Treatment regimen for onchyomycosis using allylamine antifungal compositions

Abstract

There is provided a method of treating onychomycosis of the nail, comprising topical application of a pharmaceutical composition comprising an antifungal allylamine compound and a non-aqueous solvent system, which method comprises a loading phase, during which the pharmaceutical composition is administered at least three times a week, followed by a maintenance phase, during which the pharmaceutical composition is administered no more than two times per week. There are further provided pharmaceutical compositions suitable for topical application to the nail comprising an antifungal allylamine compound, an organic acid component and a diol component, as defined herein, and their use in methods of treating onychomycosis.

1 . A method of treatment of onychomycosis of the nail, which method comprises the steps of:
 (a) a loading phase, which phase comprises the topical application to the nail of a pharmaceutically-acceptable composition comprising an antifungal allylamine compound at a frequency of least three times a week over a period of from about one to about six months; followed by   (b) a maintenance phase, which phase comprises the topical application to the nail of a pharmaceutically-acceptable composition comprising an antifungal allylamine compound at a frequency of no more than two times per week as needed, wherein the pharmaceutically-acceptable composition comprising the antifungal allylamine compound comprises a non-aqueous solvent system.   
     
     
         2 . The method of treatment as claimed in  claim 1 , wherein the loading phase is for a period of from about one month to about three months. 
     
     
         3 . The method of treatment as claimed in  claim 1  or  claim 2 , wherein, during the loading phase, the composition is applied at least 5 times a week. 
     
     
         4 . The method of treatment as claimed in  claim 3 , wherein, during the loading phase, the composition is applied once daily. 
     
     
         5 . The method of treatment as claimed in any one of  claims 1  to  4 , wherein the maintenance phase is for a period of from about two months to about twelve months. 
     
     
         6 . The method of treatment as claimed in any one of  claims 1  to  5 , wherein, during the maintenance phase, the composition is applied once a week. 
     
     
         7 . The method of treatment as claimed in any one of the preceding claims, wherein the pharmaceutically-acceptable composition comprising an antifungal allylamine compound comprises:
 (i) terbinafine, or a pharmaceutically acceptable salt thereof, in an amount of from about 8% w/w to about 12% w/w;   (ii) propane-1,2-diol in an amount of from about 50% w/w to about 70% w/w;   (iii) lactic acid in an amount of from about 5% w/w to about 15% w/w;   (iv) EDTA, or a pharmaceutically acceptable salt thereof in an amount of from about 0.03% w/w to about 0.1% w/w;   (iv) urea in an amount of from about 15% w/w to about 25% w/w.   
     
     
         8 . A pharmaceutical composition comprising:
 (i) an allylamine antifungal compound in an amount of at least about 5% w/w;   (ii) an organic acid component in an amount of about 1% w/w to about 20% w/w;   (iii) a dial component in an amount of about 10% w/w to about 50° k w/w;   (iv) a monoalcohol component in an amount of about 10% w/w to about 40% w/w;   wherein the composition is essentially water-free.   
     
     
         9 . The composition as claimed in  claim 8 , wherein the allylamine antifungal compound is terbinafine, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The composition as claimed in  claim 8  or  claim 9 , wherein the allylamine antifungal compound is present in an amount of from about 5% w/w to about 12% w/w. 
     
     
         11 . The composition as claimed in any one of  claims 8  to  10 , wherein the organic acid component comprises lactic acid. 
     
     
         12 . The composition as claimed in any one of  claims 8  to  11 , wherein the organic acid component is selected from the group consisting of lactic acid, citric acid, pentanoic acid and mixtures thereof. 
     
     
         13 . The composition as claimed in any one of  claims 8  to  12 , wherein the organic acid component is present in an amount of from about 5% w/w to about 15% w/w. 
     
     
         14 . The composition as claimed in any one of  claims 8  to  13 , wherein the diol component is selected from the group consisting of propanediol, butanediol, pentanediol and mixtures thereof. 
     
     
         15 . The composition as claimed in  claim 14 , wherein the diol component is selected from the group consisting of propane-1,2-diol, propane-1,3-diol and mixtures thereof. 
     
     
         16 . The composition as claimed in any one of  claims 8  to  15 , wherein the diol component is present in an amount of from about 10% w/w to about 45% w/w. 
     
     
         17 . The composition as claimed in  claim 16 , wherein the diol component is present in an amount of from about 15% w/w to about 35% w/w. 
     
     
         18 . The composition as claimed in any one of  claims 8  to  17 , wherein the monoalcohol component comprises ethanol. 
     
     
         19 . The composition as claimed in any one of  claims 8  to  18 , wherein the monoalcohol component is selected from the group consisting of ethanol, iso-propanol and mixtures thereof. 
     
     
         20 . The composition as claimed in any one of  claims 8  to  19 , wherein the monoalcohol component is present in an amount of from about 15% w/w to about 35% w/w. 
     
     
         21 . The composition as claimed in any one of  claims 8  to  20 , wherein the composition further comprises a sequestering agent in an amount of about 0.01% w/w to about 1% w/w. 
     
     
         22 . The composition as claimed in  claim 21 , wherein the sequestering agent is selected from EDTA, or a pharmaceutically acceptable salt thereof, and sodium phosphonate. 
     
     
         23 . The composition as claimed in  claim 22 , wherein the sequestering agent is EDTA. 
     
     
         24 . The composition as claimed in any one of  claims 21  to  23 , wherein the sequestering agent is present in an amount of from about 0.03% w/w to about 0.5% w/w. 
     
     
         25 . The composition as claimed in any one of  claims 8  to  24 , wherein the composition further comprises a urea-based component in an amount of from about 5% w/w to about 25% w/w. 
     
     
         26 . The composition as claimed in  claim 25 , wherein the urea-based component is urea. 
     
     
         27 . The composition as claimed in any one of  claims 8  to  26 , wherein the composition further comprises an organic acid ester component in an amount of from about 5% w/w to about 30% w/w. 
     
     
         28 . The composition as claimed in  claim 27 , wherein the organic ester component is selected from the group consisting of ethyl lactate, iso-propyl lactate and mixtures thereof. 
     
     
         29 . The composition as claimed in any one of  claims 8  to  28 , wherein the composition is in the form of a liquid-solution. 
     
     
         30 . A pharmaceutical composition comprising:
 (i) an allylamine antifungal compound in an amount of at least about 5% w/w;   (ii) an organic acid component in an amount of about 1% w/w to about 20% w/w;   (iii) a diol component in an amount of about 10% w/w to about 50% w/w;   and one or more component selected from:   (iv) a monoalcohol component in an amount of about 10% w/w to about 40% w/w; and   (v) an organic acid ester component in an amount of about 5% w/w to about 30% w/w;   wherein the composition is essentially water free, and wherein the organic acid component and diol component are collectively present in an amount of about 20% w/w to about 50% w/w,   
     
     
         31 . The composition as claimed in  claim 30 , wherein the composition further comprises a sequestering agent in an amount of about 0.1% w/w to about 1% w/w. 
     
     
         32 . The composition as claimed in  claim 30  or  31 , wherein the composition further comprises a urea-based component which component in an amount of about 5% w/w to about 25% w/w. 
     
     
         33 . The composition as claimed in  claim 30 , wherein the organic acid component, diol component and urea-based component are collectively present in an amount of 25% w/w to about 60% w/w or less. 
     
     
         34 . A pharmaceutical composition comprising:
 (i) an allylamine antifungal compound in an amount of at least about 5% w/w;   (ii) an organic acid component in an amount of from about 1% to about 20% w/w;   (iii) an organic ester component in an amount of about 5% w/w to about 45% w/w;   (iv) a diol component in an amount of from about 10% w/w to about 60% w/w; and   (v) a surfactant component in an amount of from about 1% lAi/w to about 15% w/w;   wherein the composition is essentially water free.   
     
     
         35 . The composition as claimed in  claim 34 , wherein the allylamine antifungal compound is terbinafine, or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The composition as claimed in  claim 34  or  claim 35 , wherein the allylamine antifungal compound is present in an amount of from about 5% w/w to about 12% w/w. 
     
     
         37 . The composition as claimed in any one of  claims 34  to  36 , wherein the organic acid component comprises lactic acid. 
     
     
         38 . The composition as claimed in any one of  claims 34  to  37 , wherein the organic acid component is lactic acid. 
     
     
         39 . The composition as claimed in any one of  claims 34  to  38 , wherein the organic acid component is present in an amount of from about 5% w/w to about 15% w/w. 
     
     
         40 . The composition as claimed in any one of  claims 34  to  39 , wherein the diol component is selected from the group consisting of ethane-1,2-dial, propanediol, butanediol, pentanediol and mixtures thereof. 
     
     
         41 . The composition as claimed in  claim 40 , wherein the diol component is selected from the group consisting of ethane-1,2-diol, propane-1,2-diol and mixtures thereof. 
     
     
         42 . The composition as claimed in any one of  claims 34  to  41 , wherein the dial component is present in an amount of from about 20% w/w to about 50% w/w. 
     
     
         43 . The composition as claimed in any one of  claims 34  to  42 , wherein the surfactant component is selected from the group consisting of polysorbates, monoglycerides, lecithin and mixtures thereof. 
     
     
         44 . The composition as claimed in  claim 43 , wherein the surfactant component is selected from the group consisting of polysorbate 60, polysorbate 80, lecithin, monoglycerides and mixtures thereof. 
     
     
         45 . The composition as claimed in any one of  claims 34  to  44 , wherein the surfactant component is present in an amount of from about 3% w/w to about 12% w/w. 
     
     
         46 . The composition as claimed in any one of  claims 34  to  45 , wherein the organic ester component is selected from ethyl acetate, propyl acetate, butyl acetate and mixtures thereof. 
     
     
         47 . The composition as claimed in any one of  claims 34  to  46 , wherein the organic ester component is present in an amount of from about 5% w/w to about 35% w/w. 
     
     
         48 . The composition as claimed in any one of  claims 34  to  47 , wherein the composition further comprises a sequestering agent in an amount of about 0.01% w/w to about 1% w/w. 
     
     
         49 . The composition as claimed in  claim 48 , wherein the sequestering agent is EDTA, or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The composition as claimed in  claim 48  or  49 , wherein the sequestering agent is present in an amount of from about 0.03% w/w to about 0.5% w/w. 
     
     
         51 . The composition as claimed in any one of  claims 34  to  50 , wherein the composition further comprises a urea-based component in an amount of from about 5% w/w to about 25% w/w. 
     
     
         52 . The composition as claimed in  claim 49 , wherein the urea-based component is urea. 
     
     
         53 . The composition as claimed in any one of  claims 34  to  52 , wherein the composition is in the form of a liquid-solution 
     
     
         54 . A method of treatment of onychomycosis of a nail, which method comprises administering a therapeutically effective amount of a composition as defined in any one of  claims 8  to  53 , to a patient in need thereof. 
     
     
         55 . A method of treatment as claimed in any one of  claims 1  to  6 , wherein the pharmaceutically-acceptable composition comprising an antifungal allylamine compound is as defined in any one of  claims 8  to  53 .