi aliquot was extracted from the sampling port of each FDC at the 1, 3, 5, 8 and 12 days. At each timepoint, fresh Receptor Fluid was added to each receptor well to replace the volume of fluid extracted. Each extracted aliquot was introduced into a well in a 96-well plate.

Analytical Methods:

The samples extracted from receptor wells for each study were analyzed using HPLC for the snake skin assays and an alternative LC/MS method for the human cadaver nail flux studies. An outline of the HPLC method including the mobile phases, column, and chromatographic conditions are shown below.

Preparation of Mobile Phases:

Mobile Phase A: Mobile Phase A was prepared by transferring 1ml of phosphoric acid (Mallinckrodt: 2788) into a 2L media bottle. 1L of HPLC grade water (Fisher: W6-4) was then measured in a volumetric cylinder and the contents transferred into the 2L media bottle. The mixture in the media bottle was shaken until the contents were fully mixed. Mobile Phase A was stored for less than one week during the course of the analysis Mobile Phase B: Mobile Phase B consisted of LC-MS grade acetonitrile (Fisher:

A955-4). The acetonitrile was added directly to a 2L media bottle. Mobile Phase B was stored for less than two weeks during the course of the analysis

Preparation of Stock Solution and Calibration Standards:

Calibration standards were prepared for efinaconazole. A“Stock Solution” was prepared by first weighing 4mg of efinaconazole with an analytical balance in a glass vial. The vial was then tared on the balance and 4ml of dimethyl sulfoxide (“DMSO”) was then introduced in to the glass vial with a pipettor. The vial was reweighed. The vial was then removed from the analytical balance and capped. The capped vial was vortexed and sonicated using an ultrasonication bath until the efinaconazole was fully dissolved.

The above procedure was used to make a lmg/ml Stock Solution for the Active. Further calibration standards containing the Active were prepared through serial dilution. In each serial dilution, 300pl of the preceding calibration standard was diluted with 1200 mΐ of the DMSO. Seven calibration standards were prepared for the Active. The Active concentration in each of the calibration standards is shown in Table 37 below.

Table 37: Calibration standards and the corresponding concentration of the Active.

Table 38: Chromatographic parameters for efinaconazole detection

Concentration Calculations

Extractions were analyzed via HPLC using Chemstation software. The AUCs of the efinaconazole were recorded and converted to mg/ml values using a calibration curve developed from the calibration standards’ AUC values and known concentration values. These concentrations were then multiplied by the receptor volume (3.3 mL), or nail extraction volume (3 ml) and divided by the surface area of the shed snake skin or nail exposed to the receptor fluid (0.55 cm or 0.2 cm , respectively) for an end cumulative amount in pg/cm . For studies with multiple receptor fluid timepoints, a correction factor was multiplied by the concentrations to take into account the dilution effect.

The results of transdermal flux (in the case of shed snake skin studies), or transungual flux and nail extraction concentrations (in the case of human cadaver nail studies) were recorded on a cell by cell basis. For all the studies, the data was analyzed by first running a Dixon’s Qtest with 95% confidence on the dataset and removing outliers identified by this statistical tool.

It is to be understood that the topical formulation is not limited to the specific embodiments described above, but encompasses any and all embodiments within the scope of the generic language of the following claims enabled by the embodiments described herein, or otherwise shown in the drawings or described above in terms sufficient to enable one of ordinary skill in the art to make and use the claimed subject matter.

Claims

CLAIMS We claim:

1. A topical formulation comprising:

(i) efinaconazole,

(ii) a monohydric alcohol,

(iii) a glycol and

(iv) at least one excipient selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycol 300 (PEG-300), diisopropyl adipate, lauric diethanolamide, hexylene glycol, octyldodecanol, oleic acid, PEG-7 methyl ether, polypropylene glycol, laureth-4, lauryl lactate, sodium lauryl sulfate, dipropylene glycol, glyceryl monooleate, cocamide diethanolamine (DEA), urea, oleyl alcohol, propylene glycol monolaurate, 2-amino-2methyl-l -propanol, myristyl alcohol, ethyl oleate, isostearic acid, isopropyl myristate, diethyl sebacate, castor oil, caprylic/capric triglyceride, lactic acid, diethylene glycol, C12-15 alkyl lactate, benzyl alcohol, levulinic acid, polysorbate 80, propylene carbonate, oleyl oleate, cholesterol, lecithin, cetyl alcohol, dexpenthanol, polyglyceryl-3 oleate, polysorbate 20, polysorbate 60, polysorbate 40, glyceryl riconoleate, sorbitan monolaurate, dimethyl sulfoxide, dimethyl isosorbide, isostearyl alcohol, olive oil, steareth-20, POLYPROPYLENE GLYCOL (15) (PPG- 15) stearyl ether, limonene, lanolin, alpha-terpineol, squalene, ethyl lactate, isopropyl palmitate, ammonium acetate, tricaprylin, PEG 40 castor oil, monolaurin, sodium docusate, glyceryl ricinoleate, glyceryl stearate methyl salicylate and combinations thereof.

2. A topical formulation comprising:

(i) efinaconazole,

(ii) ethanol,

(iii) propylene glycol and

(iv) at least one excipient selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycol 300 (PEG-300), diisopropyl adipate, lauric diethanolamide, hexylene glycol, octyldodecanol, oleic acid, PEG-7 methyl ether, polypropylene glycol, laureth-4, lauryl lactate, sodium lauryl sulfate, dipropylene glycol, glyceryl monooleate, cocamide diethanolamine (DEA), urea, oleyl alcohol, propylene glycol monolaurate, 2-amino-2methyl-l -propanol, myristyl alcohol, ethyl oleate, isostearic acid, isopropyl myristate, diethyl sebacate, castor oil, caprylic/capric triglyceride, lactic acid, diethylene glycol, C12-15 alkyl lactate, benzyl alcohol, levulinic acid, polysorbate 80, propylene carbonate, oleyl oleate, cholesterol, lecithin, cetyl alcohol, dexpenthanol, polyglyceryl-3 oleate, polysorbate 20, polysorbate 60, polysorbate 40, glyceryl riconoleate, sorbitan monolaurate, dimethyl sulfoxide, dimethyl isosorbide, isostearyl alcohol, olive oil, steareth-20, PPG- 15 stearyl ether, limonene, lanolin, alpha-terpineol, squalene, ethyl lactate, isopropyl palmitate, ammonium acetate, tricaprylin, PEG 40 castor oil, monolaurin, sodium docusate, glyceryl ricinoleate, glyceryl stearate methyl salicylate and combinations thereof.

3. The topical formulation of claim 2, wherein the at least one excipient is selected from the group consisting of diethylene glycol monoethyl ether, PEG-300, diisopropyl adipate, lauric diethanolamide, hexylene glycol, octyldodecanol, oleic acid, PEG-7 methyl ether, polypropylene glycol, laureth-4, lauryl lactate, sodium lauryl sulfate, glyceryl monooleate, cocamide DEA, urea, lactic acid, diethylene glycol, Cl 2- 15 alkyl lactate, benzyl alcohol, levulinic acid, polysorbate 80, propylene carbonate and combinations thereof; and

the topical formulation further comprises:

(v) a neutral copolymer selected from a group consisting of poly(ethyl acrylate-co- methyl methacrylate), poly(methacylic acid-co -methyl methacrylate) and combinations thereof.

4. The topical formulation of claim 2 wherein the at least one excipient is selected from the group consisting of octyldodecanol, oleic acid, sodium lauryl sulfate, dipropylene glycol, oleyl alcohol, myristyl alcohol, ethyl oleate, isostearic acid, isopropyl myristate, diethyl sebacate, caprylic/capric triglyceride, 02-15 alkyl lactate, oleyl oleate, cholesterol combined with isopropyl myristate, cetyl alcohol, polyglyceryl-3 oleate, polysorbate 40, isostearyl alcohol, olive oil, PPG- 15 stearyl ether, limonene, squalene, isopropyl palmitate, tricaprylin, glyceryl stearate and combinations thereof.

5. The topical formulation of claim 2, wherein the at least one excipient includes a first excipient and a second excipient, and wherein

the first excipient is isopropyl myristate and the second excipient is selected from the group consisting of isopropyl palmitate, ethyl oleate, squalene, limonene, caprylic/capric triglyceride, PPG- 15 stearyl ether, isostearyl alcohol, octyldodecanol, oleyl oleate, glyceryl monooleate, sodium lauryl sulfate, C12-15 alkyl lactate, polyglyceryl-3 oleate, cetyl alcohol, oleyl alcohol, polysorbate 60, oleic acid, diethyl sebacate, myristyl alcohol, cholesterol, sodium docusate, glyceryl ricinoleate, tricaprylin, glyceryl stearate, diethylene glycol monoethyl ether and combinations thereof.

6. The topical formulation of claim 4 wherein the second excipient is caprylic/capric triglyceride.

7. The topical formulation of claim 6 wherein the at least one excipient further includes a third excipient of diethylene glycol monoethyl ether; and the topical formulation further comprises (v) a fourth excipient selected from the group consisting of urea, sodium lauryl sulfate and poly(methacylic acid-co-methyl methacrylate) and combinations thereof.

8. The topical formulation of claim 5 wherein the second excipient is limonene and the at least one excipient further comprises a third excipient, wherein

(v) the third excipient is selected from the group consisting of isopropyl palmitate, caprylic/capric triglyceride, oleyl oleate, sodium lauryl sulfate, polyglyceryl-3 oleate, diethyl sebacate, myristyl alcohol, cholesterol, sodium docusate, cholesterol and combinations thereof.

9. The topical formulation of claim 8, wherein the third excipient is cholesterol.

10. The topical formulation of claim 9, wherein the ethanol is present in an amount about 30- 60 wt/wt%, the propylene glycol is present in an amount about 5-20 wt/wt%, the isopropyl myristate is present in an amount about 10-30 wt/wt%, the limonene is present in an amount about 0-10 wt/wt% and the cholesterol is present in an amount about 0-10 wt/wt%.

11. The topical formulation of claim 9, wherein the at least one excipient further comprises a fourth excipient, wherein

(vi) the fourth excipient is selected from the group consisting of sodium docusate, sodium lauryl sulfate, diethyl sebacate, polyglyceryl-3 oleate and combinations thereof.

12. A topical formulation comprising:

(i) efinaconazole,

(ii) ethanol and

(iii) at least one excipient selected from the group consisting of propylene glycol, glyceryl monooleate, dimethyl isosorbide, isopropyl myristate, caprylic/capric triglyceride, diethylene glycol monoethyl ether, isostearyl alcohol and combinations thereof.

13. The topical formulation of claim 12, comprising at least two of the excipients, including dimethyl isosorbide.

14. The topical formulation of claim 12, wherein the at least one excipient includes isopropyl myristate, caprylic/capric triglyceride and diethylene glycol monoethyl ether.

15. The topical formulation of claim 14, wherein the isopropyl myristate is present in an amount of about 5-10 wt/wt%, the caprylic/capric triglyceride is present in an amount of about 5-20 wt/wt% and the diethylene glycol monoethyl ether is present in an amount of about 5-20 wt/wt%.

16. A method for treating a subject suffering from onychomycosis, said method comprising the topical administration to said subject of a therapeutically effective amount of the topical formulation of claim 2.

17. The method of claim 16, wherein the topical administration is to a nail of the subject suffering from onychomycosis.

18. A method for treating a subject suffering from onychomycosis, said method comprising the topical administration to said subject of a therapeutically effective amount of the topical formulation of claim 12.

19. The method of claim 18, wherein the topical administration is to a nail of the subject suffering from onychomycosis.