WO2002022115A2

WO2002022115A2 - Methods and compositions for treating nail fungus

Info

Publication number: WO2002022115A2
Application number: PCT/US2001/042134
Authority: WO
Inventors: Fergus R. Mckenzie
Original assignee: The Research Foundation Of State University Of New York At Stony Brook
Priority date: 2000-09-14
Filing date: 2001-09-13
Publication date: 2002-03-21
Also published as: WO2002022115A3; AU2001291308A1

Abstract

Methods and compositions for topical treatment of fungal infections, onychomycosis and dermatophytic fungi comprising one or more active ingredients chosen from a group consisting of (-) Menthol, menthone, menthyl salicylate, (-)(1R) menthyl acetate, (-)(1R)-menthyl chloride, (-) methyloxyacetic acid, optionally also comprising camphor in a pharmaceuticallly acceptable carrier is described.

Description

METHODS AND COMPOSITIONS FOR TREATING NAIL FUNGUS

FIELD OF THE INVENTION

The present invention relates to topical compositions for the treatment of fungal infections. Specifically, the topical compositions described herein are useful for the treatment of onychomycosis.

BACKGROUND OF THE INVENTION Both humans and animals can be afflicted with microorganisms that invade beneath the nail, claw or hoof resulting in a condition which causes discoloration, thickening, brittleness, pain, and ultimately loss of the affected nail, claw or hoof. This condition, known as onychomycosis or Tinea unguium (ringworm of the nails), is caused primarily by members of a group of parasitic fungi known as Trichophyton rubrum or Trichophyton mentagrophytes, and occasionally by Aspergillus fumigatus. Epidermophytonfloccosum, Microsporum cards, Microsporum gypsum and other organisms may also be causative agents of onychomycosis. Onychomycosis is particularly prevalent in humans, affecting 15-20% of the population.

Known treatments for onchomycosis have to date been marginally effective and highly expensive. Traditionally, onychomycosis has been treated with an oral medicine known as Griseofulvin®, which is largely ineffectual and has undesired side effects. Other treatments used to combat onychomycosis include Lamisil® (terbinafine), which is taken once a day for 90 days resulting in nail clearing in 70-80% of patients for one year. However, the typical cost to treat a patient with this medicine is approximately $600 or more. Another medicine, Sporanox® (itraconazole), is taken twice a day for one week each month over the course of three to four months. Cost is also a problem, with a typical course of itraconazole treatment in the $600 range. In addition, the side effects of itraconazole are somewhat severe and the remission rate is 60-80%. Fluconazole may also be used to treat onychomycosis, however, it also has severe side effects. Given the poor cure rate, undesirable side effects and high costs associated with existing treatments, a significant need exists for effect cost effective treatments for onychomycosis.

Recent research has focused on topical preparations of known antifungal agents for treatment of onychomycosis. However, since the pathogenic fungus resides in the nail bed, effective topical compositions must be able to penetrate the affected nail in order to avoid surgical removal of the nail. However, to date, no such topical compositions have been described.

Thus, there is a need for effective topical antifungal compositions which are safe and effective in treating onychomycosis with limited side effects. In particular there is a need for effective, safe, and inexpensive topical antifungal compositions to treat onychomycosis which avoid surgical removal of the nail.

Accordingly, it is a primary object of the invention to provide compositions which are effective topical antifungal compositions and which are particularly useful against onychomycosis. It is another object of the invention to provide a method of treating fungal infections, particularly onychomycosis, using the compositions of the invention. Other features and advantages of the present invention will be apparent to those skill in the art from the following detailed description and claims.

SUMMARY OF THE INVENTION

The present invention is directed to a method of treating fungal infections, particularly onychomycosis. The method comprises topically administering the compositions of the invention to an animal in an effective amount and for sufficient duration to treat fungal infections. In one embodiment, the animal is human. The compositions for topical application comprise an effective amount of one or more of a compound selected from the group consisting of (-) menthol, menthone, menthyl salicylate, (-)(1R) menthyl acetate, (-)(1R) menthyl chloride and menthyloxyacetic acetic acid; and a pharmaceutically acceptable carrier. Preferably, the carrier is suitable for topical application to the nail. One carrier suitable for the composition of the invention is a mixti petroleum hydrocarbons. Another suitable carrier is a cream comprising one or more ingredients selected from a C₈-C₂₀ long chain alcohol, a C₁₀-C₄₀ long chain ester, a C₈-C₂₀ long chain carboxylic acid, a copolyol, EDTA, glycerin, imidazole urea, methyl paraben, polyethylene glycol-100 stearate, sodium hydroxide and turpentine.

Another suitable carrier is an alcoholic carrier. In a preferred embodiment, the alcoholic carrier comprises a C_rC₉ alcohol, a preservative or a combination thereof. A preferred C_j-Cg alkyl alcohol is ethanol.

Preferably, the composition further comprises camphor as an additive. In another embodiment, the present invention is directed to a method for the treatment of fungal infections. The method comprises topically applying the composition of the invention to an affected area of an animal in need of such treatment.

In another embodiment, the present invention is directed to a method for the treatment of onychomycosis comprising the topical application of the composition of the present invention to the nails, claws or hooves of an animal in need of such treatment.

Preferably, such treatment is administered twice during a 24 hour period over a course of time of about one to three months.

In another aspect, the invention provides an antifungal composition comprising one or more of a compound selected from the group consisting of (-) menthol, menthone, menthyl salicylate, (-)(1R) menthyl acetate, (-)(1R) menthyl chloride and menthyloxyacetic acid; and a pharmaceutically acceptable carrier selected from the group consisting of petroleum hydrocarbons, cream, and alcohol-based gel carrier. Preferably, the menthol or menthol derivative comprises between about 2% to 10% of the composition, and the carrier comprises between about 80% to 98% of the composition.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the inhibition of Trichophyton mentagrophytes growth on Sabouraud Dextrose Agar plates treated with compositions of the invention. The agar was modified by the addition of the following ingredients: Fig. 1A, G418 antibiotic; Fig. IB, Amphotericin B; Fig. 1C, Petrolatum; Fig. ID, Nicks vapor rub; Fig. IE, 5% Menthol, 5%

Camphor; Fig. IF, 5% Menthol; Fig.lG, 90% Ethanol; and Fig. 1H, 5% Camphor.

Figure 2 shows inhibition of Aspergillus fumigatus growth on Sabouraud Dextrose Agar plates treated with compositions of the invention. The agar was modified by the addition of the following ingredients: Fig. 2A, G418 antibiotic; Fig. 2B, Amphotericin B; Fig. 2C, Petrolatum; Fig. 2D, Nicks vapor rub; Fig. 2E, 5% Menthol, 5% Camphor; Fig. 2F,

5% Menthol; Fig.2G, 90% Ethanol; and Fig. 2H, 5% Camphor.

Figure 3 shows inhibition of Trichophyton rubrum growth on Sabouraud Dextrose Agar plates treated with compositions of the invention. The agar was modified by the addition of the following ingredients: Fig. 3A, G418 antibiotic; Fig. 3B, Amphotericin B; Fig. 3C, Petrolatum; Fig. 3D, Nicks vapor rub; Fig. 3E, 5% Menthol, 5% Camphor; Fig. 3F,

5% Menthol; Fig.3G, 90% Ethanol; and Fig. 3H, 5% Camphor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the findings of in vitro microbiological tests that a topical formulation containing one or more of the following active agents; (-) menthol, or a menthol derivative or analog, e.g., menthone, menthyl salicylate, (-) (1R) menthyl acetate, (-) (1R) menthyl chloride, and menthyloxyacetic acid, and preferably further comprising camphor, is effective in the topical treatment of fungal infections, particularly onychomycosis, as well as dermatophytic fungi. The formulation of the invention comprises either a cream-based carrier, petroleum hydrocarbon-based carrier, or, preferably, an alcohol-based gel carrier. The preferred alcohol-based gel carrier comprises a C_j-C₉ alkyl alcohol, preferably ethanol; a gel forming agent, preferably either hydroxypropyl cellulose or carboxy methyl cellulose; and a preservative, preferably propylene glycol or methyl paraben. The present formulation has several advantages over prior art forr are particularly desirable for treating fungal infections of the nail, which include the ability to penetrate the nail, and attack fungus residing in the nail bed.

As used herein the aforementioned term animal is understood to encompass humans.

As used herein, the term "dermatophytic fungal infection" refers to an infection of the dermis or nails (fingernails, toenails, or, for non-human animals, hooves or claws) by a fungus. Such fungi include, but are not limited to, Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophytonfloccosum, Aspergillus fumigatus, and Candida albicans. In particular, such an infection can be called "onychomycosis," which is a general term referring to the infection of the nail by any fungal species. The term "affected area" is understood herein to include dermis or nails. The term "nails" includes fingernails, toenails, or, for non-human animals, hooves or claws.

A "menthol derivative or analog" refers to a molecule that shares structural and functional features in common with menthol, and which may be prepared by chemical treatment of menthol. For purposes of the present invention, a menthol derivative or analog has antifungal activity. Examples of derivatives and analogs include, but are not limited to menthone, menthyl salicylate, menthyl acetate, menthyl chloride, and menthoxyacetic acid.

The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. A pharmaceutically acceptable a preferably enhances delivery of the active agent (menthol or menthol derivative or analog) to the nail bed. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 17^th Edition. The phrase "therapeutically effective amount'Or "effective amount" is used herein to mean an amount sufficient to reduce by at least about 15 percent, preferably by at least 50 percent, more preferably by at least 90 percent, and most preferably prevent, a clinically significant deficit in the activity, function and response of the host. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition in the host.

As used herein, the term "about" or "approximately" means that the referenced value can vary by 20%, preferably by 10%, more preferably by 5%, and more preferably by 1%. The term can also mean that the value varies by an acceptable amount, e.g. , the acceptable variance for components of a composition for regulatory approval, or within the limits of accurate measurement.

Compositions The amount of active agent(s) in the formulation of the invention may range from about 2% to about 10% by weight of the total composition, and preferably is about 4%. Additionally, camphor may be added to the formulation in an amount of from about 2% to about 11% by weight of the total composition, preferably about 2% to about 4.6%.

As noted above, the advantages of the invention in treating nail infections may be enhanced by the selection of a suitable pharmaceutically acceptable carrier. Such a carrier provides high viscosity and adhesiveness to hold the active agent in place at the nail and to ensure sufficient opportunity for effective penetration. Suitable carriers include petroleum hydrocarbon bases, creams, and gels, e.g., an alcohol-based gel.

Petroleum hydrocarbons selected for compositions of the invention are preferably high molecular weight hydrocarbons, with a melting point above body temperature (37°C). For example, petroleum or petroleum jelly may be employed as suitable carriers for the active ingredient(s). As both menthol and camphor are poorly soluble in water, petrolatum has been found to be a particularly suitable vehicle to use. For those patients who prefer a non-sticky/greasy water-based vet composition of the invention may be prepared in a a creme formulation. Cream formulations are widely used, industry standard, buffered formulations, typically used for agents which are soluble in alcohol and poorly soluble in water. Such creams may contain cetyl alcohol, cetyl palmitate, copolyol, EDTA, glycerin, H₂0, imidazole-urea, isopropyl palmitate, methyl paraben, PEG- 100 stearate, sodium hydroxide, turpentine, stearic acid, or stearyl alcohol.

Creams which include lotions, salves, and the like, are well known in the art. A preferred cream formulation comprises ingredients selected from a C₈-C₂₀ long chain alcohol, a C₁₀-C₄₀ long chain ester, C₈-C₂₀ long chain carboxylic acid, a copolyol, EDTA, glycerin, water, imidazole urea; methyl paraben, polyethylene glycol- 100 stearate, sodium hydroxide and turpentine.

A preferred alcoholic-based gel carrier contains a C C₉ alkyl alcohol, preferably ethanol, present in about 15% to about 50%) of the total composition. The carrier also preferably includes a gel forming agent, preferably either hydroxypropyl cellulose or carboxymethylcellulose present in a concentration of about 1 % to 5% by weight of the total composition. The alcohol-based gel composition can be brought to 100% by the addition of water and brought to neutral pH (pH 7) by the addition of sodium hydroxide. Preferably the alcohol used in the composition should be water free.

In a preferred embodiment, the carrier includes a preservative, preferably either propylene glycol or methyl paraben present in a concentration of about 5% to 25% by weight of the total composition.

A preferred alcoholic composition of the present invention comprises 2% (w/w) carboxymethylcellulose; 30%) (w/w) ethanol; 15% propylene glycol or methyl paraben; 4% (w/w) menthol and 2% (w/w) camphor. Water is then added to bring the total to 100% and the solution neutralized to pH 7 by the addition of sodium hydroxide.

The compositions of the present invention may be packaged in an appropriate container. The compositions may be supplied in bottles with brush applicators or applicator tipped bottles or glass rod applicator bottles. Treatment of Fungal Infections A typical protocol for using the compositions of the invention on an animal with onychomycosis is as follows.

1. Remove the affected nail, claw or hoof including all infected regions without injuring the cuticle or nail bed.

2. Wash and dry the nail, claw or hoof.

3. Apply the compositions of the invention to the nail, claw or hoof.

4. Repeat the procedure twice during each 24 hour period over the course of about one to three months. In general, topical administration of the composition of the invention, whether petroleum hydrocarbon, cream, or gel-based, should follow thorough cleansing of the affected area, and be as complete as possible. For example, in treating the nails, the composition is worked under the nail, e.g., into any spaces that have formed, and around the edge of the nail. Preferably, the antifungal compositions of the invention are applied twice within every 24 hour period. The compositions of the invention may be applied for at least about one month for a milder infection, and for about two or more months to clear a more advanced infection, or where the entire nail is involved.

Therapeutic effectiveness is observed by a reversal of nail deterioration or pain, and by an improvement in nail appearance. These methods can also be used to treat reinfection, should that occur.

The invention has been described in general terms and now specific examples are described. It should be understood that these examples are not meant to limit the present invention. EXAMPLES

EXAMPLE 1 : In Vitro Testing for Antifungal Activity Petri Dish Experiments

From a stock plate of Trichophyton mentagrophytes, mycelia were scraped from the media surface and resuspended in standard yeast media (YPD broth (Clontech, Palo Alto, CA)). Following gentle vortexing to break up clumps, the resulting supernatant was diluted 1 : 10 (in YPD) and plated on Sabouraud Dextrose Agar plates (Becton Dickinson, Franklin Lakes, NJ) which had been modified as follows: Sabouraud Dextrose A were modified by addition of a 200 microlitre solution of either: (A) G418 antiobiotic (100 mg/ml), (B) Amphotericin B anti-fungal agent (12.5 microg/ml), (C) Petrolatum, (D) Nicks vapor rub, (E) 5% (w/v) menthol, 5% (w/v) Camphor, (F) 5%(w/v) Methanol, (G) 90% Ethanol, (H) 5% (w/v) Camphor. Agents (A) and (B) were dissolved in H₂O. Agents (E), (F) and (H) were dissolved in 90% Ethanol as the vehicle. Agents (C) and (D) were heated to approximately 80 °C in a sealed container to render them more liquid and easier to spread on the petri dish. An additional petri dish with no agent added served as a control and supported fungal growth identical to that seen in the plates treated with 90% ethanol. Fungal growth is evident as black areas on the petri dish following a period of growth (typically 7-14 days) at

30 °C in a humid environment. The growth of Trichophyton rubrum and Aspergillus fumigatus were tested in a similar manner.

Results

As shown in Figures 1-3, in the in vitro experiments, Menthol and menthol derivatives inhibited the growth of the three fungal strains tested {Trichophyton rubrum,

Trichophyton mentagrophytes and Aspergillus fumigatus with the following order of potency: Menthone > Menthol = Menthyloxyacetic acid> Menthyl salicylate> Menthyl acetate> Menthyl chloride.

Camphor, on its own, has little or no detectable anti-fungal activity. However a composition of 4% Menthol with 2% Camphor was significantly more potent in its ability to kill toenail fungus. The camphor also likely acted as a penetration agent allowing better access of the Menthol to the fungus under the toenail bed.

EXAMPLE 2: Antifungal Compositions This example describes two formulations for delivery of a topical anti- onychomycotic agent. The formulations contain Menthol or an Analogue at 4% (W/V), and

Camphor at 2% (W/N). The vehicle used is either petrolatum or a cream formulation. The composition is applied to the infected nail (following removal of extraneous nail and washing) twice daily over a one month period. EXAMPLE 3: Gel Formulation

This example describes a simplified gel for topical delivery of Menthol and Camphor, useful as an anti-onychomycotic agent. The formulation of the gel is: 2% (w/v) carboxymethylcellulose (gelling agent), 30% (v/v) ethanol (to maintain Menthol and Camphor in solution), 15% (w/v) propylene glycol or methyl paraben (as a preservative), neutralized with sodium hydroxide, and completed to 100% with H₂0.

Menthol is added to 4% (w/v), and camphor to 2% (w/v).

EXAMPLE 4: Antifungal Activity of Compositions This example reports results using menthol at concentrations of 0, 0.1 , 0.3 , 1 ,

3, and 5 %, used alone, or in combination with camphor at concentrations of 1, 2 or 4%.

Either petrolatum base (Example 2), or cellulose-alcohol base (Example 3) were used as carriers.

Materials and Methods Trichophyton rubrum, Trichophyton mentagrophytes, Aspergillus fumigatus,

Candida albicans and Epidermophytonfloccosum were each inoculated onto a petri dish, scraped off, vortexed to break up mycelial bodies and diluted before being replated on petri dishes with menthol or menthol/camphor in the concentrations described above. After the appropriate growth period (2-3 weeks for Trichophyton rubrum, Trichophyton mentagrophytes and Epidermophytonfloccosum, 1 week for Aspergillus fumigatus and 5 days for Candida albicans) each dish was scored for colony number compared to the control plates.

"100% cell survival" represents the same number of colonies as the control plates for the fungal strain tested.

Results All assays were carried out in duplicate. Fungal analysis by microscopy suggested that the fungi died by cell- wall lysis. The results are summarized in Tables 1 and 2. Table 1 Petrolatum base in-vitro results

Table 2 Gel-base in-vitro results

The results in Tables 1 and 2 show that using either petrolatum-based or gel- based formulations containing the composition of the invention demonstrated increasing antifungal activity with increasing concentration of menthol. EXAMPLE 5: Patient Protocol

1) Affected nail including all 'white-tarnished' infected regions is removed, without injuring the cuticle or underlying nail bed. A sharp pair of nail-clippers is an ideal tool, preferably not leaving infected sections of nail undisturbed.

2) The nail is washed and dried.

3) The composition of the invention is applied, paying particular attention to spaces where the nail is no longer attached to the nail bed. The composition is pushed under and in-between all accessible areas. 4) Application is repeated twice daily (once in the morning and once at night) for 6 weeks for less severe infections, or for two months where the infection is long- term and the entire nail is affected. A significant improvement in the treated nail's appearance is evident after 3-4 weeks.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims. It is further to be understood that all numerical values are approximate and are provided for description only.

Patents, patent applications, and publications cited throughout this application are incorporated herein by reference in their entireties.

Claims

WHAT IS CLAIMED IS: L A method for the topical treatment of dermatophytic fungal infections, which method comprises applying to an affected area of an animal in need of such treatment an effective amount of a composition comprising: a) one or more of a compound selected from the group consisting of (-) menthol, menthone, menthyl salicylate, (-)(1R) menthyl acetate, (-)(1R) menthyl chloride, and menthyloxyacetic acid; and b) a pharmaceutically acceptable carrier.

2. The method of claim 1 wherein the composition further comprises camphor.

3. The method of claim 1 wherein the carrier comprises one or more petroleum hydrocarbons.

4. The method of claim 1 wherein the carrier isa cream comprising one or more ingredients selected from the group consisting of a C₈-C₂₀ long chain alcohol, C₁₀-C₄₀ long chain ester, C₈-C₂₀ long chain carboxylic acid, copolyol, EDTA, glycerin, imidazole urea, methyl paraben, polyethylene glycol- 100 stearate, sodium hydroxide, and turpentine.

5. The method of claim 1 , wherein the dermatophytic fungal infection is caused by Candida albicans.

6. The method of claim 1 , wherein the dermatophytic fungal infection is caused by a fungus selected from the group consisting of Trichophyton rubrum, Trichophyton mentagrophytes, and Aspergillus fumigatus, Epidermophytonfloccosum, Microsporum canis, and Microsporum gypsum.

7. The method of claim 1 wherein the animal is a human.

8. The method of claim 1 wherein the carrier comprises a C_rC₉ alkyl alcohol and a gel forming agent.

9. The method of claim 8 wherein the carrier is ethanol.

10. The method of claim 8 wherein the gel forming agent is hydroxypropyl cellulose or carboxymethyl cellulose.

11. The method of claim 8 wherein the carrier further comprises a preservative.

12. The method of claim 11 wherein the preservative is propylene glycol or methyl paraben.

13. A method for the treatment of nail, hoof or claw fungal infections, which method comprises applying to the nail, hoof or claw of an animal in need of such treatment an effective amount of a composition comprising: a) one or more of a compound selected from the group consisting of (-) menthol, menthone, menthyl salicylate, (-)(1R) menthyl acetate, (-)(1R) menthyl chloride, and menthoxyacetic acid; and b) a pharmaceutically effective carrier.

14. The method of claim 13, wherein the composition further comprises camphor.

15. The method of claim 13 , wherein the fungal infection is caused by a fungus selected from the group consisting of Trichophyton rubrum, Trichophyton mentagrophytes, Aspergillus fumigatus, Epidermophytonfloccosum, Microsporum canis, and Microsporum gypsum.

16. The method of claim 13 wherein the carrier is a mixture of petroleum hydrocarbons.

17. The method of claim 13, wherein the carrier is a cream comprising one or more ingredients selected from the group consisting of C₈-C₂₀ long chain alcohols, C₁₀-C₄₀ long chain esters, C₈-C₂₀ long chain carboxylic acids, copolyol, EDTA, glycerin, imidazole urea, methyl paraben, polyethylene glycol- 100 stearate, sodium hydroxide and turpentine.

18. The method of claim 13 wherein the carrier is a neutral alcoholic gel carrier.

19. The method of claim 18 wherein the carrier comprises a C_j-Cg alkyl alcohol.

20. The method of claim 18 wherein the carrier further comprises a gel forming agent.

21. The method of claim 20 wherein the gel forming agent is hydroxypropyl cellulose or carboxymethylcellulose.

22. The method of claim 18 wherein the carrier further comprises a preservative.

23. The method of claim 22 wherein the preservative is propylene glycol or methyl paraben.

24. The method of claim 13 comprising applying the composition to the nail, claw or hoof two times within a 24-hour period.

25. The method of claim 13 comprising applying the composition to the nail, claw or hoof two times within a 24-hour period of about between one to three months.

26. The method of claim 13 wherein the animal is a human.

21. A method for the treatment of onychomycosis, which method comprises applying to a nail, claw or hoof of an animal in need of such treatment an effective amount of a composition comprising: a) one or more of a compound selected from the group consisting of (-) menthol, menthone, menthyl salicylate, (-)(1R) menthyl acetate, (-)(1R) menthyl chloride, and menthoxyacetic acid; and b) a pharmaceutically effective carrier.

28. The method of claim 27, wherein the composition further comprises camphor.

29. The method of claim 27 wherein the animal is a human.

30. The method of claim 27 wherein the carrier comprises a mixture of petroleum hydrocarbons.

31. The method of claim 27 wherein the carrier comprises a cream.

32. The method of claim 27 wherein the carrier is a neutral alcoholic gel carrier comprising a C,-C₉ alkyl alcohol, a gel forming agent, and a preservative.

33. The method of claim 32 wherein the C_rC₉ alkyl alcohol is ethanol.

34. The method of claim 32 wherein the gel forming agent is hydroxypropyl cellulose or carboxy methyl cellulose.

35. The method of claim 32 wherein the preservative is propylene glycol or methyl paraben.

36. The method of claim 27 comprising applying the composition to the nail, claw or hoof two times within a 24-hour period.

37. The method of claim 27 comprising applying the composition to the nail, claw or hoof two times during a 24-hour period for a period of about one to three months.

38. A composition for the topical treatment of fungal infections of nails comprising: a) an effective amount of one or more of a compound selected from the group consisting of (-) menthol, menthone, menthyl salicylate, Θ(1R) menthyl acetate, (-)(1R) menthyl chloride, and menthyloxyacetic acid; and b) a pharmaceutically acceptable carrier.

39. The composition of claim 38 wherein the compound is present in an amount of about 2 to 10% by weight of the total composition.

40. The composition of claim 38, further comprising camphor.

41. The composition of claim 40 wherein the camphor is present in an amount of about 2 to 11 % by weight of the total composition.

42. The composition of claim 38, wherein the fungal infection is caused by a fungus selected from the group consisting of Trichophyton rubrum, Trichophyton mentagrophytes, Aspergillus fumigatus, Epidermophytonfloccosum, Microsporum canis, and Microsporum gypsum.

43. The composition of claim 38 wherein the carrier is a mixture of petroleum hydrocarbons.

44. The composition of claim 38, wherein the carrier is a cream, comprising one or more ingredients selected from the group consisting of C₈-C₂₀ long chain alcohols, C₁₀-C₄₀ long chain esters, C₈-C₂₀ long chain carboxylic acids, copolyol, EDTA, glycerin, imidazole urea, methyl paraben, polyethylene glycol- 100 stearate, sodium hydroxide and turpentine.

45. The composition of claim 38 wherein the carrier comprises a C_j-C₉ alkyl alcohol and a gel forming agent.

46. The composition of claim 45 wherein the carrier is ethanol.

47. The composition of claim 46 wherein the ethanol is present in an amount of about 15 to 50% by weight of the total composition.

48. The composition of claim 45 wherein the gel forming agent is hydroxypropyl cellulose or carboxymethylcellulose.

49. The composition of claim 48 wherein the gel forming agent is present in an amount of about 1 to 5% by weight of the total composition.

50. The composition of claim 45 wherein the carrier further comprises a preservative.

.

51. The composition of claim 50 wherein the preservative is propylene glycol or methyl paraben.

52. The composition of claim 51 wherein the preservative is present in an amount of about 5 to 25% by weight of the total composition