PHARMACEUTICAL COMPOSITIONS FOR TREATING NAIL INFECTIONS

Abstract: Compositions containing a high concentration of an imidazole antifungal agent in a long-chain fatty acid remain liquid on application and are effective in the treatment of fungal infections of the finger and toe nails. The composi­ tions may be diluted with a volatile organic solvent to facilitate application. A composition containing tioconazole, undecylenic acid and ethyl acetate or 2-butanone is prefer­ red.

Description: This invention relates to pharmaceutical compositions and in particular to compositions for treating fungal infections of the nails and surrounding tissues. Treatment of nail disorders due to fungal infections in the past has been notoriously difficult being both lengthy and often prone to failure. The most common conditions may be classified as chronic paronychia, where the finger nails and nail folds are invaded by Candida species; ringworm infections of the nail plate (usually the toe-nails and often associated with tinea pedis), and non-dermatophyte mould infections. The organisms implicated are the dermatophytes, most commonly Trichophyton rubrum or Trichophyton interdigitalis; moulds,such as Aspergillus versicolor;and yeasts, Candida albicans and Candida parapsilosis being the two species most commonly found. A variety of treatments have been used in the past but in recent years the newer broad-spectrum imidazole antifungal agents such as clotrimazole, miconazole and tioconazole have been advocated. The proven clinical efficacy of these agents has led to their widespread acceptance for the topical treatment of fungal infections. However treatment of nail infections remains protracted and somewhat uncertain due to the difficuLty of penetrating the horny nail plate to reach the site of infection which is frequently.inthe nail bed and the inner layers of the nail. We have now discovered that compositions may be prepared containing a high concentration of the imidazole antifungal agent in a long-chain fatty acid solvent and these are able to facilitate penetration of the antifungal agent through the nail-plate. Moreover the composition is readily applied to the nail and surrounding tissues where the antifungal agent remains in liquid solution and is therefore better able to penetrate the nail plate to reach the site of infection. Thus according to the present invention, there is provided a pharmaceutical composition for the treatment of fungal nail infections which comprises a solution of an imidazole antifungal agent in a long-chain fatty acid. The imidazole antifungal agents are well known as a class, they are characterised by possessing an imidazole ring as part of their chemical structure and include such agents as clotrimazole, miconazole, econazole, tioconazole and isoconazole. Tioconazole is particularly preferred because of its broad spectrum and high potency. The long-chain fatty acid may be any linear or branched-chain, saturated or unsaturated fatty acid which is pharmaceutically acceptable, and in which the imidazole antifungal agent is soluble. Suitable fatty acids are those having a carbon-atom content in the range C8 to C20 as lower acids tend to be more acidic and can cause local skin irritation while higher acids generally have higher melting points. Unsaturated fatty acids are especially valuable in facilitating penetration of the nail by the antifungal agent. Undecylenic acid is a particularly preferred fatty acid for use in the formulations of the invention. Generally the proportion of imidazole antifungal agent to fatty acid will be determined by the solubility of the agent in the particular fatty acid up to a practical maximum proportion of a 1:1 molar ratio of the two compounds. We have discovered that solutions containing over 50% by weight of the imidazole in the fatty acid can easily be achieved. In practice a proportion of 40-60% by weight of the imidazole antifungal agent in the fatty acid is preferred; such solutions remain liquid on application and, because of the high concentration of the antifungal agent, only a thin film is needed to provide effective therapy. The compositions of the invention may be applied in a number of ways. They are most simply brushed or painted onto the affected areas or they may be applied using a felt-tip applicator or cotton wool pad. For ease of application the solution of the imidazole and the fatty solvent is best diluted with a non-toxic volatile organic solvent. This reduces the viscosity of the composition and assists application and spread of the composition onto the affected regions. After application, however, the solvent evaporates leaving the composition of the antifungal agent and the fatty acid as a film on the surface of the nail plate and surrounding tissues. Suitable solvents for this application are those pharmaceutically acceptable organic solvents in which the mixture of the imidazole and the fatty acid is soluble and which have a sufficiently low boiling point to ensure their rapid evaporation after application. Examples are lower alkanols such as ethanol and isopropyl alcohol, esters such as ethyl acetate and ketones such as acetone and 2-butanone; ethyl acetate and 2-butanone being preferred solvents. The amount of volatile solvent required in any particular case will depend upon the nature of the solvent and the components of the composition and may vary from 10 to 90% by weight of the total formulation. Normally a proportion of 40 to 60% by weight of solvent in the composition will be sufficient to produce a solution having the desired mobility. Other components may be added to the compositions if desired, for example perfumes, colouring or antioxidants. The compositions of the invention have advantages over simple solutions of the imidazole antifungal agent in volatile solvents which dry to produce a hard glassy film on the surface of the nail, or over conventional formulations, which do not produce high concentrations of the antifungal agent on the nail or facilitate penetration. The ability of the compositions of the invention to penetrate nail tissue is assessed using an apparatus consisting of a cell in which two compartments are separated by a nail disc cut from human toe nails. The nail disc is 1 cm. in diameter and is mounted between 2 two teflon rings leaving a surface area of 0.71 cm exposed. The cell is vaccum tested for leaks before use. The formulation containing the imidazole antifungal agent is placed in one compartment and methanol in the other. The cell is rotated at a constant 30 revolutions per minute and samples of the methanol are removed from time to time and assayed for presence of the antifungal agent, using both bioassay and radiolabelling techniques. At the end of 30 days the experiment is terminated and the nail disc sectioned using a microtome. Each section is examined and the distribution of the antifungal agent throughout the nail recorded. Results of such experiments show that formulations of tioconazole and undecylenic acid are particularly effective, good levels of the antifungal agent being observed both in the methanol solution and throughout the nail disc. The following Examples are provided to further illustrate the invention. EXAMPLE 1 Tioconazole (0.56 g) was added to undecylenic acid B.P. (0.44 g) and the mixture gently warmed and agitated until all the tioconazole had dissolved. The mixture was cooled to yield a clear solution. No separation was observed even after prolonged storage at 4 0C. EXAMPLE 2 The procedure of Example 1 was followed but using the following imidazole antifungal agents and undecylenic acid. In each case a clear solution was obtained on cooling. EMI5.1 <tb> Antifungal <SEP> Proportion <SEP> in <SEP> Composition <SEP> (g) <tb> <SEP> Agent <tb> <SEP> Imidazole <SEP> Undecylenic <SEP> Acid <tb> Miconazole <SEP> 0.60 <SEP> 0.44 <tb> Clotrimazole <SEP> 0.50 <SEP> 0.44 <tb> Econazole <SEP> 0.40 <SEP> 0.44 <tb> EXAMPLE 3 The procedure of Example 1 was followed but using the following proportions of tioconazole and undecylenic acid. In each case a clear solution was obtained on cooling. EMI6.1 <tb> <SEP> Proportion <SEP> in <SEP> Composition <SEP> (X <SEP> by <SEP> weight) <tb> Tioconazole <SEP> Undecylenic <SEP> Acid <tb> <SEP> 10 <SEP> 90 <tb> <SEP> 10 <SEP> 90 <tb> <SEP> 30 <SEP> 70 <tb> <SEP> 50 <SEP> 50 <tb> <SEP> 60 <SEP> 40 <tb> EXAMPLE 4 Tioconazole (0.45 g) was added to oleic acid B.P. (0.55 g) and the mixture gently warmed. The tioconazole dissolved to give a clear solution upon cooling. EXAMPLE 5 The procedure of Example 4 was followed but using the following fatty acids and tioconazole. In each case a clear solution is obtained on cooling. EMI6.2 <tb> <SEP> Fatty <SEP> Proportion <SEP> in <SEP> Composition <SEP> (g) <tb> <SEP> Acid <tb> <SEP> Tioconazole <SEP> Acid <tb> Octanoic <SEP> 0.69 <SEP> 0.31 <tb> Iso-stearic <SEP> 0.45 <SEP> 0.55 <tb> Stearic <SEP> 0.58 <SEP> 0.42 <tb> EXAMPLE 6 The product of Example 1 (0.5 g) was diluted with ethyl acetate U.S.N.F. (0.5 g) to give a clear solution. EXAMPLE 7 Tioconazole (0.28 g) and undecylenic acid B.P. (0.22 g) were added to ethyl acetate U.S.N.F. (0.5 g) to give a clear solution identical to the product of Example 6. EXAMPLE 8 The procedure of Example 7 is followed but using the following volatile solvents instead of ethyl acetate: Acetone Ethanol Isopropyl alcohol Butan-2-one EXAMPLE 9 The procedure of Example 7 is followed but using the following proportions of active ingredients and volatile solvents: EMI7.1 <tb> Tioconazole <SEP> (g) <SEP> Undecylenic <SEP> acid <SEP> (g) <SEP> Ethyl <SEP> Acetate <SEP> (g) <tb> <SEP> 0.28 <SEP> 0.22 <SEP> 5.0 <tb> <SEP> 0.28 <SEP> 0.22 <SEP> 1.25 <tb> <SEP> 2.8 <SEP> 2.2 <SEP> 2.2 <tb> <SEP> 2.8 <SEP> 2.2 <SEP> 0.55 <tb> EXAMPLE 10 A solution was prepared by the procedure of Example 7 having the following composition: : Parts/100 g Tioconazole 28 Undecylenic acid 22 Butan-2-one 50 Butylated hydroxy toluene BP 0.1 The solution was filtered and filled into dark glass bottles (10 ml) which were fitted with a cap and applicator brush.

Claims: CLAIMS 1. A pharmaceutical composition for the treatment of nail infections which comprises a solution of an imidazole antifungal agent in a long-chain fatty acid. 2. A composition as claimed in claim 1 wherein the long-chain fatty acid is a C8 to C20 fatty acid. 3. A composition as claimed in claim 2 wherein the fatty acid is undecylenic acid. 4. A composition as claimed in any preceding claim wherein the imidazole antifungal agent is present in a proportion of from 40% to 60% by weight of the mixture of imidazole antifungal agent and fatty acid. 5. A composition as claimed in any preceding claim wherein the imidazole antifungal agent is tioconazole. 6. A composition as claimed in any preceding claim which further contains a non-toxic volatile organic solvent. 7. A composition as claimed in claim 6 wherein the volatile organic solvent is ethyl acetate or 2-butanone. 8. A composition as claimed in claim 6 or 7 wherein the volatile organic solvent is present in an amount of from 40% to 60% of the weight of the composition. 9. A composition as claimed in claim 4 wherein the imidazole antifungal agent is tioconazole, the fatty acid is undecylenic acid and wherein the mixture is diluted with ethyl acetate or 2-butanone in an amount of from 40 to 60% of the total weight of the composition. CLAIMS FOR {tV5TS:4 1. A process for preparing a pharmaceutical composition for the treatment of nail infections which comprises dissolving an imidazole antifungal agent in a long-chain fatty acid. 2. A process as claimed in claim 1 wherein the long-chain fatty acid is a C8 to C20 fatty acid. 3. A process as claimed in claim 2 wherein the fat-ty acid is undecylenic acid. 4. A process as claimed in any preceding claim wherein the imidazole antifungal agent is present in a proportion of from 40% to 60% by weight of the mixture of imidazole antifungal agent and fatty acid. 5. A process as claimed in any preceding claim wherein the imidazole antifungal agent is tioconazole. 6. A process as claimed in any preceding claim which further comprises diluting the mixture of the imidazole antifungal agent and long-chain fatty acid with a non-toxic volatile organic solvent. 7. A process as claimed in claim 6 wherein the volatile organic solvent is ethyl acetate or 2-butanone. 8. A process as claimed in claim 6 or 7 wherein the volatile organic solvent is present in an amount of from 40% to 60% of the weight of the composition. 9. A process as claimed in claim 4 wherein the imidazole antifungal agent is tioconazole, the fatty acid is undecylenic acid and wherein the mixture is diluted with ethyl acetate or 2-butanone in an amount of from 40 to 60% of the total weight of the composition.

Inventors: DAVISON, EDWARD
Applicants: PFIZER CORPORATION, PFIZER LIMITED
Application year: 1982
Main classification: A61K7
IPC codes: A61P31, A61K9, C07D233, A61K31, A61Q3, A61K8