Dermal delivery compositions and methods

Abstract

A composition for transdermal delivery of a progestin for progestin hormone therapy is disclosed. Also disclosed is a transdermal delivery device comprising the composition. For progestin-only hormone therapy, the composition contains an anti-oxidant and does not contain an estrogen. For therapy involving a progestin and an estrogen, the composition contains the progestin, the estrogen and an additional anti-oxidant. Methods of improving the stability of progestin-containing compositions comprising oxidative agents are also disclosed. The methods comprise including one or more anti-oxidants in the compositions.

1 . An adhesive polymer matrix composition for transdermal delivery of levonorgestrel, wherein:
 (a) the composition comprises levonorgestrel and a skin permeation enhancer in a polymeric pressure sensitive adhesive (PSA);   (b) the composition comprises at least one component that contributes to oxidative degradation of the levonorgestrel, wherein the least one component is one or more of (i) the PSA wherein the PSA is polymerized by free radical polymerization, (ii) the skin permeation enhancer wherein the enhancer is an organic solvent, and (iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer;   (c) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the one or more of the PSA, the organic solvent and the PVP or PVP copolymer; and   (d) the stability of the composition is improved over the stability of such composition lacking an anti-oxidant.   
     
     
         2 . The composition of  claim 1 , wherein the anti-oxidant is selected from Vitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, alcohols, amines, amides, sulfoxides, surfactants, or any combination thereof. 
     
     
         3 . The composition of  claim 1  wherein the anti-oxidant is selected from sodium bisulfate, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT, pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 
     
     
         4 . The composition of  claim 1  that lacks an estrogen. 
     
     
         5 . The composition of  claim 2  that lacks an estrogen. 
     
     
         6 . The composition of  claim 1 , wherein the PSA contributes to oxidative degradation of the levonorgestrel and the PSA is a polyacrylate PSA, a polyisobutylene PSA, or a silicone PSA that is polymerized by free radical polymerization. 
     
     
         7 . The composition of  claim 1 , wherein the skin permeation enhancer contributes to the oxidative degradation of the levonorgestrel and the skin permeation enhancer is DMSO. 
     
     
         8 . The composition of  claim 1 , wherein the PVP or PVP copolymer contributes to the oxidative degradation of the levonorgestrel and the PVP copolymer is PVP/vinyl acetate (PVP/VA). 
     
     
         9 . The composition of  claim 1 , further comprising one or more other skin permeation enhancers selected from a fatty (C 8 -C 20 ) alcohol ester of a hydroxyl acid, a lower (C 1 -C 4 ) alkyl ester of a hydroxyl acid, and a C 6 -C 18  fatty acid. 
     
     
         10 . The composition of  claim 1 , disposed within a transdermal delivery device that comprises a skin contacting surface and a non-skin contacting surface, a release liner adjacent the skin contacting surface and a backing layer adjacent the non-skin contacting surface. 
     
     
         11 . A method of improving the stability of a levonorgestrel transdermal delivery composition comprising levonorgestrel and a skin permeation enhancer in a polymeric pressure sensitive adhesive (PSA) matrix; wherein the composition comprises one or more of: (a) the PSA being polymerized by free radical polymerization; (b) the skin permeation enhancer being an organic solvent; and (c) the composition comprising PVP or a PVP copolymer. 
     
     
         12 . The method of  claim 11 , wherein the composition comprises two or more of: (a) the PSA being polymerized by free radical polymerization; (b) the skin permeation enhancer being an organic solvent; and (c) the composition comprising PVP or a PVP copolymer. 
     
     
         13 . The method of  claim 11 , wherein the PSA is polymerized by free radical polymerization, the permeation enhancer is an organic solvent, and the composition comprises PVP or a PVP copolymer. 
     
     
         14 . The method of  claim 11 , comprising adding an antioxidant selected from Vitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof, salicylic acid and esters thereof, sulfites, alcohols, amines, amides, sulfoxides, surfactants, or any combination thereof. 
     
     
         15 . The method of  claim 11 , comprising adding an antioxidant is selected from sodium bisulfate, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT, pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 
     
     
         16 . The method of  claim 11 , wherein the composition lacks an estrogen. 
     
     
         17 . The method of  claim 11 , wherein the PSA is a polyacrylate PSA, a polyisobutylene PSA, or a silicone PSA. 
     
     
         18 . The method of  claim 13 , wherein the skin permeation enhancer is DMSO. 
     
     
         19 . The method of  claim 13 , wherein the PVP copolymer is PVP/VA. 
     
     
         20 . The method of  claim 11 , wherein the composition further comprises one or more other skin permeation enhancers selected from a fatty (C 8 -C 20 ) alcohol ester of a hydroxyl acid, a lower (C 1 -C 4 ) alkyl ester of a hydroxyl acid, and a C 6 -C 18  fatty acid.