Compositions and methods for treating diseases of the nail

Abstract

Methods and compositions for treating disorders of the nail and nail bed. Such compositions contain a vehicle in which all components of the composition are dissolved, suspended, dispersed, or emulsified, a non-volatile solvent, a wetting agent, and a pharmaceutically active ingredient that is soluble in the non-volatile solvent and/or a mixture of the vehicle and the non-volatile solvent, and which composition is effective in treating a disorder of the nail or nail bed.

1 . A method for the treatment of a disorder of the nail or nail bed comprising topically applying to the surface of the nail of an individual suffering from said disorder a pharmaceutical composition comprising a vehicle that is volatile and/or that rapidly penetrates a nail following the application onto the surface of the nail, a non-volatile solvent that is dissolved, suspended, dispersed, or emulsified within the vehicle, an active pharmaceutical ingredient (API) that is soluble in the non-volatile solvent or in a mixture of the non-volatile solvent and the vehicle, and a wetting agent, and wherein the application of the composition is in an amount and for a time sufficient to ameliorate the symptoms of the disorder. 
     
     
         2 . The method of  claim 1  wherein the wetting agent and the vehicle are the same compound. 
     
     
         3 . The method of  claim 1  wherein the wetting agent is a volatile silicone. 
     
     
         4 . The method of  claim 1  wherein the vehicle is an alcohol. 
     
     
         5 . The method of  claim 1  wherein the non-volatile solvent is non-polar. 
     
     
         6 . The method of  claim 5  wherein the non-volatile solvent is one or more esters of the formula RCO—OR′, wherein R and R′ may be identical or different and each of R and R′ represents a linear or branched chain of an alkyl, alkenyl, alkoxycarbonylalkyl, or alkoxycarbonyloxyalkyl radical having from 1 to 25 carbon atoms. 
     
     
         7 . The method of  claim 1  wherein the API is an antifungal agent. 
     
     
         8 . The method of  claim 6  wherein the antifungal agent is a triazole compound. 
     
     
         9 . The method of  claim 8  wherein the triazole compound is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol. 
     
     
         10 . The method of  claim 1  wherein the pharmaceutical composition comprises an alcohol vehicle, a non-volatile solvent comprising one or more esters of the formula RCO—OR′, wherein R and R′ may be identical or different and each of R and R′ represents a linear or branched chain of an alkyl, alkenyl, alkoxycarbonylalkyl, or alkoxycarbonyloxyalkyl radical having from 1 to 25 carbon atoms, and a volatile silicone wetting agent, and wherein the composition does not form a film upon application to the nail. 
     
     
         11 . The method of  claim 10  wherein the pharmaceutical formulation further comprises a hydrophobic API. 
     
     
         12 . The method of  claim 11  wherein the API is an antifungal agent. 
     
     
         13 . The method of  claim 12  wherein the antifungal agent is a triazole compound. 
     
     
         14 . The method of  claim 13  wherein the triazole compound is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol. 
     
     
         15 . The method of  claim 10  wherein the alcohol is ethanol. 
     
     
         16 . The method of  claim 10  wherein the non-volatile solvent comprises diisopropyl adipate and C12-15 alkyl lactate. 
     
     
         17 . The method of  claim 10  wherein the volatile silicone wetting agent is cyclomethicone. 
     
     
         18 . The method of  claim 1  wherein the disorder is onychomycosis. 
     
     
         19 . The method of  claim 1  wherein the composition does not comprise a polymeric film forming compound. 
     
     
         20 . A pharmaceutical composition for the topical treatment of a disorder of the nail or nail bed comprising alcohol, a volatile silicone, an anti-oxidant, one or more esters of the formula RCO—OR′, wherein R and R′ may be identical or different and each of R and R′ represents a linear or branched chain of an alkyl, alkenyl, alkoxycarbonylalkyl, or alkoxycarbonyloxyalkyl radical having from 1 to 25 carbon atoms, and a triazole antifungal agent, wherein the volatile silicone is present in the composition at a concentration less than 25% w/w, wherein the composition does not form a film when topically applied to the surface of a nail. 
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the ester is a combination of diisopropyl adipate and C12-15 alkyl lactate. 
     
     
         22 . The pharmaceutical composition of  claim 20  wherein the ester is a combination of diisopropyl adipate and myristyl lactate. 
     
     
         23 . The pharmaceutical composition of  claim 20  wherein the triazole antifungal agent is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol. 
     
     
         24 . The pharmaceutical composition of  claim 20  wherein the alcohol is ethanol. 
     
     
         25 . The pharmaceutical composition of  claim 20  wherein the volatile silicone is a cyclic silicone. 
     
     
         26 . The pharmaceutical composition of  claim 25  wherein the cyclic silicone is a cyclomethicone. 
     
     
         27 . The pharmaceutical composition of  claim 20  wherein the concentration of volatile silicone is less than 20%. 
     
     
         28 . The pharmaceutical composition of  claim 20  wherein the concentration of volatile silicone is less than 15%. 
     
     
         29 . The pharmaceutical composition of  claim 20  that comprises alcohol, cyclomethicone, diisopropyl adipate, either or both of C12-15 alkyl lactate and isopropyl myristate, an antioxidant, and a triazole antifungal agent. 
     
     
         30 . The pharmaceutical composition of  claim 29  that comprises the following components in the following ranges of concentrations % w/w:
 a. alcohol—10% to 80%   b. cyclomethicone—0.01% to less than 25%   c. diisopropyl adipate plus either or both of C12-15 alkyl lactate and isopropyl myristate—5% to 90%   d. antioxidant—0.001% to 0.50%   e. triazole antifungal agent—0.0001% to 30%.   
     
     
         31 . The pharmaceutical composition of  claim 30  that comprises:
 a. alchohol—50% to 70%,   b. cyclomethicone—10% to 15%   c. diisopropyl adipate—8% to 15%   d. either or both of C12-15 alkyl lactate and isopropyl myristate—8% to 15%   e. antioxidant—0.001% to 0.50%   f. triazole antifungal agent—2% to 15%.   
     
     
         32 . The pharmaceutical composition of  claim 29  wherein the triazole antifungal agent is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol. 
     
     
         33 . A pharmaceutical composition for the topical treatment of a disorder of the nail or nail bed comprising alcohol, a volatile silicone, an anti-oxidant, one or more esters of the formula RCO—OR′, wherein R and R′ may be identical or different and each of R and R′ represents a linear or branched chain of an alkyl, alkenyl, alkoxycarbonylalkyl, or alkoxycarbonyloxyalkyl radical having from 1 to 25 carbon atoms, and a triazole antifungal agent, wherein the ratio of alcohol to volatile silicone in the composition % w/w is at least 2:3, wherein the composition does not form a film when topically applied to the surface of a nail. 
     
     
         34 . The pharmaceutical composition of  claim 33  wherein the ester is a combination of diisopropyl adipate and C12-15 alkyl lactate. 
     
     
         35 . The pharmaceutical composition of  claim 33  wherein the ester is a combination of diisopropyl adipate and myristyl lactate. 
     
     
         36 . The pharmaceutical composition of  claim 33  wherein the triazole antifungal agent is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol. 
     
     
         37 . The pharmaceutical composition of  claim 33  wherein the alcohol is ethanol. 
     
     
         38 . The pharmaceutical composition of  claim 33  wherein the volatile silicone is a cyclic silicone. 
     
     
         39 . The pharmaceutical composition of  claim 38  wherein the cyclic silicone is a cyclomethicone. 
     
     
         40 . The pharmaceutical composition of  claim 33  wherein the ratio of alcohol to volatile silicone is at least 1:1. 
     
     
         41 . The pharmaceutical composition of  claim 33  wherein the ratio of alcohol to volatile silicone is at least 2:1. 
     
     
         42 . The pharmaceutical composition of  claim 33  wherein the ratio of alcohol to volatile silicone is at least 3:1. 
     
     
         43 . The pharmaceutical composition of  claim 33  that comprises alcohol, cyclomethicone, diisopropyl adipate, either or both of C12-15 alkyl lactate and isopropyl myristate, an antioxidant, and a triazole antifungal agent. 
     
     
         44 . The pharmaceutical composition of  claim 43  that comprises the following components in the following ranges of concentrations % w/w:
 a. alcohol—10% to 80%   b. cyclomethicone—0.01% to less than 25%   c. diisopropyl adipate plus either or both of C12-15 alkyl lactate and isopropyl myristate—5% to 90%   d. antioxidant—0.001% to 0.50%   e. triazole antifungal agent—0.0001% to 30%.   
     
     
         45 . The pharmaceutical composition of  claim 44  that comprises:
 a. alcohol—50% to 70%,   b. cyclomethicone—10% to 15%   c. diisopropyl adipate—8% to 15%   d. either or both of C12-15 alkyl lactate and isopropyl myristate—8% to 15%   e. antioxidant—0.001% to 0.50%   f. triazole antifungal agent—2% to 15%.   
     
     
         46 . The pharmaceutical composition of  claim 43  wherein the triazole antifungal agent is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol. 
     
     
         47 . The pharmaceutical composition of  claim 20  that is free of polymeric film forming compounds. 
     
     
         48 . The pharmaceutical composition of  claim 33  that is free of polymeric film forming compounds.