Dermal delivery compositions and methods
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 the matrix comprises:
a) a polymeric pressure sensitive adhesive (PSA)
b) levonorgestrel,
c) a skin permeation enhancer comprising an organic solvent,
d) polyvinyl pyrrolidone (PVP) or a PVP copolymer, and
e) an anti-oxidant
wherein
(i) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the organic solvent or the PVP or PVP copolymer;
(ii) the composition lacks and estrogen; and
(iii) the stability of the composition is improved over the stability of such composition lacking and anti-oxidant.
2. The composition of claim 1 , wherein the PSA is a polyacrylate adhesive, a polyisobutylene adhesive, or a silicone adhesive and the organic solvent is DMSO.
3. The composition of claim 2 , wherein the anti-oxidant is sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxiphenyl) propionate), or tris (2,4di-tert-butylphenyl) phosphate or any combination of two or more of said anti-oxidants.
4. The composition of claim 1 , wherein the composition further comprises one or more or of: alcohols; alkanones; amides and other nitrogenous compounds; 1-substituted azacycloheptan-2-ones; bile salts; cholesterol; cyclodextrins and substituted cyclodextrins; ethers; saturated and unsaturated fatty acids; saturated and unsaturated fatty acid esters; saturated and unsaturated fatty alcohol esters; glycerides and monoglycerides; organic acids; methyl nicotinate; pentadecalactone; polyols and esters thereof; phospholipids; sulfoxides; surfactants; terpenes; and combinations thereof, as skin permeation enhancers.
5. The composition of claim 1 , wherein the organic solvent is dimethyl sulfoxide (DMSO) and wherein the composition further comprises one or more of: a fatty (C 8 -C 20 ) alcohol ester of a hydroxy acid, a lower (C 1 -C 4 ) alkyl ester of a hydroxy acid, and a C 6 -C 18 fatty acid, as the skin permeation enhancers.
6. The composition of claim 4 , wherein the organic solvent is DMSO.
7. A method of improving the stability of a progestin transdermal delivery composition comprising
a) a polymeric pressure sensitive adhesive (PSA)
b) levonorgestrel,
c) a skin permeation enhancer comprising an organic solvent, and
d) polyvinyl pyrrolidone (PVP) or a PVP copolymer;
wherein the composition lacks an estrogen;
the method comprising adding an anti-oxidant to the composition, thereby improving the stability of the composition over the stability of such composition lacking the anti-oxidant.
8. The method of claim 7 , wherein the PSA is a polyacrylate adhesive, a polyisobutylene adhesive, or a silicone adhesive.
9. The method of claim 7 , wherein the anti-oxidant is sodium bisulfite, sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), or tris(2,4-di-tert-butylphenyl) phosphite or any combination of two or more of said anti-oxidants.
10. The method of claim 7 , wherein the composition further comprises one or more of: alcohols; alkanones; amides and other nitrogenous compounds; 1-substituted azacycloheptan-2-ones; bile salts; cholesterol; cyclodextrins and substituted cyclodextrins; ethers; saturated and unsaturated fatty acids; saturated and unsaturated fatty acid esters; saturated and unsaturated fatty alcohol esters; glycerides and monoglycerides; organic acids; organic solvents; methyl nicotinate; pentadecalactone; polyols and esters thereof; phospholipids; sulfoxides; surfactants; terpenes; and combinations thereof, as skin permeation enhancers.
11. The method of claim 10 , wherein the skin permeation enhancer comprises one or more of: DMSO, a fatty (C 8 -C 20 ) alcohol ester of a hydroxy acid, a lower (C 1 -C 4 ) alkyl ester of a hydroxy acid, and a C 6 -C 18 fatty acid.
12. The composition of claim 1 wherein the organic solvent is DMSO and wherein the stability of the composition is improved over the stability of such composition with ethinyl estradiol but lacking an anti-oxidant.
13. A contraceptive progestin-only composition for transdermal delivery of levonorgestrel that comprises:
a) a polyacrylate pressure sensitive adhesive (PSA),
b) levonorgestrel,
c) a skin permeation enhancer comprising DMSO,
d) PVP/VA copolymer, and
e) an anti-oxidant
wherein
(i) the anti-oxidant protects against oxidative degradation of the levonorgestrel by the polyacrylate PSA, the DMSO, or the PVP/VA copolymer,
(ii) the composition lacks an estrogen,
(iii) the stability of the levonorgestrel is improved over the stability of levonorgestrel in such composition lacking an anti-oxidant, and
(iv) the stability of the levonorgestrel is improved over the stability of levonorgestrel in such composition comprising ethinyl estradiol and lacking an anti-oxidant.
14. A contraceptive progestin-only composition for transdermal delivery of levonorgestrel, wherein the composition lacks estrogen and consists of:
a) a pressure sensitive adhesive,
b) levonorgestrel,
c) one or more skin permeation enhancers, at least one of which is an organic solvent,
d) PVP or a PVP copolymer, and
e) an anti-oxidant.