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 the levonorgestrel, an anti-oxidant, and a skin permeation enhancer in a polyacrylate pressure sensitive adhesive (PSA);   (b) the composition comprises at least one component that contributes to oxidative degradation of the levonorgestrel, wherein the at least one component is one or more of (i) the polyacrylate PSA, (ii) the skin permeation enhancer wherein the enhancer comprises dimethyl sulfoxide (DMSO), and (iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer;   (c) (i) the anti-oxidant is not an estrogen; (ii) the anti-oxidant is not a sulfoxide or a fatty acid; and (iii) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the one or more of the PSA, the DMSO and the PVP or PVP copolymer; and   (d) the stability of the composition is improved over the stability of such composition lacking the anti-oxidant.   
     
     
         2 . The composition of  claim 1  that lacks an estrogen. 
     
     
         3 . 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, or any combination thereof. 
     
     
         4 . The composition of  claim 3  that lacks an estrogen. 
     
     
         5 . The composition of  claim 1  wherein the anti-oxidant is selected from sodium bisulfite, 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. 
     
     
         6 . The composition of  claim 5  that lacks an estrogen. 
     
     
         7 . The composition of  claim 1 , wherein the polyacrylate PSA contributes to oxidative degradation of the levonorgestrel. 
     
     
         8 . The composition of  claim 1 , wherein the skin permeation enhancer is DMSO and the DMSO contributes to the oxidative degradation of the levonorgestrel. 
     
     
         9 . The composition of  claim 8  that lacks an estrogen. 
     
     
         10 . 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). 
     
     
         11 . The composition of  claim 10  that lacks an estrogen. 
     
     
         12 . 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. 
     
     
         13 . The composition of  claim 12  that lacks an estrogen. 
     
     
         14 . 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. 
     
     
         15 . A method of improving the stability of a transdermal delivery composition comprising levonorgestrel, the method comprising adding an anti-oxidant other than an estrogen to the composition; wherein
 (a) the composition comprises the levonorgestrel and a skin permeation enhancer in a polyacrylate pressure sensitive adhesive (PSA);   (b) the composition comprises at least one component that contributes to oxidative degradation of the levonorgestrel, wherein the at least one component is one or more of (i) the polyacrylate PSA, (ii) the skin permeation enhancer wherein the enhancer comprises DMSO, and (iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer; and   (c) (i) the anti-oxidant is not a sulfoxide or a fatty acid; and (iii) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the one or more of the PSA, the DMSO and the PVP or PVP copolymer.   
     
     
         16 . The method of  claim 15 , comprising adding an anti-oxidant 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, or any combination thereof. 
     
     
         17 . The method of  claim 15 , comprising adding an anti-oxidant selected from sodium bisulfite, 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. 
     
     
         18 . The method of  claim 15 , wherein the composition lacks an estrogen. 
     
     
         19 . The method of  claim 15 , wherein the composition comprises a PVP copolymer that is PVP/VA. 
     
     
         20 . The method of  claim 15 , 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.