Technical Field. The invention relates to certain methods and compositions for the treatment of onychomycoses (i.e. fungal infections of the toenail or fingernail).

Background Art. Fungal infections of the fingernails and toenails are a bane to the person who suffers from them. The infection variably spreads from nail to nail. The infection is unsightly, and, in some instances, it evolves from a superficial infection of the nails to a life-threatening systemic infection. It can also lead to secondary bacterial" infections. Occasionally the person's leg needs to be amputated.

Subjects who are immunocompromised are especially susceptible to such infections. Diabetes, drug (e.g. cancer chemotherapy) therapy, AIDS, and other disease states can immunocompromise a subject, and the occurrence of onychomycoses in these groups of people is greater than the population as a whole.

Current treatment usually involves completely removing ("avulsing") the affected nail, and treating the patient with oral antifungal agents ("antifungals or antimycotics"). However this treatment is believed to have nearly a 100% relapse rate within five years.

Griseofiilvin is one oral antifungal agent that is produced by, for example, Penicillium griseofurvum Dierck or Penicillinm jaczewski Zal. (see, e.g. U.S. Patent 3,607,656 to Laine et al., patented Sept. 21, 1971).

Topical compositions containing griseofiilvin have been described. For example, U.S. Patent 3,524,916 to Mima et al. (Aug. 18. 1970) describes griseofiilvin dissolved in ethylene glycol monosalicylate solution for treating athlete's foot, by topically applying the solution. U.S. Patent 3,899,578 to Bird et al. (Aug. 12, 1975) describes a topical griseofiilvin composition for treating fungal skin infections comprising, for example, griseofiilvin, dimethyl phthalate, and benzyl alcohol. U.S. Patents 3,932,653 (Jan. 13, 1976) and 4,039,664 (Aug. 2, 1977) both to Stoughton et al. describe methods for topically administering griseofiilvin to a human. U.S. Patent 3,981,996 to Leigh (Sept. 21, 1976) describes a skin cream having a continuous hydrophobic medium in which there is dispersed

an inert water-insoluble powder, the particles of which carry absorbed thereon an aqueous solution or dispersion of medicament emulsion.

For treating onychomycoses specifically, unspecified solutions of unspecified antimycotic agents are mentioned in U.S. Patent 5,263,206 to Bonn et al. (Nov. 23, 1993). However these solutions are described as requiring application to the nails several times a day. Furthermore the treatment associated with these solutions was also described as including applications of dressings at night. Such therapy is difficult for someone to follow, and this therapy is described as being unsuccessful. A gel containing dimethyl sulfoxide ("DMSO"), urea, ethanol, water, isopropyl palmitate, carbomer-940, di(2-ethylhexyl)amine, and griseofiilvin is disclosed in EXAMPLE 17 of U.S. Patent 4,296,104 to Herschler (Oct. 20, 1981). Methods of treating toenails and fingernails with undergrowing fungal infections are described in EXAMPLES 14 through 20 of this U.S. patent. In all of the described methods however, the affected nails were removed (e.g. by forcep urging) during the treatment with the DMSO containing composition.

Under the best of circumstances, having one's fingernail or toenail removed is not a pleasant experience. The removal can be painful. The sensitive skin underlying the nail is left exposed and unprotected until the fingernail or toenail grows back. When the nail finally does grow back, no guarantee exists that it will not be deformed.

DMSO has been studied to assess how it might influence permeation through the human nail. Walters et al. "Solvent Effects on Nail Permeation", Journal of Pharmacy & Pharmacology. 37:771-775 (1985). DMSO was found to retard permeation rates of model molecules such as methanol and hexanol. Id. A need exists for a once daily, relatively cost-effective therapy for effectively treating toenail or fingernail fungal infections in a way that does not necessarily involve avulsion or debridement of the affected nail or nails.

Disclosure of Invention Surprisingly, an effective treatment for onychomycosis which need not involve avulsion of the nail. The treatment involves topically applying an antifungal agent dissolved in a dimethyl sulfoxide solution, on a regular basis, to the nail and to the nail's epinychium. The antifungal agent is present in the composition in at

least a minimum inhibitory concentration for the antirnycotic agent for the particular fungus when the antifungal agent is dissolved in DMSO. The composition is applied to the infected nail and epinychium on a no more than once daily basis, and the infected nail need not necessarily be removed by avulsion or debridement. The invention thus includes a method of treating or preventing onychomycosis, associated pharmaceutical compositions for treating or preventing onychomycosis (especially ones conta ing dimethyl sulfoxide and from about 0.1 % to about 10% by weight griseofiilvin), and methods of making the pharmaceutical compositions.

Best Mode for Carrying Out the Invention Antifungal agents, as used herein, include both fungistatic compounds (i.e. such compounds merely inhibit the growth of the fungus without killing it) and fungicidal compounds. Specific antifungal agents include flucytosine (also known as 5-fluorocytosine in amounts generally ranging from lmg/ml to lOmg/ml by weight of the composition), griseofiilvin, polyene macrolide antibiotics, especially the heptaenes (e.g. amphotericin B), the imidazole derivatives such as ticonazole, clotrimazole, econazole, oxiconazole, isoconazole, and miconazole (see, e.g. U.S. Patent 3,717,655 to Godefroi et al., patented Feb. 20, 1973 and U.S. Patent 3,839,574 also to Godefroi et al., patented Oct. 1, 1974), bifonazole (U.S. Patent 4,118,487 to Regel et al., patented Oct. 3, 1978), itraconazole (U.S. Patent 4,267,179 to Heeres et al., patented May 12, 1981), naftifine (U.S. Patent 4,282,251 to Berney, patented Aug. 4, 1981), ketoconazole (U.S. Patent 4,335,125 to Heeres et al., patented June 15, 1982), ketoconazole derivatives (U.S. Patent 4,789,587 to Le Clef et al., patented Dec. 6, 1988), fluconazole (U.S. Patent 4,404,216 to Richardson, patented Sep. 13, 1983), thiocarbamic acid derivatives (such as tolnaftate), terbinafine (forms of which are available from Sandoz under the trade designation LAMASIL), and the pharmaceutically acceptable salts (e.g. acid addition salts) thereof. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids such as sulfuric, nitric, phosphoric, and preferably hydrochloric acid, as well as organic acids such as acetic, propionic, succinic, fumaric, maleic, citric, tartaric, cinnamic, lactic, mandelic, and ethanedisulfonic acid. The salts may

be made by reacting the free base of the particular antifungal agent with the chosen acid in a stoichiometric ratio in an appropriate solvent.

The DMSO to be incorporated into the inventive compositions is preferably of a purified grade (i.e. not a technical grade), which means that it should be sufficiently purified so that it does not cause any untoward reaction or injury to the body of the subject from contaminants and the like. Various methods of purifying technical grade DMSO are known (see, e.g. U.S. Patent 3,358,036), and include fractional distillation, solvent extraction, and freezing.

Concentrations of DMSO incorporated into the topical pharmaceutical compositions of the invention will preferably be of greater than 90% (e.g. 100%) strength. However, also of use are solutions containing at least about 50 % DMSO along with a minor amount of a pharmaceutically acceptable diluent, such as ethanol, n-propanol, isopropanol, propylene glycol, or glycerol. As used herein, solutions containing more than 50% DMSO by weight as a solvent for the composition are "dimethyl sulfoxide solutions". Dimethyl sulfoxide solutions containing greater than 90% DMSO may cause some skin drying and irritation. The amount of diluent should be chosen so as not to interfere with the solubility of the particular antifungal agent. The dimethyl sulfoxide solution preferably contains, by weight, from 80% to 100% dimethyl sulfoxide. Concentrations of the antifungal agents in the composition will of course vary dependent on the antifungal agent and (possibly) salt used. Concentrations will preferably be at least at high as the respective compound or compounds' minimum inhibitory concentration ("MIC") for fungi, and more preferably at least as great as the respective compound or compounds' minimum fungicidal concentration ("MFC") in DMSO. As a general statement, the antifungal compositions will be present in the inventive compositions in an amount varying from 0.1 to 50 weight percent, preferably 1 to 10 weight percent, of the total composition.

The compositions may also contain pharmaceutical necessities such as thickening agents and preservatives. The invention also includes the use of the components of the herein described compositions (e.g. dimethyl sulfoxide solution and antimycotic agent or agents) in the manufacture of a medicament for the treatment or prophylaxis of onychomycoses.

Once made, the composition may be used to treat or prophylax against onychomycosis. A method of treating a fungal infection of a nail, without avulsing the nail, includes topically applying to the nail and to the nail's epinychium, on a regular basis (e.g. one to three times a week, although for convenience's sake, it may be applied on a more frequent e.g. daily basis), a composition comprising an antimycotic agent dissolved in a dimethyl sulfoxide solution. The antimycotic agent is present in the composition at an MIC for the antimycotic agent.

Application of the composition may be accomplished by eye-dropper, Q- TrP -like swab, brush (e.g. such as a nail polish brush, aerosol, atomizer, dipping, a nail-sized transdermal drug delivery pad containing the two compounds, and equivalent structure.

Afterwards, the treated area may (but need not) be occluded by subsequent application of a bandage, tape, cotton, or nail cap.

Prophylaxis, according to the invention, will be especially of the nails adjacent to fungally infected nails. Typically for prophylaxis, the composition need not be applied as often (e.g. once to three times a week). Typical candidates for prophylaxis include the elderly and patients suffering from HIN, diabetes, peripheral vascular disease, or undergoing immunosuppressive therapy.

Packaging for the composition will typically include a glass or other inert container for the composition as well as one of the aforementioned applicators and instructions for using the composition either to treat onychomycosis or prevent its occurrence. This packaging may further include material to occlude the nail after treatment or prophylaxis.

The invention is further explained by the following illustrative EXAMPLES:

EXAMPLES

EXAMPLE I A composition comprising 660 mg of ultramicrosize griseofiilvin dissolved in 30 ml DMSO was made. 2 tablets of FULNICIΝ™ P/G 330 griseofiilvin USP (available from Schering Corporation of Kenilworth, ΝJ, USA) were ground and dissolved in 30 ml of 99% DMSO.

EXAMPLE Π

The composition of EXAMPLE I was applied daily to the top of the nail and the epinychium of ten subjects ranging in age from 25 to 70 years old, all of whom were suffering from onychomycoses. Beneficial results were seen in all patients in 3 to 4 weeks. All new nail growth was noted to be fungus-free. No relapses were seen after one year.

EXAMPLE m A composition comprising 200 mg of fluconazole dissolved in 30 ml DMSO was made. 4 tablets (50 mg each) of DIFLUCAN™ fluconazole USP (available from Roerig Division of Pfizer Labs, of New York, NY, USA) were ground and dissolved in 30 ml of DMSO.

EXAMPLE IV

The composition of EXAMPLE in was applied daily to the top of the nail and the epinychium of five subjects suffering from onychomycosis. Beneficial results were seen in all patients in three weeks.

EXAMPLE V

A composition containing 750 mg of flucytosine dissolved in 30 ml DMSO is made by dissolving the contents of three 250 mg capsules of ANCOBON™ flucytosine USP (available from Roche Labs, of Nutley, NJ, USA) into 30 ml of DMSO (density 1.0955 g/ml).

EXAMPLE VI A composition containing 200 mg of amphotericin B dissolved in 30 ml DMSO is made by dissolving the already lyophilized contents of 4 vials of FUNGIZONE™ Intravenous amphotericin B USP (available from Apothecon of Princeton, NJ, USA) in 30 ml of DMSO.

EXAMPLE VH A composition containing 200 mg of itraconazole dissolved in 30 ml DMSO is made by dissolving the contents of two 100 mg capsules of SPORANAX™ itraconazole USP (available from Janssen Pharmaceutica of Titusville, NJ, USA) into 30 ml of DMSO.

EXAMPLE VIE A composition containing 400 mg of ketoconazole dissolved in 30 ml DMSO is made by crushing two 200 mg tablets of NIZORAL™ ketoconazole USP (available from Janssen Pharmaceutica of Titusville, NJ, USA) and dissolving the crushed tablets into 30 ml of DMSO.

EXAMPLE LX A composition containing 1000 mg of clotrimazole dissolved in 30 ml DMSO is made by dissolving 1000 mg of clotrimazole USP into 30 ml of DMSO.

EXAMPLE X The composition of EXAMPLE Vm is placed into a brown glass bottle having a brush associated with its lid. Instructions for once daily use of the composition are included on a label associated with the bottle.

Although the invention has been described with the use of various examples and preferred embodiments, these are illustrative only, and the scope of the invention is to be determined by the appended claims.