WO2011014850A2 - Topical eutectic-based formulations - Google Patents

Abstract

The present invention provides topical compositions, methods of preparation, and methods of treatment involving the incorporation of a eutectic melt into a formulation. The improved formulation can enhance permeability and bioavailability. In certain specific embodiments, the invention provides an anti-fungal pharmaceutical composition for topical application comprising an anti-fungal agent, at least one eutectic agent, and a pharmaceutically acceptable low-boiling solvent.

Description

TOPICAL EUTECTIC-BASED FORMULATIONS

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61/230,473, filed July 31, 2009, the disclosure of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] A eutectic temperature is a temperature at which a mixture of two or more substances can exist in equilibrium with the same proportional composition in both liquid and solid phases. Figure 1 illustrates the behavior of a two-component system containing substances A and B that form a eutectic mixture. A eutectic point is a point on the phase diagram describing a composition and temperature at which all of the mixture's components will melt or (assuming no supercooling or hysteresis) crystallize simultaneously from the molten state, hi Figure 1, the eutectic point describes a composition containing 50% B, but it can occur at another percentage depending on the compounds involved.

[0003] The formation of a eutectic mixture is often undesired, but it can be a useful property of drug combinations or formulations. Although formulations comprising eutectic mixtures have been viewed as unstable, the melting point depression of a eutectic mixture can be accompanied by an increase in the mixture's dermal solubility and transdermal permeation, which can increase a drug's bioavailability. See, e.g., Barry, B. W. Eur. J.

Pharm. Sd. 2001, 14, 101-114; Benson, H. A. E. Curr. Drug Del. 2005, 2, 23-33; and U.S. Patent No. 6,368,618.

[0004] One example of using eutectic mixtures to enhance topical drug delivery is the eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA). See U.S. Patent No. 4,529,601. EMLA's lidocaine-prilocaine binary eutectic system is said to produce high thermodynamic activity and a high driving force for transdermal permeation of lidocaine.

[0005] Although recently eutectic mixtures and solutions prepared from eutectic mixtures have been employed in transdermal formulations, they have been rarely if at all used in the delivery of drugs to or through the nail. In certain aspects, an object of this invention is to improve the transungual delivery of a drug, particularly an anti-fungal agent, and to increase its retention in the nail, which is frequently suggested to be correlated with drug

effectiveness.

[0006] Onychomycosis is a fungal infection that affects the toenails (-80% of cases) and the fingernails (-20% of cases). The most common causative pathogens of onychomycosis are Trichophyton rubrum and Trichophyton interdigitale (also known as Trichophyton mentagrophytes). These pathogens represent the cause of roughly 70% and 20% of onychomycosis cases, respectively. Other causative agents include Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Trichophyton tonsurans, Trichophyton soudanense, Trichophyton verrucosum, Candida and Neoscytalidium (also known as Scytalidium), Scopulariopsis, and Aspergillus. The infection may involve any component of the nail unit, including the nail matrix, the nail bed or the nail plate. See Blumberg, M. "Onychomycosis," http://www.emedicine.com/derm/topic300.htm, accessed July 7, 2008.

[0007] Distal lateral subungual onychomycosis is the most common form of infection, hi this variant, the infection begins around the edges of the nail and can cause inflammation in these areas while concurrently spreading to the underside of the nail. The result is

disfigurement of the nail and potentially some pain, discomfort and transmission of infection to other nails. If left untreated, onychomycosis can result in permanent nail deformity.

[0008] Onychomycosis is a very difficult condition to cure. Today, it is commonly treated with an antifungal medication that is delivered to the systemic circulation, in spite of the fact that the onychomycosis infection is localized to the nail structure. This can result in serious and unwanted side effects, including gastrointestinal symptoms, liver abnormalities, rashes, taste disturbances, hypertension, and drug-drug interactions with a wide range of other medications. Topical drugs for the treatment of onychomycosis are available. However, they are not very effective in the treatment of the disease. For example, Penlac^® (ciclopirox 8% solution) is a topical treatment which has been approved in the United States for the treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum. However, the drug is not very effective in the treatment of onychomycosis, providing complete cure (defined as clear nail and negative mycology) in less than 10% of the intent-to-treat population in the Phase III studies used to obtain approval in the United States. Further, relapse appears to be a significant issue with this drug. See Casciano J. et al. Manag. Care 2003, 12(3), 47-54;

Tosti, A. et al. Dermatology 1998, 197(2), 162-166; Sigurgeirsson, B. et al. Arch. Dermatol. 2002, 138(3), 353-7; and Penlac^® prescribing information, http://products.sanofi- aventis.us/penlac/penlaαhtml, accessed May 19, 2008.

[0009] One of the leading anti-fungal agents for oral treatment of onychomycosis is the drug terbinafine. Terbinafine has also been approved by the US Food and Drug

Administration in cream, gel, solution and spray doseage forms for use in topical treatment of fungal infections. However, these products are not approved for the treatment of

onychomycosis. For example, terbinafine hydrochloride cream 1% (tradename Lamisil^®) is available as an over-the-counter product, and the label specifically notes that the product should not be used on nails. (For package information, see

http://www.accessdata.fda.gov/drugsatfda docs/label/2007/020980s0051bl.pdf, accessed July 30, 2010.)

[0010] There is a strong need for a new topical drug composition that can provide good efficacy in treating onychomycosis while avoiding the systemic side effects of oral treatments. The present invention satisfies these and other needs.

BRIEF SUMMARY OF THE INVENTION

[0011] The present invention provides topical compositions, methods for preparation, and methods of treatment involving the incorporation of a eutectic melt into a formulation. The formulations enhance permeability and bioavailability, and they are useful in ungual or dermal applications.

[0012] As such, in one embodiment, the present invention provides an anti-fungal

pharmaceutical composition for topical application. The pharmaceutical composition comprises, consists essentially of, or consists of an anti-fungal agent, a eutectic agent, and an optional pharmaceutically acceptable low-boiling solvent. The anti-fungal agent and the eutectic agent form a eutectic melt, which enhances the delivery of the anti-fungal agent or permits higher concentrations of the anti-fungal agent to be incorporated into the

pharmaceutical composition. In certain instances, the composition is substantially anhydrous.

[0013] In another embodiment, the present invention provides an alternative anti-fungal pharmaceutical composition for topical application. The pharmaceutical composition comprises, consists essentially of, or consists of an anti-fungal agent, a eutectic agent, a second eutectic agent, and a pharmaceutically acceptable low-boiling solvent. The eutectic agent and the second eutectic agent form a eutectic melt, which enhances the delivery of the anti-fungal agent or permits higher concentrations of the anti-fungal agent to be incorporated into the pharmaceutical composition. In certain instances, the composition is substantially anhydrous.

[0014] In yet another embodiment, the present invention provides a method for preparing a pharmaceutical composition for topical use, the method comprising, consisting essentially of, or consisting of the steps of 1) adding an anti-fungal agent to a eutectic agent to form an admixture and 2) heating the admixture until it is substantially homogeneous. When mixed and heated, the anti-fungal agent and the eutectic agent form a eutectic melt.

[0015] hi still yet another embodiment, the present invention provides an alternative method for preparing a pharmaceutical composition for topical use, the method comprising, consisting essentially of, or consisting of the steps of 1) forming a eutectic melt by admixing two or more eutectic agents and heating the admixture until it is substantially homogeneous; 2) adding an anti-fungal agent to the eutectic melt to form a further admixture and 3) heating the further admixture until it is substantially homogeneous.

[0016] hi another embodiment, the present invention provides a method for treating a fungal infection in a subject, the method comprising, consisting essentially of, or consisting of the step of applying a topical anti-fungal composition to a subject to treat the fungal infection. The topical anti-fungal composition comprises an anti-fungal agent, a eutectic agent, and an optional pharmaceutically acceptable low-boiling solvent. The anti-fungal agent and the eutectic agent form a eutectic melt, which enhances the permeability of the anti-fungal agent. [0017] hi yet another embodiment, the present invention provides an alternative method for treating a fungal infection in a subject, the method comprising, consisting essentially of, or consisting of the step of applying a topical anti-fungal composition to a subject to treat the fungal infection. The topical anti-fungal composition comprises an anti-fungal agent, a eutectic agent, a second eutectic agent, and a pharmaceutically acceptable low-boiling solvent. The eutectic agent and the second eutectic agent form a eutectic melt, which enhances the permeability of the anti-fungal agent.

[0018] hi certain aspects of these embodiments, an anti-fungal agent and a eutectic agent form a eutectic melt, and as a whole, the pharmaceutical composition that comprises them is substantially a eutectic melt, hi an alternative and preferred aspect, although the anti-fungal agent and the eutectic agent form a eutectic melt, as a whole, the pharmaceutical composition that comprises them is not a eutectic melt. [0019] In certain other aspects of these embodiments, the eutectic agent and at least one other eutectic agent in the formulation form a eutectic melt, and as a whole, the

pharmaceutical composition that comprises them is also substantially a eutectic melt, hi an alternative and preferred aspect, although the eutectic agent and the second eutectic agent form a eutectic melt, as a whole, the pharmaceutical composition is not a eutectic melt.

[0020] In preferred aspects of these embodiments, the pharmaceutical composition is substantially or essentially anhydrous. In an alternative preferred aspect, the pharmaceutical composition comprises less than 5% water (e.g., 4%, 3%, 2%, 1%, or less than 1% water).

[0021] Further aspects, objects, and advantages of the invention will become apparent upon consideration of the detailed description and figures that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which: [0023] FIG. 1 illustrates the behavior of a two-component system containing substances A and B that form a eutectic mixture. The liquidus line separates the completely molten (liquidus) phase from the melt+crystal phase. The solidus line separates the melt+crystal phase from the all-crystal (solidus) phase.

[0024] FIG. 2A describes the terbinafine penetration profiles through shed snake skin from the first series of specific eutectic formulations (Table 2) at 4, 20, and 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard error of the mean.

[0025] FIG. 2B describes the terbinafine retention in shed snake skin from the first series of specific eutectic formulations (Table 2) at 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard deviation of the mean.

[0026] FIG. 3A describes the terbinafine penetration profiles through shed snake skin from the second series of specific eutectic formulations (Table 3) at 4, 20, and 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard error of the mean. [0027] FIG. 3B describes the terbinafine retention in shed snake skin from the second series of specific eutectic formulations (Table 3) at 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard deviation of the mean.

[0028] FIG. 4A describes the terbinafine penetration profiles through shed snake skin from the third series of specific eutectic formulations (Table 4) at 4, 20, and 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard error of the mean.

[0029] FIG. 4B describes the terbinafine retention in shed snake skin from the third series of specific eutectic formulations (Table 4) at 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard deviation of the mean.

[0030] FIG. 5A describes the terbinafine penetration profiles through shed snake skin from the fourth series of specific eutectic formulations (Table 6) at 4, 20, and 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard error of the mean. [0031] FIG. 5B describes the terbinafine retention in shed snake skin from the fourth series of specific eutectic formulations (Table 6) at 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard deviation of the mean.

[0032] FIG. 6A describes the terbinafine penetration profiles through shed snake skin from the fifth series of specific eutectic formulations (Table 7) at 4, 20, and 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard error of the mean.

[0033] FIG. 6B describes the terbinafine retention in shed snake skin from the fifth series of specific eutectic formulations (Table 7) at 24 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard deviation of the mean. [0034] FIG. 7 describes the terbinafine penetration profiles through shed snake skin from the sixth, lacquer-type series of specific eutectic formulations (Table 8) at 4 and 20 hours after application. Lamisil^® was used as the control. Each set of error bars represents the standard error of the mean.

[0035] FIG. 8 A describes a comparison of the terbinafine retention in bovine hoof after 306 hr of a control (Lamisil®) and two specific eutectic formulations (Table 9). Each set of error bars represents the standard deviation of the mean. [0036] FIG. 8B describes a comparison of the terbinafine permeation profiles through bovine hoof of a control (Lamisil^®) and two specific eutectic formulations (Table 9) at 66, 114, 162, 210, 258, and 306 hours after application. Each set of error bars represents the standard error of the mean. [0037] FIG. 9A illustrates the terbinafine permeation from exemplary terbinafine

formulation NRI-1002-03 (identified in the figure legend as NRI-1002-03-030310) through human cadaver nail, compared to a control (Lamisil^®). Each set of error bars represents the standard error of the mean.

[0038] FIG. 9B illustrates the terbinafine permeation from exemplary terbinafine formulation NRI-1002-04 (identified in the figure legend as NRI-1002-04-0302.0) through human cadaver nail, compared to a control (Lamisil^®). Each pair of error bars represents the standard error of the mean.

[0039] FIG. 9C illustrates the terbinafine permeation from exemplary terbinafine formulations NRI-1002-04vl and NRI-1002-04 v2 through human cadaver nail, compared to a control (Lamisil^®). Each pair of error bars represents the standard error of the mean

[0040] FIG. 9D illustrates the terbinafine permeation from exemplary terbinafine formulation NRI-1002-04v3 (identified in the figure legend as NRI-04-60710-v3) through human cadaver nail, compared to a control (Lamisil^®). Each pair of error bars represents the standard error of the mean [0041] FIG. 10 illustrates the relative terbinafine permeation through human cadaver nail of exemplary terbinafine formulations NRI-1002-04vl, NRI-1002-04v2, and NRI-1002-04v3, expressed as enhancement in accumulated terbinafine flux relative to Lamisil^®.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

[0042] The terms "a," "an," or "the" as used herein not only include aspects with one member, but also include aspects with more than one member. For example, an embodiment including "an anti-fungal agent and a eutectic agent" should be understood to present certain aspects with two or more antifungal agents, two or more eutectic agents, or both. [0043] In compositions consisting of, consisting essentially of, or comprising a "first" and a "second" component, the second component as used herein is chemically different from the first component (e.g., a composition comprising terbinafine hydrochloride and lidocaine).

[0044] The term "about" as used herein to modify a numerical value indicates a defined range around that value. If "X" were the value, "about X" would generally indicate a value from 0.95X to 1.05X. Any reference to "about X" specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, LOlX, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide written description support for a claim limitation of, e.g., "0.98X." When the quantity "X" only includes whole-integer values (e.g., "X carbons"), "about X" indicates from (X-I) to (X+l). In this case, "about X" as used herein specifically indicates at least the values X, X-I, and X+l.

[0045] When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "from about 5 to 20%" is equivalent to "from about 5% to about 20%." When "about" is applied to the first value of a set of values, it applies to all values in that set. Thus, "about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%."

[0046] "Anti-fungal agent" as used herein includes a compound that has the ability to kill, to stop the growth, or to slow the growth of a fungus in vitro or in vivo as well as a compound that can prevent or alleviate a fungal infection in vitro or in vivo. Representative anti-fungal agents include allylamine anti-fungal agents such as terbinafine, amorolfϊne, naftifine, butenafine, and pharmaceutically acceptable salts thereof.

[0047] "Eutectic agent" as used herein includes a compound that, in combination with at least a second eutectic agent, forms a eutectic melt. Representative eutectic agents include menthol, phenol, 2-amino-2-methylpropanol, choline chloride, urea, panthenol, niacinamide, citric acid, betaine, arginine, resorcinol, butylated hydroxytoluene, 4-chloroxylenol, camphor, glycerin monolaurate, lauryl alcohol, certain pharmaceutical agents (e.g., allylamine antifungal agents such as terbinafine and butenafine; local anesthetics such as lidocaine and prilocaine), and the like.

[0048] In certain aspects, if a mixture of compounds A and B or compounds B and C can form a eutectic melt, compounds A, B, and C can each be a eutectic agent as defined herein even if compounds A and C cannot be combined with each other to form a eutectic melt. However, if a compound is a eutectic agent in a specific embodiment of a composition, it is able to form a eutectic melt with at least a second compound contained in that embodiment of the composition. [0049] "Eutectic melt" as used herein includes a combination of two or more eutectic agents that form a substantially homogeneous mixture of liquids that is stable at one or more temperatures between about 10 °C and about 50 °C (e.g., between about 10 ⁰C, 15 °C, 20 ⁰C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 ⁰C, and the temperatures in between). The eutectic melt is further characterized in that the melting point of the eutectic melt is lower than the melting point of at least one of the two or more eutectic agents that comprise the mixture, hi another embodiment, the melting point of the eutectic melt is lower than the melting points of two or more eutectic agents that comprise the mixture. In a further embodiment, the melting point of the eutectic melt is lower than the melting point of all of the eutectic agents that comprise the mixture.

[0050] In certain aspects, at the melting point of a eutectic melt, both the solid and liquid phases have about the same proportional composition of eutectic agents.

[0051] hi certain aspects, the melting point of a eutectic melt is lower than the melting point of other mixtures containing the same components, but with different proportions of the same eutectic agents.

[0052] hi certain aspects, at least one of the liquid components of the eutectic melt is a solid when in purified or non-mixed form at the same temperature, and the component's change from solid to liquid state is caused by its melting point depression upon mixing with the other component or components. [0053] hi certain aspects, the melting point of at least one, more than one, or all of the eutectic agents is greater than 24 °C, 30 ⁰C, 36 ⁰C, 40 °C, or 50 ⁰C. hi one embodiment, the melting point of all of the eutectic agent components of the eutectic melt is greater than 10 ⁰C. hi another embodiment, the melting point of the eutectic melt is lower than 24 °C, and the melting point of at least one, more than one, or all of the eutectic agent components of the eutectic melt is greater than 24 °C, 30 °C, 36 °C, 40 ⁰C, or 50 ⁰C.

[0054] hi certain embodiments, a mixture is heated until the components are liquid or substantially liquid to form a eutectic melt, hi still other embodiments, a mixture is heated to a temperature above 50 °C to form a eutectic melt (e.g., 60 °C, 65 °C, 70 °C, 70 ⁰C, 80 °C, 85 ⁰C, 90 °C, 95 °C, or l00 °C). [0055] "Finite dosing" as used herein generally includes an application of a limited reservoir of an active agent. The reservoir of the active agent is depleted with time, leading to a tapering off of the active absorption rate after a maximum absorption rate is reached. [0056] "Infinite dosing" as used herein generally includes an application of a large reservoir of an active agent. The reservoir of the active agent is not significantly depleted with time, thereby providing a long-term, continuous steady-state of active absorption.

[0057] "Low-boiling solvent" indicates a pharmaceutically acceptable solvent or mixture of solvents with a boiling point of less than 100 °C at standard temperature and pressure.

Representative low-boiling solvents include acetone, ethyl acetate, ethanol, and the like.

[0058] "Lower alkanol" as used herein includes straight- or branched-chain alkyl alcohols of 1 to about 6 carbon atoms. Representative lower alkanols include methanol, ethanol, n- propanol, isopropanol, n-butanol, t-butanol, n-pentanol, 3-pentanol, and the like. [0059] "Melt composition" as used herein includes a mixture of at least two liquids.

[0060] The "melting point" as used herein is the temperature at which a solid changes from solid to liquid phase under standard pressure (i.e., 1 atm or 101.325 kPa). If a solid melts over a temperature range, the melting point is the temperature at which the liquid phase first appears under standard pressure. [0061] The term "or" as used herein should in general be construed non-exclusively. For example, an embodiment of "a composition comprising A or B" would typically present an aspect with a composition comprising both A and B. "Or" should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g., a formulation pH that is between 9 and 10 or between 7 and 8). [0062] "Penetration enhancer" as used herein includes an agent or a combination of agents that improves the transport of molecules such as a pharmaceutically or cosmetically active agent into or through a natural membrane such as skin or nail. Various conditions may occur at different sites in the body, either in the skin or below the skin, creating a need to target delivery of compounds. For example, in a treatment for onychomycosis, delivery of the active agent to the tissue underlying the nail may be necessary to achieve therapeutic benefit. Thus, a "penetration enhancer" may be used to assist in the delivery of an active agent i) directly to the skin, nail, or underlying tissue; or ii) indirectly via systemic distribution to the site of the disease. A penetration enhancer may be a pure substance or may comprise, consist essentially of, or consist of a mixture of different chemical entities. [0063] Generally, when a percentage range is taught, it incorporates all full or partial percentages in between (i.e., within the bounds of the range). For example, a percentage range of 15 to 25% would also teach the specific values of 17.36% and 21%. A percentage range of about 13% to 17% would also teach the specific values of 12.97%, 16%, and 14.1%.

[0064] "Substantially anhydrous" as used herein includes compositions without deliberately added water. A substantially anhydrous composition can contain up to 5% w/w water, which may be adventitiously incorporated from impurities in the starting materials, side products from reactions or manufacturing processes, or air absorption.

[0065] "Substantially homogeneous" as used herein designates a composition that includes at least 90%, 95%, or 99% by weight of a single phase, although it may include small amounts of a different phase (e.g., a liquid phase containing a small amount of immiscible liquid or a solid).

[0066] "Substantially liquid" as used herein designates a composition that includes at least 90%, 95%, or 99% by weight of a liquid phase, although it may include small amounts of at least one solid phase.

[0067] "Substituted phenol" as used herein includes hydroxybenzenes and

dihydroxybenzenes with from 1 to 3 additional substituents independently selected from the group of acyl, alkyl, alkenyl, alkoxy, amido, amino, aryl, carboxy, and halo substituents.

[0068] "Topical application" as used herein includes the administration of a composition, (e.g., a formulation containing a pharmaceutically or cosmetically active agent) to the skin, nail, mucosa, or other localized region of the body. Topical application may result in the delivery of an active agent to the skin, the nail plate, the nail bed, a localized region of the body, a localized volume of the body, or the systemic circulation.

[0069] "Topical formulation" as used herein includes a formulation that is suitable for topical application to the skin, a nail, or a mucosa. A topical formulation may, for example, be used to confer a therapeutic or cosmetic benefit to its user. Topical formulations can be used for local, regional, transdermal, or transungual application of substances.

[0070] "Transdermal" as used herein includes a process that occurs through the skin. The terms "transdermal," "percutaneous," and "transcutaneous" can be used interchangeably. In certain embodiments, "transdermal" may also include epicutaneous.

[0071] "Transdermal application" as used herein includes administration through the skin. Transdermal application can be used for systemic delivery of an active agent; however, it is also useful for delivery of an active agent to tissues underlying the skin with minimal systemic absorption. In certain embodiments, "transdermal application" may also include epicutaneous application.

[0072] "Transungual" as used herein includes a process that occurs through the nail.

[0073] "Transungual application" as used herein includes administration to or through a nail. Transungual application can be used for systemic delivery of an active agent. However, it is preferably used for delivery of an active agent to the nail or to tissues underlying or surrounding the nail with minimal systemic absorption.

II. Anti-Fungal Agents

[0074] hi certain aspects, the pharmaceutical compositions of the instant invention incorporate an anti-fungal agent. In a preferred aspect, the anti-fungal agent is a member of the classes of azoles (including imidazoles and triazoles) such as miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, itraconazole, fluconazole, voriconzole, terconazole, isavuconazole, ravuconazole, and posaconazole; polyenes such as natamycin, rimocidin, filipin, nystatin, candicidin, nystatin, candicidin, and amphoteracin B; thiazoles such as abafungin; echinocandins; allylamines such as terbinafine, amorolfine, naftifine, and terbinafme; thiocarbamates such as tolnaftate; phenolic compounds such as haloprogin;

pyridones such as ciclopirox olamine; and miscellaneous antifungal agents such as undecylenic acid. See Brunton, L. L. et al. The Goodman and Gilman 's Manual of

Pharmocology and Therapeutics, McGraw-Hill, New York, 2007.

[0075] In a more preferred aspect, the antifungal agent is an allylamine anti-fungal agent, hi a more preferred embodiment, the allylamine anti-fungal agent is selected from the group consisting of amorolfine, butenafine, naftifine, terbinafine, and a pharmaceutically acceptable salt thereof. In an even more preferred embodiment, the allylamine anti-fungal agent is terbinafine or a pharmaceutically acceptable salt thereof.

[0076] hi an alternative preferred aspect of the invention, the anti-fungal agent's mechanism of action is inhibition of the ergosterol synthesis pathway in a fungus. In a more preferred aspect, the anti-fungal agent's mechanism of action is inhibition of the enzyme squalene epoxidase. [0077] In still another preferred aspect, the anti-fungal agent is useful in the treatment of a mammal, including a human and a domestic or farm animal, such as a dog, horse, cat, sheep, pig, or cow. Non-limiting preferred mammals are humans. [0078] In still yet another preferred aspect, the formulation comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 25, 30, 31 or 35% of the anti-fungal agent by weight.

Alternatively, the formulation comprises at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 25, 30, 31 or 35% of the anti-fungal agent by weight. Alternatively, the formulation comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25% of the anti-fungal agent by weight as well as all partial percentages in between.

[0079] In a more preferred aspect, the formulation comprises from about 5 to 25% of the anti-fungal agent by weight. Still more preferably, the formulation comprises from about 8 to about 22%. Yet still more preferably, the formulation comprises from about 8 to about 15, about 10 to about 15, about 10 to about 20, about 13 to about 22, about 13 to about 20, or about 15 to about 20% by weight. Still more preferably, the formulation is about 10% by weight. Alternatively, the formulation is about 15% by weight. Alternatively, the formulation is about 20% by weight.

[0080] Although the compositions described as specific embodiments herein include anti- fungal agents, the inventive eutectic melts and formulations should not be construed as being limited to anti-fungal agents. Other classes of drugs that are potentially useful in topical, transdermal, or transungual drug delivery can also benefit from the permeation enhancement afforded by use of eutectic melts and the solutions prepared from them (e.g., local anesthetics, analgesics, steroidal or non-steroidal anti-inflammatory drugs, hormones, nicotine or nicotine analogs, and the like).

III. Eutectic Agents

[0081] In certain aspects, several broad classes of eutectic agents are used in the present invention. The compounds can be classified as phenol and certain substituted phenols, certain terpenes that are solid at room temperature, urea, choline chloride-type zwitterionic materials (e.g., deep eutectic solvents), and combinations thereof. However, the instant invention is intended to embrace all pharmaceutically acceptable eutectic agents and is not restricted to these classes.

[0082] Table 1 provides a list of exemplary eutectic agents useful in some specific embodiments of the instant invention. Table 1 : Exemplary Eutectic Agents and Their Melting Points

[0083] Some specific embodiments of eutectic melts useful for the instant invention are the following:

• Phenol/Menthol

• Phenol/Choline chloride

• Phenol/Choline chloride/Urea

• Choline chloride/Urea

• Betaine hydrochloride or Choline chloride/Urea

• Resorcinol/Choline chloride

• BHT/Choline chloride

• Chloroxylenol/Choline chloride/Menthol

• Choline chloride/Citric acid monohydrate

• Choline chloride/Arginine/Urea

• Choline chloride/Niacinamide/Urea

• Camphor/Menthol/

• Camphor/Menthol/Lauryl alcohol

• Camphor/Glycerin monolaurate/Menthol

• Terbinafine hydrochloride/lidocaine

The slash "/" indicates that the agents can be used in a eutectic melt. For example, "choline chloride/niacinamide/urea" indicates that choline chloride, niacinamide, and urea can be combined to form a eutectic melt of the instant invention. [0084] hi one preferred aspect, the eutectic agent is selected from the group of phenol, a pharmaceutically acceptable substituted phenol, a quaternary aminoalkanol, a quaternary amino acid salt, a terpene, and urea. In a more preferred aspect, the eutectic agent is selected from the group of phenol, resorcinol, thymol, choline chloride, camphor, menthol, and urea.

[0085] In another aspect, the eutectic melt is a permeation enhancer. Preferably, the eutectic melt provides a rate of permeation at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-fold that of a comparative formulation without the eutectic melt. An exemplary procedure for identifying the rate of permeation is, e.g., a Franz cell procedure such as the one described in Example 26.

[0086] hi a preferred embodiment, the formulation comprises about 0.1% to 25% (w/w) urea. In more preferred aspects, the formulation comprises about 5% to 15% (w/w) urea. Still more preferably, the formulation comprises about 5% to 10%, about 7% to 10%, about 7% to 13%, about 10% to 13% (w/w), about 10% to 15%, or about 12% to 15% (w/w) urea. Alternatively, the formulation comprises about 7, 8, 9, 10, 11, 12, or 13% (w/w) urea; more preferably, about 10% (w/w) urea.

[0087] In still another aspect, at least one of the eutectic agents is a pharmaceutically active agent (e.g., an anti-fungal agent as described above or a local anesthetic). Preferably, the pharmaceutically active agent is selected from the group of benzocaine, chloroprocaine, cyclomethycaine, larocaine, propoxycaine, procaine, proparacaine, tetracaine, articaine, bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, and a pharmaceutically acceptable salt thereof (i. e. , a pharmaceutically acceptable salt of any compound in the group). More preferably, the pharmaceutically active agent is lidocaine or a pharmaceutically acceptable salt thereof.

[0088] In still yet another aspect, the eutectic agent is an aromatic or heteroaromatic ester (ArCOOR) with an alkyl substituent on the aromatic or heteroaromatic ring (Ar) and an alkylamino or dialkylamino substituent on the ester alcohol (i.e., R Ar-COO-R-NR R ).

Alternatively, the eutectic agent is an aromatic or heteroaromatic amide (ArCON(R')R) with an alkyl substituent on the aromatic or heteroaromatic ring and an alkylamino or

dialkylamino substituent on the amine that is comprised in the amide (i.e., R¹Ar-CON(R^-R- NR²R³). More preferably, the amide or ester eutectic agent is also a pharmaceutically active agent.

[0089] In another aspect, the formulation comprises at least about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, 60, 70, 75, 80, 90, or 100% of the eutectic melt by weight. In other aspects, the formulation comprises at most about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, or 60% of the eutectic melt by weight.

[0090] In still another aspect, the formulation consists or consists essentially of the eutectic melt and an optional low-boiling solvent. Alternatively, the formulation comprises a eutectic melt. In certain aspects, the formulation comprising the eutectic melt is not itself a eutectic melt.

[0091] In yet still another aspect, the eutectic melt forms a stable, substantially

homogeneous mixture of liquids at one or more temperatures between about 10 °C and about 15 °C, between about 15 ⁰C and about 20 ⁰C, between about 20 °C and about 25 °C, between about 25 °C and about 30 °C, between about 30 ⁰C and about 35 °C, between about 35 °C and about 40 °C, between about 40 °C and about 45°C, or between about 45 ⁰C and about 50 ⁰C. Alternatively, the eutectic melt forms a stable, substantially homogeneous mixture of liquids at one or more temperatures between 10 °C and 15 °C, between 15 °C and 20 °C, between 20 °C and 25 °C, between 25 °C and 30 °C, between 30 ⁰C and 35 °C, between 35 °C and 40 °C, between 40 °C and 45°C, or between 45 ⁰C and 50 ⁰C.

IV. Other Components

[0092] In one preferred aspect, the low-boiling solvent is a lower alkanol. More preferably, the low-boiling solvent is ethanol. hi certain aspects, the formulation comprises about 5 to 60% as well as all full or partial percentages in between. In certain other aspects, the formulation comprises at least about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, or 60% of the low-boiling solvent by weight, hi still other aspects, the formulation comprises at most about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, 60, 70, 75, 80, 90, or 100% of the low- boiling solvent by weight.

[0093] hi certain preferred embodiments, the formulation comprises about 20 to about 50% ethanol as well as all full or partial percentages in between (e.g., 44% or 43.68% ethanol). More preferably, the formulation comprises about 25 to about 45% ethanol. Still more preferably, the formulation comprises about 30 to about 45, about 30 to about 41, about 35 to about 45, about 40 to about 45, about 25 to about 40, about 25 to about 36, about 30 to about 36, or about 25 to about 31% ethanol. [0094] hi an alternative preferred aspect, a low-boiling solvent has a boiling point of less than 90 ⁰C at standard temperature and pressure. More preferably, the low-boiling solvent has a boiling point of less than 80 °C at standard temperature and pressure. [0095] In another aspect, the pharmaceutical composition is a homogeneous mixture. In an alternative aspect, the pharmaceutical composition is a solution or a liquid and is substantially free of precipitates at about 37 ⁰C. More preferably, the pharmaceutical composition is a solution or a liquid and is substantially free of precipitates at about 25 °C. [0096] In yet another aspect, the composition additionally comprises at least one pharmaceutically acceptable surfactant, emulsifier, thickener, or lacquer-forming agent. In a preferred aspect, the composition additionally comprises at least one surfactant, emulsifier, thickener, or lacquer-forming agent.

[0097] In certain preferred aspects, the thickener is selected from the group consisting of a cellulose polymer, a carbomer, a polyvinyl pyrrolidone, a polyvinyl alcohol, a poloxamer, a xanthan gum, a locust bean gum, a guar gum and mixtures thereof. Preferably, the formulation includes a cellulosic thickener. Suitable cellulosic thickeners include, but are not limited to, hydroxypropyl cellulose (HPC) of various grades, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, dextran, guar gum, pectin, starch, cellulose, and the like. More preferably, the cellulosic thickener is HPC.

[0098] hi a preferred embodiment, the formulation comprises about 0.5% to about 5% (w/w) of the thickener, such as about 0.5, about 0.6, about 0.7, about 0.8, 0.9, 1, 1.5, 1.8, 1.9, 2, 2.1, 2.2, 2.5, 3, 4, or 5% as well as all full or partial percentages in between. More preferably, the formulation comprises from about 0.5% to 1% or about 0.5 to 2% of a thickener. Still more preferably, the formulation comprises about 2% of a thickener.

Alternatively, the formulation comprises about 1% of a thickener.

[0099] hi certain other preferred aspects, the formulation comprises isopropyl myristate (IPM). In one aspect, the isopropyl myristate is present from about 2.5% to 15% (w/w), such as about 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, or 15%. Alternatively, the isopropyl myristate is present from about 2.5% to 10%, about 2.5% to 7.5%, about 2.5% to 10%, about 5% to 15%, or about 10% to 15% (w/w) isopropyl myristate. Preferably, the formulation includes about 2.5, 5, 7.5, or 10% (w/w) isopropyl myristate.

[0100] In still yet another aspect, the formulation is a composition selected from the group consisting of a cream, an emulsion, a lotion, an organogel, an ointment, and a transdermal patch. [0101] In one aspect, the composition additionally comprises an anti-oxidant. Preferred anti-oxidants for use in the present invention include butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl linoleate, ascorbyl dipalmitate, ascorbyl tocopherol maleate, calcium ascorbate, ascorbic acid, carotenoids, kojic acid and its pharmaceutically acceptable salts, thioglycolic acid and its pharmaceutically acceptable salts (e.g., ammonium), tocopherol, alpha tocopherol, tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth- 18, or tocophereth-80. In certain aspects, the anti-oxidant may also be a eutectic agent.

[0102] hi certain embodiments, the composition comprises about 0.01% to 5.0% of antioxidant as well as all fractions or percentages in between. Alternatively, the composition comprises up to about 5% anti-oxidant. Alternatively, the composition comprises about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10% of the anti-oxidant. Alternatively, the composition comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0% of the antioxidant. Alternatively, the composition comprises 0.5, 1,0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0% antioxidant. [0103] hi an alternative aspect, the formulation is more viscous than water at standard temperature and pressure (STP). Alternatively, the formulation has a kinematic viscosity of more than about 1 centistokes (cSt) or a dynamic viscosity of more than about 1 centipoise (cP). In certain aspects, the dynamic viscosity of the formulation is at least about 2, 3, 4, 5, 7, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, 150, 200, 250, 500, 1000, 2000, 3000, 5000, 10,000 cP at STP. In certain other aspects, the dynamic viscosity of the formulation is at least about 10⁴, 5 x 10⁴, 10⁵, 5 x 10⁵, 10⁶, 5 x 10⁶, 10⁷ or 10⁸ cP at STP. hi yet other aspects, the formulation is thixotropic (i.e., it decreases in viscosity upon being stirred or shaken).

[0104] hi another aspect, the formulation is acidic, hi certain aspects, the formulation has a pH of below 7.5, of below 6.5, of below 5.5, of below 4.5, of below 3.5, or of below 2.5. hi certain other aspects, the pH of the formulation may range from about 1.5 to about 7, about 2 to about 7, about 3 to about 7, about 4 to about 7, or about 5 to about 7. hi still other aspects, the pH of the formulation may range from about 1.5 to about 5.5, about 2.5 to about 5.5, about 3.5 to about 5.5, or about 4.5 to about 5.5. [0105] hi yet another aspect, the formulation is basic, hi certain aspects, the formulation has a pH of above 7, of above 8, of above 9, of above 10, of above 11, or of above 12. hi certain other aspects, the pH of the formulation may range from about 7 to about 12.5, about 7 to about 11.5, about 7 to about 10.5, about 7 to about 9.5, or about 7 to about 8.5. hi still other aspects, the pH of the formulation may range from about 9 to about 12.5, about 9 to about 11.5, about 9 to about 10.5, or about 8.5 to about 10.

[0106] In still yet another aspect, the formulation is neutral. In certain aspects, the formulation has a pH of about 7. In certain other aspects, the formulation has a pH from about 6 to about 8.5, from about 5.5 to about 8, about 6 to about 8, about 6.5 to about 8.5, or from about 6.5 to about 7.5.

[0107] hi a preferred aspect, the topical formulations of the present invention comprise a pH-adjusting agent, hi one embodiment, the pH-adjusting agent is a base. Suitable pH- adjusting bases include amines (e.g., diethanolamine or triethanolamine), bicarbonates, carbonates, and hydroxides such as alkali or alkaline earth metal hydroxides as well as transition metal hydroxides. The pH-adjusting agent is preferably sodium hydroxide and is present in an amount sufficient to adjust the pH of the composition to between about pH 4.0 to about 8.5; more preferably, to between about pH 5.5 to about 7.0, such as 6.0 or 6.5.

Alternatively, the pH-adjusting agent can also be an acid, an acid salt, or mixtures thereof, hi a preferred embodiment, the pH-adjusting agent is an acid.

[0108] Further, the pH-adjusting agent can also be a buffer. Suitable buffers include citrate/citric acid buffers, acetate/acetic acid buffers, phosphate/phosphoric acid buffers, formate/formic acid buffers, propionate/propionic acid buffers, lactate/lactic acid buffers, carbonate/carbonic acid buffers, ammonium/ammonia buffers, and the like, hi certain embodiments, the buffer is an acidic buffer system (e.g., benzocaine).

V. Characteristics of Topical Formulations

Solubility

[0109] m certain preferred aspects, the formulations of the current invention have the advantage of containing high concentrations of low-solubility or hard-to-formulate drugs such as terbinafine or butenafine. Such concentrated formulations may be of particular benefit in treatment of chronic diseases of the nail or other difficult-to-treat areas of the body (e.g., onychomycosis) because the high concentrations can 1) increase the effective concentration of drug in the affected area or 2) improve retention of the drug at or near the affected area. [0110] The solubility of terbinafine in various aqueous and organic solvents was investigated (Example 29). The findings indicated that terbinafine shows high solubility in organic solvents, lower solubility in non-polar solvents and moderate solubility in aqueous solvents with a pH of 4 and 6.

[0111] Despite difficulties in solubilizing terbinafϊne, the inventors have surprisingly been able to prepare topical formulations with high concentrations of active. As shown in Table 14, for example, the solubility of terbinafine in preferred formulations of the invention was relatively high and ranged from 214 - 235 mg/ml (21-24% w/v). In certain aspects of the invention, the pharmaceutical composition has a terbinafine solubility ranging from about 10% to about 30% (w/v). In certain other aspects of the invention, the pharmaceutical composition has a terbinafine solubility of at least 10% (w/v), at least 15% (w/v), at least 20% (w/v), at least 25% (w/v), or at least 30% (w/v). In still other aspects of the invention, the pharmaceutical composition has a terbinafine solubility of at least 21% (w/v), at least 22% (w/v), at least 23% (w/v), or at least 24% (w/v).

Stability

[0112] As discussed, the formation of eutectic mixtures is often undesirable. For example, formulations comprising eutectic mixtures have typically been viewed as unstable. In certain aspects of the instant invention, the topical formulations have the advantage of maintaining chemical and/or physical stability over time, even where the concentration of the active has been increased. In Tables 15 to 24, for instance, the chemical and physical attributes of preferred topical formulations were monitored over the course of a one- or three-month period.

[0113] In certain aspects invention, the pharmaceutical composition is substantially stable with respect to its chemical and/or physical attributes over a predetermined period of time. The measurable attributes may include, but are not limited to, percentage of active, percentage of impurities, or visual attributes such as colour and the presence of particulates. In other aspects the invention, the pharmaceutical composition is substantially stable following storage for about 4, 8 or 12 weeks at 25°C. In still other aspects of the invention, the pharmaceutical composition is substantially stable following storage for about 4, 8 or 12 weeks at 40°C.

Active Penetration and Retention [0114] In certain aspects, the eutectic melt formulations of the current invention can function as penetration enhancers because of their decreased melting points. See Dhamecha, D. L. et al. Intl. J. ofPharm. and Pharmaceut. ScL 2009, 1(1), 24-46. In certain preferred aspects, a eutectic melt formulation can display superior penetration ability in comparison to a non-eutectic melt formulation with a similar concentration of active ingredient.

[0115] In certain other aspects, a formulation is designed for high penetration, for high retention in the skin or nail, or for both high penetration and high retention of the anti-fungal agent. The optimal formulation will have a balance between penetration and retention, enabling an effective amount of the active ingredient to pass through the skin or nail, but also enabling it to stay in the target area for a sufficient duration to achieve its intended effect upon the fungus.

[0116] hi a preferred aspect, the topical formulations of the present invention provide nail retention of the anti-fungal agent which exceeds that provided by oral therapy. For example,

Finlay has reported that in onychomycosis patients receiving oral terbinafme therapy (250 mg/day), concentrations of terbinafme in distal nail clippings were in the range of 0.25-0.55 ng/mg. See Finlay, A. Y.. "Pharmacokinetics of terbinafme in the nail," Br J Dermatol.

1992, 126 Suppl 39:28-32. As evidenced in Example 28 of the instant application, the concentration of terbinafme in test nails treated with the inventive formulations can reach at least 3.1+ mcg/mg, which is more than three orders of magnitude higher than that observed in the patients receiving oral therapy.

[0117] Thus, in a preferred aspect of the present invention, the permeation rate of the anti- fungal agent will be sufficient to provide concentrations of the agent in the nail that exceed those attained when the anti-fungal agent is administered orally, hi more preferred aspects of the invention, concentrations of the anti-fungal agent achieved in the nail are at least 2-, 10-, 100-, 1000- or 10,000-fold greater than the level achieved by oral therapy to achieve effective treatment of onychomycosis, hi even more preferred aspects of the invention, concentrations of the anti-fungal agent achieved in the nail are at least 1-, 2-, 3-, A-, 5-, 10-, 50-, 100-, 500-, 1000-, 2000-, 4000-, 5000-, or 10,000-fold greater than the level achieved by oral therapy to achieve effective treatment of onychomycosis.

VI. Methods of Preparation

[0118] hi one aspect, the pharmaceutical composition is formulated as a cream, an emulsion, a gel (e.g., a hydrogel, an organogel, or an inorganic or silica gel ), a lotion, a lacquer, an ointment, a solution (e.g., a highly viscous solution), or a transdermal patch. See also U.S. Patent Application 2007/0224261 and U.S. Patent No. 6,368,618. In a preferred aspect, the composition is a solution or a gel. [0119] In an alternative preferred aspect, the composition is a lacquer or a patch. Although the permeation from a lacquer may be lower, it may be easier to incorporate eutectic melts. Another advantage is that it is possible that to obtain a formulation with high amount of active (e.g., up to 35 %). Eutectic melts may also be incorporated into various types of patches (e.g., adhesive, reservoir, and the like).

[0120] In one aspect, the eutectic melt is prepared by heating above 80 °C. Alternatively, the eutectic melt is prepared by heating to about 80 °C. In another aspect, the eutectic melt is prepared by heating above 85 ⁰C. Alternatively, the eutectic melt is prepared by heating to about 85 ⁰C. hi still another aspect, the eutectic melt is prepared by heating above 90 °C. Alternatively, in a preferred embodiment, the eutectic melt is prepared by heating to about 90 ⁰C. hi yet still another alternative aspect, the eutectic melt is prepared by heating to a temperature between about 80 °C to about 90 °C.

VII. Methods of Treatment

[0121] In certain embodiments, the invention describes a method for treating a fungal infection comprising the step of applying a topical anti-fungal composition to a subject to treat the fungal infection.

[0122] In certain aspects, the pharmaceutical composition is applied to a nail of the subject, hi other aspects, the pharmaceutical composition is applied to the nail and the surrounding tissue of the nail of the subject, hi another aspect, the pharmaceutical composition is applied to the skin of the subject.

[0123] In another aspect, the anti-fungal agent or other drug is delivered locally to the nail with minimal systemic absorption, hi yet another aspect, the anti-fungal agent or other drug is delivered to and through the nail with minimal systemic absorption. In a still yet another aspect, the anti-fungal agent or other drug is delivered to the tissue surrounding or under the nail with minimal systemic absorption.

[0124] In another aspect, the anti-fungal agent or other drug is delivered locally to the skin with minimal systemic absorption, hi yet another aspect, the anti-fungal agent or other drug is delivered to and through the skin with minimal systemic absorption. In a still yet another aspect, the anti- fungal agent or other drug is delivered to the tissue surrounding or under the area of skin application with minimal systemic absorption.

[0125] In other aspects, the subject is a human. Alternatively, the subject is a non-human mammal. [0126] In still other aspects, the fungal infection is onychomycosis, hi one aspect, the fungal infection is caused by Trichophyton rubrum or Trichophyton interdigitale (also known as Trichophyton mentagrophytes).

[0127] hi yet still other aspects, the treatment is continued for at least 12 weeks. More preferably, the treatment is continued for at least six months.

[0128] hi other aspects, the treatment is applied one, two, three or four times a day for 1, 2, 3, 4, 5, 6 or 7 days, hi alternative aspects, the treatment is applied ,once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days or once every week. hi still other aspects, the nail or tissue to which the treatment will be applied is cleaned and the remains of prior treatment removed prior to fresh application of the treatment.

[0129] Compositions of the present invention may, if desired, be presented in a bottle, jar, or other container-closure system approved by the FDA or other regulatory bodies, which may contain one or more unit dosage forms containing the active ingredient. The package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of

pharmaceuticals, the notice indicating approval by the agency.

VIII. Examples

[0130] Below, the present invention will be described by way of examples, which are provided for illustrative purposes only. Accordingly, they are not to be construed as limiting the scope of the present invention as defined by the appended claims.

General Methods for Preparation of Eutectic Formulations

[0131] These examples describe the permeation-enhancing effects of eutectic melts in a model of nail delivery. The transdermal permeation and retention of eutectic formulations was compared to a marketed formulation (Lamisil^® cream) and to the 10% terbinafine hydrochloride formulation taught in PCT Patent Application WO04084826A2. Solutions were prepared from various eutectic agents and an exemplary active pharmaceutical ingredient (terbinafine hydrochloride).

[0132] Method A: Preparation of Eutectic Melt with Active Agent As a Eutectic Agent: hi this method, an active agent is added to at least one eutectic agent and heated at approximately 80-90 ⁰C until melting to form a eutectic melt. [0133] Method B: Preparation of Eutectic Melt with Addition of Active Agent: In this method, a eutectic agent and at least a second eutectic agent are mixed and heated to form a eutectic melt. An active agent is added to the molten mixture and stirred with heating at approximately 80-90⁰C until the active agent is dissolved. The mixture is allowed to cool to room temperature. The observed liquid phase is either opaque or transparent without any large amount of crystals.

[0134] The eutectic melt produced by either method is generally very viscous and formulated by dissolving in an appropriate solvent (generally ethanol and/or ethyl acetate, in some cases with small amount of lactic acid or similar materials) to give a non-aqueous eutectic formulation. After preparation, these formulations are each applied to the nail model membrane on the top compartment of a Franz diffusion cell for membrane permeation and membrane retention studies as described below.

Preparation of Specific Formulations:

Example 1 (Table 2-Fl):

[0135] Terbinafine hydrochloride and lidocaine (1:1.5 w/w) were heated at a temperature of 90 ⁰C to form a liquid eutectic melt. After the mixture is cooled, the resulting melt was stable at room temperature. Ethanol (21%) was used to dissolve the formed melt, producing the final formulation as a highly viscous solution. Example 2 (Table 2-F2) :

[0136] Terbinafine hydrochloride and lidocaine (1:1.5 w/w) were heated at a temperature of 90 ⁰C to form a liquid eutectic melt. After the mixture was cooled, the resulting gel is stable at room temperature. A 1 : 1 ethanol and ethyl acetate mixture was used to dissolve the formed gel, producing the final formulation as a highly viscous solution.

Example 3 (Table 2-F3):

[0137] 2-Amino-2-methylpropanol was added to terbinafme hydrochloride and mixed to generate terbinafϊne base in situ. Lidocaine was added to the resulting composition. This mixture forms a liquid eutectic melt at a temperature of 90⁰C. After cooling, the resulting gel is stable at room temperature. Ethanol was used to dissolve the formed gel, producing the final formulation as a highly viscous solution. Example 4 (Table 2-F4) :

[0138] Terbinafine hydrochloride and lidocaine (1.35:1 w/w) were heated at a temperature of 90⁰C. After the addition of menthol and phenol, the mixture was heated again to form the liquid eutectic melt. After cooling, the resulting gel is stable at room temperature. Ethanol was used to dissolve the formed gel, producing the final formulation as a highly viscous solution. Example 5 (Table 2-F5):

[0139] 2-Amino-2-methylpropanol was added to terbinafine hydrochloride and mixed to generate terbinafine base in situ. A eutectic melt of choline chloride and urea was prepared by heating and added to the terbinafine base. The combined mixture was heated, phenol was added, and the mixture was further heated at a temperature of 90 ⁰C to obtain a liquid eutectic melt. Without addition of phenol, no homogeneous eutectic was obtained. After cooling, the resulting low-viscosity gel is stable at room temperature. Example 6 (Table 2-F6):

[0140] A eutectic melt of menthol and phenol was prepared by mixing at room

temperature. Terbinafine hydrochloride was added and mixed until fully dissolved, forming a viscous gel that is stable at room temperature. Ethanol (10%) was used to dissolve the formed gel, producing the final formulation as a highly viscous solution. Example 7 (Table 2-F7):

[0141] A eutectic melt of menthol and phenol was prepared by mixing at room

temperature. Terbinafine hydrochloride was added and mixed until fully dissolved, forming a viscous gel that is stable at room temperature. A 1:1 mixture of ethanol and ethyl acetate was used to dissolve the formed gel, producing the final formulation as a highly viscous solution.

Example 8 (Table 2-F8):

[0142] A eutectic melt of menthol and phenol was prepared by mixing at room

temperature. After D-panthenol was stirred into the mixture, terbinafine hydrochloride was added and mixed until fully dissolved, forming a viscous gel that is stable at room

temperature. Ethanol was used to dissolve the formed gel, producing the final formulation as a highly viscous solution. Example 9 (Table 3-F21):

[0143] 2-Amino-2-methylpropanol was added to terbinafine hydrochloride and mixed to generate terbinafine base in situ. A eutectic melt of choline chloride and urea was prepared by heating and added to the terbinafine base. The combined mixture was heated, phenol was added, and the mixture was further heated at a temperature of 90 ⁰C to obtain a liquid eutectic melt. After cooling, the resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, and lactic acid was added to enhance the solution's clarity. The final formulation is a highly viscous solution.

Example 10 (Table 3-F22):

[0144] A eutectic melt of choline chloride and urea was prepared by heating. Arginine base was added, and the mixture was heated to 90 ⁰C to form a further eutectic melt.

Terbinafine hydrochloride was added to the mixture, and after re-heating and cooling, the resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, and lactic acid was added to enhance the solution's clarity. The final formulation is a highly viscous solution. Example 11 (Table 3-F23):

[0145] A eutectic melt of choline chloride and urea was prepared by heating. Niacinamide was added, and the mixture was heated to 90⁰C to form a eutectic melt. Terbinafine hydrochloride was added to the mixture, and after re-heating and cooling, the resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, and lactic acid was added to enhance the solution's clarity. The final formulation is a highly viscous solution.

Example 12 (Table 3-F24):

[0146] A eutectic melt of choline chloride and phenol was prepared by mixing and heating at 90⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution. Example 13 (Table 3-F25):

[0147] A eutectic melt of choline chloride and resorcinol was prepared by mixing and heating at 90⁰C. After addition of terbinafme hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.

Example 14 (Table 3-F26):

[0148] A eutectic melt of choline chloride and BHT was prepared by mixing and heating at 90 ⁰C. After addition of terbinafme hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution. Example 15 (Table 3-F27):

[0149] A eutectic melt of choline chloride and citric acid was prepared by mixing and heating at 90 ⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution. Example 16 (Table 3-F28):

[0150] A eutectic melt of choline chloride, urea, and betaine was prepared by mixing and heating at 90 ⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution.

Example 17 (Table 3-F29):

[0151] A eutectic melt of choline chloride, menthol, and 4-chloroxylenol was prepared by mixing and heating at 90 ⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution. Example 18 (Table 4-F31):

[0152] 2-Amino-2-methylpropanol was added to terbinafme hydrochloride and mixed to generate terbinafine base in situ. A eutectic melt of choline chloride and urea was prepared by heating and added to the terbinafine base. The combined mixture was heated, phenol was added, and the mixture was further heated at a temperature of 90⁰C to obtain a liquid eutectic melt. After cooling, the resulting low viscosity gel is stable at room temperature. Without the addition of phenol, no homogeneous eutectic melt was obtained. Ethanol was used to dissolve the gel, and the final formulation is a highly viscous solution.

Example 19 (Table 4-F32):

[0153] A eutectic melt of choline chloride and urea was prepared by mixing and heating at 90⁰C. After addition of terbinafme hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, and lactic acid was added to enhance the solution's clarity. Hydroxypropyl cellulose (low- viscosity form, HYl 17, available from Spectrum Chemical and Laboratory Products, Gardena California) was added to obtain a gel. The final formulation is a highly viscous gel. Example 20 (Table 4-F33):

[0154] A eutectic melt of choline chloride and urea was prepared by mixing and heating at 90 ⁰C. After addition of menthol and camphor, the mixture was heated at 90 ⁰C and mixed to obtain a eutectic melt. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol and dimethyl sulfoxide ("DMSO") were used to dissolve the resulting gel, and hydroxypropyl cellulose (low- viscosity form, HY 117) was added to obtain the final formulation as a highly viscous gel. Example 21 (Table 4-F34):

[0155] A eutectic melt of menthol and camphor was prepared by mixing and heating at 90 ⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol, ethyl acetate, and glycerin monolaurate was used to dissolve the gel, producing the final formulation as a highly viscous solution. Example 22 (Table 4-F35):

[0156] A eutectic melt of menthol, phenol, and camphor was prepared by mixing and heating at 90⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol/ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.

Example 23 (Table 4-F36):

[0157] A eutectic melt of menthol, resorcinol, and camphor was prepared by mixing and heating at 90⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution. Example 24 (Table 4-F37):

[0158] A eutectic melt of menthol, resorcinol, lauryl alcohol, and camphor was prepared by mixing and heating at 90⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.

Example 25 (Table 4-F38):

[0159] A eutectic melt of choline chloride and urea was prepared by mixing and heating at 90⁰C. After addition of menthol and lauryl alcohol, the mixture was heated at 90⁰C and mixed to obtain a eutectic melt. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol and glycerin monolaurate was used to dissolve the resulting gel, and hydroxypropyl cellulose (low- viscosity form, HY 117) was added to obtain the final formulation as a highly viscous gel. Example 26: Results of Transdermal Experiments

[0160] The effect of eutectic melts containing an exemplary active agent (terbinafine) on transdermal permeation and skin retention was examined through shed snake skin as a model membrane. Each formulation was tested in five-fold replicate. Lamisil^® cream was used as the control.

General Methods for Transdermal Experiments

[0161] Shed snake skin was used as a model membrane as it is composed of keratinaceous material similar to that of a nail. Analysis was carried out on an Agilent 1100 high performance liquid chromatography (HPLC) instrument. An isocratic elution method was used in conjunction with acetonitrile and an ion-pairing reagent in a phosphate buffer at pH 3.0 as the mobile phase on a Zorbax Reverse Phase C8 column.

General Method for Permeation Studies:

[0162] Franz cells with a 3-mL receptor well volume were used in conjunction with shed snake skin. The donor well had an area of -0.55 cm². Receptor wells were filled with isotonic phosphate buffered saline ("PBS") with a pH of 5.5. The flanges of the Franz cells were coated with vacuum grease to ensure a complete seal and were clamped together with uniform pressure. After the Franz cells were assembled, the skin was allowed to pre-hydrate for about 45 minutes. The dosing level was 100 μl. The Franz cells were maintained at 32 ⁰C by placement in a humidified incubator, and the receptor wells of the Franz cells were stirred with a magnetic stir bar. Sample aliquots were drawn from the receptor wells at varying time points and replaced with fresh buffer. Measurements for each formulation were carried out in five- fold replicate. The concentration of the active in the sample aliquots was analyzed using HPLC.

General Method for Skin Retention Studies: [0163] At the end of the permeation study, skin samples were removed from the Franz cells for skin retention studies. Any excess of formulation was carefully wiped away, first with cotton swabs and then with lint-free paper. The skin samples were quickly washed with cold water and ethanol, and the skin samples were then dried for 1 h at room temperature. After being cut into small pieces with a pair of stainless steel scissors, the samples were transferred into 5 HiL scintillation vials, and 2 mL of absolute ethanol was added. The mixtures were homogenized with a laboratory homogenizer (PRO 250 from PRO Scientific, Oxford CT) for approximately 2 min. During this process, extra care was taken to avoid any excessive temperature increase. The homogenate was filtered through 9 mm diameter disposable syringe filters (0.45 μm, Acrodisc®). The filtrate, after appropriate dilution, was assayed by HPLC.

[0164] Results from these studies and formulations used are described in the following Tables 2-4 and FIGS 2-4. In all permeation figures, each set of error bars represent the standard error of the mean, whereas in all retention figures, each set of error bars represent the standard deviation of the mean.

[0165] Table 2: First Set of Eutectic Formulations

[0166] As displayed in FIG. 2A, formulations F1-F4 are eutectic melts with lidocaine. It is evident that the addition of other eutectic agents enhance the permeation significantly.

Among the lidocaine-containing formulations, F3, which contains 2-amino-2-rnethylpropanol ("AMP"), and F4, which contains menthol/phenol, exhibit the highest permeation

enhancement.

[0167] F5-F8 do not contain lidocaine. F5 is a gel-type eutectic formulation with choline chloride/urea/AMP and shows the best permeation behavior from the first set.

[0168] The remaining formulations F6-F8 form liquids or gels at room temperature, but do not to show substantial permeation improvement.

[0169] As displayed in FIG. 2B, the highest skin retention was also observed with F3. The remaining formulations, although having lower skin retention than F3, exhibit better skin retention than the control cream (Lamisil^®).

[0170] The control and placebo do not provide any significant permeation or retention.

[0171] Table 3: Second Set of Eutectic Formulations

[0172] FIGS. 3 A and 3B illustrate the results of transdermal studies on eutectic melts with additional ingredients. The formulations F21-F23 show the highest permeation behavior in this second set. All contain a urea/choline chloride-based eutectic melt in conjunction with other excipients.

[0173] F21, F22, F24 and F25 exhibit the highest retention of the above formulations. The data shows that certain phenolic eutectic agents, such as phenol (F24) and resorcinol (F25), produce terbinafine fluxes lower than those from other formulations in the set, such as F21 and F22. [0174] Table 4: Third Set of Eutectic Formulations

[0175] Referring to the terbinafine permeation data displayed in FIG. 4 A, formulations F31-F34 contain 10% or less of the active agent, whereas formulations F35-F37 have 14.3% active and formulation F38 contains -10.9% active. It appears that at least for this set of formulations, the precise terbinafine concentration is not critical to performance.

[0176] F31-F33 are choline chloride/urea-based eutectic formulations and they all provide similar terbinafine permeation behavior, whereas F34 is a camphor/menthol/glycerin monolaurate-based eutectic formulation. F35 has similar constituents to F34, except glycerin is replaced by phenol. F36 is a resorcinol version of F35, and F37 contains additional lauryl alcohol as compared to F36. F38 is a choline chloride/urea based eutectic formulation containing glycerin monolaurate, lauryl alcohol, and menthol eutectic melts.

[0177] From the above data it appears that choline chloride/urea based eutectic

formulations are especially effective.

[0178] As displayed in FIG. 4B, formulations F31, F32 and also F36 and F37 show the highest terbinafine skin retention from among the third formulations set. As displayed in the earlier examples, the marketed control (Lamisil^®) affords minimal terbinafine skin retention.

[0179] Table 5: Selected Eutectic Terbinafine Formulations I:

[0180] Based on various permeation and retention studies, eutectic melts of terbinafine and eutectic solutions of terbinafine exhibit various degrees of permeation and retention. Even the least effective formulations of the first three sets (Tables 2, 3 and 4) exhibit terbinafine skin permeation behavior that is at least similar to that of the controls. The most effective formulations show approximately tenfold higher terbinafine skin permeation than commercial and clinically tested controls. From these data, it is apparent that the formulations of the present invention are remarkably effective at delivering terbinafme through a model membrane.

[0182] As displayed in FIG. 5 A, the addition of glycerin monolaurate to a composition comprising 10% choline chloride and 20% urea (F41) enhances permeation (F43). The removal of one eutectic agent, urea, in F44 results in a reduction of terbinafme permeation and retention, as does the removal of the eutectic agent choline chloride (F45) or the removal of both choline chloride and urea (F46). The composition comprising 5% choline chloride and 10% urea (F47) evidently enhances terbinafme permeation relative to F41. F48 is a non- eutectic melt formulation, identical in composition to that of F41, but obtained by simple combination of the ingredients. Notably, it does not provide significant terbinafme permeation enhancement. [0183] As displayed in FIG. 5B, these composition modifications that lead to substantial changes in terbinafme permeation, have little impact on terbinafme skin retention in the shed- snake-skin model system.

[0185] As displayed in FIG. 6A, lecithin, a choline derivative (namely,

phosphatidylcholine) has some potential benefit as a terbinafme permeation enhancer (F53 and F55). However, a high lecithin concentration reduces terbinafme permeation (F51). Other anionic detergents (F56-F58) tested as replacements for choline chloride do not exhibit synergistic behavior with urea like that of choline chloride.

[0186] As displayed in FIG. 6B, inclusion of sodium N-lauroyl sarcosinate (formulation F57) can increase terbinafme skin retention.

[0188] FIG. 7 illustrates the results for exemplary lacquer-type formulations (Table 8). Although the lecithin-containing formulation F61 shows some terbinafme permeation enhancement, the choline chloride-containing formulation F66 exhibits the most pronounced terbinafme permeation enhancement of the set.

Example 27: Permeation and Retention Model Studies of Terbinafine Eutectic Melt Through Bovine Hoof [0189] Bovine hoof was used as a model nail substrate as it is composed of keratinaceous material quite similar to human nail. Franz cells with a 3-mL receptor well volume were used in conjunction with bovine hoof slices. The donor well had an area of ~0.55 cm². Receptor wells were filled with isotonic phosphate buffered saline (PBS) with a pH of 5.5. Bovine hoof slices of thickness 1 mm were cut from a bovine hoof obtained from a local

slaughterhouse using a sharp knife. The slices were soaked for at least 24 hours in water and then glued to the donor and receptor cell of the Franz cell with adhesive. A pinch clamp was applied to the assembly. Test formulations were applied to the hoof at a dosing level of 5 μl per dose. Formulation was applied to the hoof slice on a daily basis. Before each application, a dry Q-tip cotton swab was used mechanically to remove any residual formulation from previous applications. The Franz cells were maintained at 32 °C by placement in an incubator, and the receptor wells of the Franz cells were stirred with a magnetic stir bar. Sample aliquots were drawn from the receptor wells at varying times (as shown in the figures reporting permeation data) and replaced with fresh buffer.

Measurements for each formulation were carried out in at least five-fold replicate. The concentration of the active in the sample aliquots was analyzed using HPLC. Retention of antifungal in the hoof slice was assessed at the end of the experiment by mechanically cleaning the slice and then wiping with pure ethanol. The bovine hoof slice was cut into small pieces using scissors, and an extraction was performed using a mixture of

[0190] Table 9: Selected Terbinafϊne Eutectic Formulations II

[0191] As shown in FIG. 8B, the eutectic melt formulations exhibited higher terbinafine permeation enhancement even at micro doses in comparison to the control cream (Lamisil^®). Dosing was performed at 5 μl/day for every formulation tested, including the control.

Although the permeation enhancement ratio for formulation T09501-01 relative to control is modest at early time points, the ratio increases significantly with time. [0192] As shown in FIG. 8 A, the eutectic melt formulations display terbinafine bovine hoof retentions of up to ten-fold greater than that seen with Lamisil^® Cream.

Example 28: Terbinafine Human Cadaver Nail Penetration Studies

[0193] The effect of eutectic melts containing an exemplary active agent (terbinafine) on transungual permeation and nail retention was examined with human cadaver nails as the model. Franz cells with a 3-mL receptor well volume were used in conjunction with human cadaver fingernail substrates obtained from Science Care (Phoenix, AZ). The protocol applied was similar to that described in Example 27 with human nail replacing the bovine hoof. Each formulation was tested in five- fold replicate. Lamisil^® Cream was used as the control.

[0194] Table 1OA: Terbinafine Exemplary Formulations

Ingredients NRM 002-03

% w/w

Terbinafine HCI 10

Ethanol 43.68

Water 5

Urea 10

Choline chloride 3

L-Lactic acid 5

GML 3

Limonene 5

IPA 10

Tween 20 3

Alpha tocopherol 0.02

Ascorbic acid 0.3

HPC HY117 2

[0195] Table 1OB: Terbinafine Exemplary Formulations

[0196] Tables 1OA and 1OB describe several exemplary anti-fungal compositions, at differing terbinafine concentrations. To prepare these formulations, a eutectic melt of choline chloride and urea was generated by mixing and heating at 90⁰C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Afterwards, lactic acid, Tween 20, EPM, limonene (if present) and antioxidants (if present) were added. Ethanol, water, isopropanol, and glycerin monolaurate was used to dissolve the resulting gel, and hydroxypropyl cellulose (low- viscosity form, HY 117) was added to obtain the final formulation as a gel. [0197] FIGS. 9A-D illustrate terbinafine permeation test results for four exemplary antifungal compositions with differing terbinafine concentrations. As demonstrated, penetration for the active compositions was much better than for the control. In the case of the experiment for which accumulated dose data are depicted in FIG. 9B₅ nail retention of terbinafine was 1.82 mcg/cm (corresponding to 0.20 + 3 mcg/mg nail) and 28.19 mcg/cm (corresponding to 3.1 + 8 mcg/mg nail) for Lamisil and NRI- 1002-04, respectively.

[0198] Table 11 provides a comparison of the relative terbinafine permeation

enhancements provided by the different formulations of Tables 1OA and 1OB; the data are also illustrated in FIG. 10. [0199] Table 11: Comparison of Relative Enhancement of Terbinafine Permeation

[0200] As shown in Table 11 and FIG. 10, terbinafine permeation increases at a higher terbinafine concentration (i.e., 10% vs. 15%), but terbinafine permeation does not increase linearly with terbinafine concentration over the concentration range tested. [0201] Example 29: Solubility Study on Terbinafine Hydrochloride

[0202] This example describes the results of a solubility study on terbinafine

hydrochloride.

Procedure

[0203] Buffer Preparation: Buffers were prepared at 50 mM concentration using ammonium acetate (pH values of 4.0 and 10.0) or ammonium phosphate (pH values of 6.0, 7.0, and 8.0).

[0204] Solubility Sample Preparation: 100 to 800 mg of terbinafine hydrochloride was transferred to separate 4-mL vials. To each vial 2 ml of the solvent to be investigated was added. Samples were capped and then rotated for 24 hours at room temperature. The samples were then allowed to settle overnight at room temperature. Approximately 0.4 mL of the supernatant was removed and transferred to a 0.45 μm Nylon microcentrifuge filter and clarified. Samples were diluted with 50% methanol to within the calibration range. [0205] Sample Analysis: Samples were analyzed by HPLC using methodology based on Standard Test Method STM.004. The STM.004 HPLC conditions were modified to reduce the run time to about 5 minutes. Calibration standards at approximately 0.00, 0.02, 0.1, 0.25, 0.65, and 1.0 mg/mL were used to construct a calibration curve, from which sample concentrations were determined and corrected for dilution to achieve the final solubility result.

[0206] Results: The solubility of terbinafme in the solvents investigated is presented in Table 14.

[0207] Table 12. Summary of Terbinafine Solubility Results.

[0208] Terbinafine hydrochloride shows moderate solubility in aqueous solvents with pHs of 4 and 6, but it shows substantially lower solubility at pHs 7, 8, and 10. Terbinafine hydrochloride shows high solubility in polar organic solvents such as ethanol and DMSO, but lower solubility in non-polar solvents such as ethyl acetate and isopropyl myristate. The solubility in current prototype topical formulations (NRI- 1002-03 and NRI- 1002-04) is high and ranges from 214 to 235 mg mL^'1, corresponding to 21-24% w/v.

[0209] Example 30: Stability Studies of Exemplary Terbinafine Formulations [0210] This example describes the short-term physical and chemical stability of terbinafine formulations for a period of up to three months under long-term {i.e., 25 ± 2° C, 40% ± 5% relative humidity (RH)) conditions.

[0211] General Methods: Terbinafine formulations as provided in Table 1OB were placed in stability chambers at appropriate temperatures in a horizontal orientation.

[0212] Test Methods: High-performance liquid chromatography (HPLC) was used for the assay of terbinafine in raw materials and in formulations. The presence of impurities was also assayed by HPLC.

[0213] Results: The results of the stability studies for certain preferred embodiments are presented in Tables 13 to 22.

[0214] Table 13: Three-Month Stability Study of Terbinafine Formulation NRI-1002-

03 (25 ⁰C)

[0215] Table 13 sets forth the results of a three-month stability study on NR1-1002-03 at 25 °C and ambient humidity.

[0216] Table 14: Three-Month Stability Study of Terbinafme Formulation NRI-1002-

03 (40 ⁰C)

[0217] Table 14 sets forth the results of a three-month stability study on NR1-1002-03 at 40 °C and 75% relative humidity.

[0218] Table 15: Three-Month Stability Study of Terbinafine Formulation NRI-1002-

04 (25 ⁰C)

[0219] Table 15 sets forth the results of a three-month stability study on NR1-1002-04 at 25 °C and ambient humidity. [0220] Table 16: Three-Month Stability Study of Terbinafine Formulation NRl-1002- 04 (40 ⁰C)

[0221 ] Table 16 sets forth the results of a three-month stability study on NRl - 1002-04 at 40 °C and 75% relative humidity.

[0222] Table 17: One-Month Stability Study of Terbinafine Formulation NR1-1002- 04vl (25 ⁰C)

[0223] Table 17 sets forth the results of a one-month stability study on NRI- 1002-04v 1 at 25 °C and ambient humidity. [0224] Table 18: One-Month Stability Study of Terbinafme Formulation NRl -1002- 04vl (40 ⁰C)

[0225] Table 18 sets forth the results of a one-month stability study on NRI- 1002-04v 1 at 40 °C and 75% relative humidity.

[0226] Table 19: One-Month Stability Study of Terbinafine Formulation NR1-1002- 04v2 (25 ⁰C)

[0227] Table 19 sets forth the results of a one-month stability study on NRI- 1002-04v2 at 25 ⁰C and ambient humidity. [0228] Table 20: One-Month Stability Study of Terbinafme Formulation NRl-1002- 04v2 (40 ⁰C)

[0229] Table 20 sets forth the results of a one-month stability study on NRI- 1002-04v2 at 40 ⁰C and 75% relative humidity.

[0230] Table 21 : One-Month Stability Study of Terbinafine Formulation NR1-1002- 04v3 (25 ⁰C)

[0231 ] Table 21 sets forth the results of a one-month stability study on NRI- 1002-04- 060710- v3 at 25 ⁰C and ambient humidity. [0232] Table 22: One-Month Stability Study of Terbinafme Formulation NRl-1002- 04v3 (40 ⁰C)

[0233] Table 22 sets forth the results of a one-month stability study on NRI- 1002-04- 060710-v3 at 40 °C and 75% relative humidity.

[0234] It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0235] The disclosures of all articles and references, including patent applications, patents, and PCT publications, are incorporated herein in their entirety for all purposes. The disclosures are incorporated to the same extent as if each individual article or reference was specifically and individually indicated to be incorporated by reference in its entirety.

Claims

WHAT IS CLAIMED IS: 1. A homogeneous pharmaceutical composition for topical application, said pharmaceutical composition comprising:

a) an anti-fungal agent;

b) a eutectic agent; and

c) optionally a pharmaceutically acceptable low-boiling solvent; wherein said anti-fungal agent and said eutectic agent form a eutectic melt.

2. The pharmaceutical composition of claim 1, wherein said

pharmaceutical composition is substantially anhydrous.

3. A homogeneous pharmaceutical composition for topical application, said pharmaceutical composition comprising:

a) an anti-fungal agent;

b) a eutectic agent;

c) a second eutectic agent; and

d) a pharmaceutically acceptable low-boiling solvent; wherein said eutectic agent and said second eutectic agent form a eutectic melt.

4. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition is substantially anhydrous.

5. The pharmaceutical composition of any of claims 1-4, wherein said low-boiling solvent is a lower alkanol.

6. The pharmaceutical composition of any of claims 1 -4, wherein said composition additionally comprises at least one pharmaceutically acceptable surfactant, emulsifier, or thickener.

7. The pharmaceutical composition of any of claims 1-4, wherein said eutectic melt is a permeation enhancer.

8. The pharmaceutical composition of any of claims 1-4, wherein said eutectic agent is a member selected from the group consisting of phenol, a pharmaceutically acceptable substituted phenol, a quaternary aminoalkanol, a quaternary amino acid salt, a betaine, a terpene, and urea.

9. The pharmaceutical composition of claim 8, wherein said eutectic agent is a member selected from the group consisting of phenol, resorcinol, thymol, choline chloride, camphor, menthol, and urea.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises choline chloride and urea.

11. The pharmaceutical composition of claim 8, wherein said anti-fungal agent is an allylamine anti-fungal agent.

12. The pharmaceutical composition of claim 11, wherein said allylamine anti-fungal agent is an agent selected from the group consisting of amorolfine, butenafme, naftifme, terbinafine, and a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 12, wherein said

composition comprises at least 2% of the anti-fungal agent by weight.

14. The pharmaceutical composition of claim 13, wherein said

composition comprises at least 10% of the anti-fungal agent by weight.

15. The pharmaceutical composition of claim 14, wherein said

composition comprises at least 15% of the anti- fungal agent by weight.

16. The pharmaceutical composition of claim 15, wherein said

composition comprises about 20% of the anti-fungal agent by weight.

17. The pharmaceutical composition of claim 12, wherein said anti-fungal agent is terbinafine or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 17, wherein said

composition comprises at least 2% of the anti- fungal agent by weight.

19. The pharmaceutical composition of claim 18, wherein said

composition comprises at least 10% of the anti-fungal agent by weight.

20. The pharmaceutical composition of claim 19, wherein said

composition comprises at least 15% of the anti-fungal agent by weight.

21. The pharmaceutical composition of claim 19, wherein said

composition comprises about 20% of the anti-fungal agent by weight.

22. The pharmaceutical composition of any of claims 1-4, wherein said eutectic agent is a pharmaceutically active agent.

23. The pharmaceutical composition of claim 22, wherein said pharmaceutically active agent is an anti-fungal agent.

24. The pharmaceutical composition of claim 23, wherein said anti-fungal agent is a member selected from the group consisting of amorolfine, butenafme, naftifme, terbinafine, and a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition of claim 24, wherein said anti-fungal agent is terbinafine or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 22, wherein said pharmaceutically active agent is an aromatic ester, a heteroaromatic ester, an aromatic amide, a heteroaromatic amide, and a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition of claim 26, wherein said pharmaceutically active agent is a member selected from the group consisting of benzocaine, chloroprocaine, cyclomethycaine, larocaine, propoxycaine, procaine, proparacaine, tetracaine, articaine, bupivacaine, carticaine, cinchocame, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, and a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition of claim 27, wherein said pharmaceutically active agent is lidocaine or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition of any of claims 1-4, wherein said composition comprises a pharmaceutically acceptable emulsifying agent and a

pharmaceutically acceptable thickening agent.

30. The pharmaceutical composition of any of claims 1 -4, said pharmaceutical composition further comprising:

a) lactic acid;

b) a surfactant; and c) a lower alkanol; wherein said anti-fungal agent is an allylamine anti- fungal agent and comprises about 10 to 25% of the pharmaceutical composition by weight, and wherein said eutectic agent is choline chloride or urea.

31. The pharmaceutical composition of claim 30, wherein said surfactant is a fatty acid ester or a polysorbate.

32. The pharmaceutical combination of claim 31, wherein said allylamine anti-fungal agent is terbinafme.

33. The pharmaceutical composition of claim 31, wherein said composition comprises polysorbate 20, isopropyl myristate, and glycerin monolaurate; and wherein the lower alcohol is ethanol or isopropanol.

34. The pharmaceutical composition of claim 31, wherein said composition comprises from about 8 to 12% urea, from about 2 to about 5% choline chloride, and from about 2 to about 5% lactic acid.

35. A method for preparing a pharmaceutical composition for topical use, said method comprising:

adding an anti-fungal agent to a eutectic agent to form an admixture; and optionally heating said admixture until it is substantially homogeneous, wherein said anti-fungal agent and said eutectic agent form a eutectic melt.

36. A method for preparing a pharmaceutical composition for topical use, said method comprising:

adding an anti-fungal agent to a eutectic melt to form an admixture, wherein said eutectic melt comprises a eutectic agent and a second eutectic agent; and

optionally heating said admixture until said anti-fungal agent is substantially dissolved, thereby forming a homogeneous mixture.

37. The method of claim 35 or 36, wherein said pharmaceutical composition is formulated as a member selected from the group consisting of a cream, an emulsion, a gel, a lotion, an ointment, a solution, and a patch.

38. The method of claim 35 or 36, wherein the admixture is heated to a temperature between about 80 °C to about 95 °C.

39. The method of claim 38 , wherein the admixture is heated to about 90 ⁰C.

40. A pharmaceutical composition for topical application prepared by the method of claim 35.

41. A pharmaceutical composition for topical application prepared by the method of claim 36.

42. A pharmaceutical composition for topical application prepared by the method of claim 39.

43. A method for treating a fungal infection in a subject, said method comprising:

applying a topical anti-fungal composition to a subject to treat said fungal infection, wherein said topical composition comprises:

a) an anti-fungal agent;

b) a eutectic agent; and

c) optionally a pharmaceutically acceptable low-boiling solvent; wherein said anti-fungal agent and said eutectic agent form a eutectic melt.

44. The method of claim 43, wherein said pharmaceutical composition is substantially anhydrous.

45. A method for treating a fungal infection, said method comprising: applying a topical anti-fungal composition to a subject to treat said fungal infection, wherein said topical composition comprises:

a) an anti-fungal agent;

b) a eutectic agent;

c) a second eutectic agent; and

d) a pharmaceutically acceptable low-boiling solvent; wherein said eutectic agent and said second eutectic agent form a eutectic melt.

46. The method of claim 45, wherein said pharmaceutical composition is substantially anhydrous.

47. The method of any of claims 43-46, wherein said low-boiling solvent is a lower alkanol.

48. The method of any of claims 43-46, wherein said topical anti-fungal composition is applied to a nail of said subject.

49. The method of claim 48, wherein the method further comprises measuring the concentration of said anti-fungal agent in the nail.

50. The method of any of claims 43-46, wherein said subject is a human.

51. The method of any of claims 43-46, wherein said fungal infection is onychomycosis.

52. The method of any of claims 43-51, wherein said topical anti-fungal composition is formulated as a member selected from the group consisting of a cream, an emulsion, a lotion, an organogel, an ointment, a lacquer, and a transdermal patch.

53. Use of a homogeneous pharmaceutical composition for topical application, wherein said pharmaceutical composition comprises:

a) an anti-fungal agent;

b) a eutectic agent; and

c) an optional pharmaceutically acceptable low-boiling solvent; wherein said anti-fungal agent and said eutectic agent form a eutectic melt.

54. The use of claim 53, wherein said pharmaceutical composition is substantially anhydrous.

55. Use of a homogeneous pharmaceutical composition for topical application, wherein said pharmaceutical composition comprises:

a) an anti-fungal agent;

b) a eutectic agent;

c) a second eutectic agent; and

d) a pharmaceutically acceptable low-boiling solvent; wherein said eutectic agent and said second eutectic agent form a eutectic melt.

56. The use of claim 55, wherein said pharmaceutical composition is substantially anhydrous.

57. The use of a pharmaceutical composition for treating a fungal infection, wherein said pharmaceutical composition is set forth in any of claims 1-34 or 40- 42.

58. The method of claim 57, wherein the concentration of the anti-fungal agent in the nail is at least twofold the level achieved by oral therapy with said anti-fungal agent.

59. The method of claim 58, wherein the concentration of the anti-fungal agent in the nail is at least twofold greater than the level achieved by oral therapy with said anti-fungal agent