Methods of administering topical antifungal formulations for the treatment of fungal infections

Abstract

The present invention relates to topical antifungal formulations comprising one or more antifungal (e.g., terbinafine), a lipid and a surfactant, and uses thereof for the treatment of skin and nail fungal infections.

1 . A method for treating a fungal infection in a human subject comprising topically administering to the subject an aqueous pharmaceutical formulation comprising terbinafine or a pharmaceutically acceptable salt thereof, a phospholipid and a surfactant, wherein the formulation comprises 0.5-10% terbinafine or a pharmaceutically acceptable salt thereof by weight, 2-10% phospholipid by weight, and 1-5% surfactant by weight, and wherein the molar ratio of phospholipid to surfactant in the formulation is 1/1 to 5/1. 
     
     
         2 . The method of  claim 1  wherein the fungal infection is onychomycosis. 
     
     
         3 . The method of  claim 1 , wherein the pharmaceutical formulation is a cream, lotion, ointment, gel, solution, spray, lacquer or film forming solution. 
     
     
         4 .- 7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the formulation comprises about 1.5% by weight terbinafine or a pharmaceutically acceptable salt thereof. 
     
     
         9 .- 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the phospholipid is phosphatidylcholine. 
     
     
         14 . The method of  claim 1 , wherein the surfactant is a polyoxyethylene sorbitan, a polyhydroxyethylene stearate, or a polyhydroxyethylene laurylether. 
     
     
         15 . The method of  claim 1 , wherein the surfactant is polysorbate 80 (Tween 80). 
     
     
         16 . The method of  claim 1 , wherein said topically administering comprises applying the formulation to the subject's nail and/or the surrounding skin. 
     
     
         17 . (canceled) 
     
     
         18 . A method for the delivery of terbinafine to a subject's nail in an amount effective for treating onychomycosis comprising topically administering to the nail a pharmaceutical formulation comprising a therapeutically effective amount of terbinafine or a pharmaceutically acceptable salt thereof, a phospholipid and a surfactant wherein the formulation comprises 2-10% phospholipid by weight and 1-5% surfactant by weight, and wherein the molar ratio of phospholipid to surfactant in the formulation is 1/1 to 5/1. 
     
     
         19 . The method of  claim 18 , wherein the pharmaceutical formulation is a cream, lotion, ointment, gel, solution, spray, lacquer or film forming solution. 
     
     
         20 .- 23 . (canceled) 
     
     
         24 . The method of  claim 18 , wherein the formulation comprises about 1.5% by weight terbinafine or a pharmaceutically acceptable salt thereof. 
     
     
         25 .- 27 . (canceled) 
     
     
         28 . The method of  claim 18 , wherein the phospholipid is phosphatidylcholine. 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 18 , wherein the surfactant is a polyoxyethylene sorbitan, a polyhydroxyethylene stearate, or a polyhydroxyethylene laurylether. 
     
     
         31 . The method of  claim 18 , wherein the surfactant is polysorbate 80 (Tween 80). 
     
     
         32 . The method of  claim 18 , wherein said topically administering comprises applying the formulation to the subject's nail and/or the surrounding skin. 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . A pharmaceutical formulation suitable for topical delivery of terbinafine comprising terbinafine or a pharmaceutically acceptable salt thereof, a lipid and a surfactant, in an aqueous solution, wherein the formulation comprises 0.5-10% terbinafine or a pharmaceutically acceptable salt thereof by weight, 2-10% lipid by weight, and 1-5% surfactant by weight, wherein the formulation is suitable for topical delivery. 
     
     
         36 . The formulation of  claim 35 , wherein the formulation further comprises a thickener, an antioxidant, and an antimicrobial agent. 
     
     
         37 .- 40 . (canceled) 
     
     
         41 . The formulation of  claim 35 , wherein the aqueous solution has a pH ranging from 4.0 to 7.5. 
     
     
         42 . The formulation of  claim 35 , wherein the lipid is a phospholipid. 
     
     
         43 . The formulation of  claim 42 , wherein the molar ratio of phospholipid to surfactant is from about 1/1 to 5/1. 
     
     
         44 . (canceled) 
     
     
         45 . The formulation of  claim 35 , wherein the lipid is phosphatidylcholine. 
     
     
         46 . (canceled) 
     
     
         47 . The formulation of  claim 35 , wherein the surfactant is a polyoxyethylene sorbitan, a polyhydroxyethylene stearate, or a polyhydroxyethylene laurylether. 
     
     
         48 . The formulation of  claim 35 , wherein the surfactant is polysorbate 80 (Tween 80). 
     
     
         49 .- 153 . (canceled) 
     
     
         154 . A method of administering terbinafine to the nail tissue of a human comprising topically administering a formulation to the nail and/or surrounding skin of a human subject, wherein said formulation comprises terbinafine or a pharmaceutically acceptable salt thereof, a lipid and a surfactant, and wherein said administration results in a mean concentration of terbinafine per gram of nail tissue of at least about 2.5 mg/g; wherein the mean concentration is determined at least two weeks after ceasing administration of said formulation; and wherein said administering results in a mean serum concentration of terbinafine in the human subject of less than 10 ng/mL. 
     
     
         155 . (canceled) 
     
     
         156 . The method of  claim 154 , wherein said administering results in a mean serum concentration of terbinafine in the human subject of less than 5 ng/mL. 
     
     
         157 . The method of  claim 154 , wherein said administering results in a mean serum concentration of terbinafine in the human subject of less than 1 ng/mL. 
     
     
         158 . The method of  claim 154 , wherein said formulation comprises about 3.0 mg of terbinafine. 
     
     
         159 . The method of  claim 154 , wherein said formulation is administered twice daily. 
     
     
         160 . The method of  claim 159 , wherein said formulation is administered for at least two weeks. 
     
     
         161 .- 189 . (canceled) 
     
     
         190 . A method of causing a greater than 90% mycological cure rate in the treatment of a fungal infection in a human subject, comprising topically administering to the subject an aqueous pharmaceutical formulation comprising terbinafine or a pharmaceutically acceptable salt thereof, a phospholipid and a surfactant.