Compositions and methods for transdermal delivery of hormones and other medicinal agents
The invention provides transdermal delivery systems, medical kits, and methods for using the transdermal delivery systems and kits for medical applications, such as delivery of contraceptive agents to control fertility.
1. A transdermal delivery system, comprising a backing layer affixed to an adhesive polymer matrix, wherein the adhesive polymer matrix comprises:
a. about 0.5% (w/w) to about 10% (w/w) of a first penetration enhancer selected from the group consisting of levulinic acid and a pharmaceutically acceptable salt thereof;
b. about 0.5% (w/w) to about 10% (w/w) of a second penetration enhancer selected from the group consisting of glyceryl monooleate and lauryl lactate;
c. an adhesive polymer;
d. a humectant;
e. levonorgestrel; and
f. ethinyl estradiol.
2. The transdermal delivery system of claim 1 , wherein the first penetration enhancer is levulinic acid.
3. The transdermal delivery system of claim 1 , wherein the second penetration enhancer is glyceryl monooleate.
4. The transdermal delivery system of claim 1 , wherein the second penetration enhancer is lauryl lactate.
5. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 3% (w/w) to about 5% (w/w) of the first penetration enhancer.
6. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 3.5% (w/w) to about 4.0% (w/w) of the first penetration enhancer.
7. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 2.0% (w/w) to about 3.0% (w/w) of the second penetration enhancer.
8. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 2.25% (w/w) to about 2.75% (w/w) of the second penetration enhancer.
9. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 7.0% (w/w) to about 8.0% (w/w) of the second penetration enhancer.
10. The transdermal delivery system of claim 1 , wherein the ratio of weight percent of first penetration enhancer to second penetration enhancer in the adhesive polymer matrix is in the range of about 1:1 to 2:1.
11. The transdermal delivery system of claim 1 , wherein the adhesive polymer is a polyacrylate copolymer.
12. The transdermal delivery system of claim 1 , wherein the adhesive polymer is a polyacrylate copolymer comprising a 2-ethylhexyl acrylate monomer.
13. The transdermal delivery system of claim 1 , wherein the adhesive polymer is a random copolymer of 2-ethylhexyl acrylate and vinyl acetate.
14. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 80% (w/w) to about 92% (w/w) adhesive polymer.
15. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 88% (w/w) to about 90% (w/w) adhesive polymer.
16. The transdermal delivery system of claim 1 , wherein the humectant comprises a polyvinylpyrrolidone copolymer.
17. The transdermal delivery system of claim 1 , wherein the humectant comprises a copolymer of vinylpyrrolidone and vinyl acetate.
18. The transdermal delivery system of claim 1 , wherein the humectant is a copolymer of vinylpyrrolidone and vinyl acetate, said copolymer having a weight average molecular weight of about 30,000 g/mol to about 50,000 g/mol.
19. The transdermal delivery system of claim 1 , wherein the humectant is a copolymer of vinylpyrrolidone and vinyl acetate, said copolymer having a weight average molecular weight of about 40,000 g/mol.
20. The transdermal delivery system of claim 19 , wherein the copolymer of vinylpyrrolidone and vinyl acetate comprises (i) from about 55% (w/w) to about 65% (w/w) vinylpyrrolidone and (ii) from about 35% (w/w) to about 45% (w/w) vinyl acetate.
21. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 2.75% (w/w) to about 3.75% (w/w) humectant.
22. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 0.6% (w/w) to about 1.0% (w/w) levonorgestrel.
23. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix comprises from about 0.6% (w/w) to about 1.0% (w/w) ethinyl estradiol.
24. A transdermal delivery system, comprising a backing layer affixed to an adhesive polymer matrix, wherein the adhesive polymer matrix comprises:
a. about 3.5% (w/w) to about 4% (w/w) of a first penetration enhancer selected from the group consisting of levulinic acid and a pharmaceutically acceptable salt thereof;
b. about 2.2% (w/w) to about 2.8% (w/w) of a second penetration enhancer that is glyceryl monooleate;
c. about 86% (w/w) to about 90% (w/w) of an adhesive polymer that is a random copolymer of 2-ethylhexyl acrylate and vinyl acetate;
d. about 2% (w/w) to about 4% (w/w) of a humectant that is a copolymer of vinylpyrrolidone and vinyl acetate;
e. about 0.7% (w/w) to about 0.9% (w/w) levonorgestrel; and
f. about 0.7% (w/w) to about 0.9% (w/w) ethinyl estradiol.
25. A transdermal delivery system, comprising a backing layer affixed to an adhesive polymer matrix, wherein the adhesive polymer matrix comprises:
a. about 3.5% (w/w) to about 4% (w/w) levulinic acid;
b. about 6% (w/w) to about 9% (w/w) lauryl lactate;
c. about 80% (w/w) to about 88% (w/w) of an adhesive polymer that is an acrylate-vinylacetate copolymer;
d. about 2% (w/w) to about 4% (w/w) of a humectant that is a copolymer of vinylpyrrolidone and vinyl acetate;
e. about 0.7% (w/w) to about 0.9% (w/w) levonorgestrel; and
f. about 0.7% (w/w) to about 0.9% (w/w) ethinyl estradiol.
26. The transdermal delivery system of claim 1 , formulated for delivery of ethinyl estradiol and levonorgestrel, wherein the ethinyl estradiol is transdermally delivered at a rate of from about 5 μg to about 25 μg per day for a term of about seven days, and the levonorgestrel is transdermally delivered at a rate of about 25 μg to about 35 μg per day for a term of about seven days.
27. The transdermal delivery system of claim 1 , formulated for delivery of ethinyl estradiol and levonorgestrel, wherein the ethinyl estradiol is transdermally delivered at a rate of from about 10 μg to about 20 μg per day for a term of about seven days, and the levonorgestrel is transdermally delivered at a rate of about 30 μg per day for a term of about seven days.
28. The transdermal delivery system of claim 1 , wherein the levonorgestrel is transdermally delivered in an amount sufficient to produce a serum concentration of at least 1,000 pg/mL in a human.
29. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix has a thickness of about 50 μm to about 150 μm.
30. The transdermal delivery system of claim 1 , wherein the adhesive polymer matrix has a thickness of about 100 μm.
31. A method of transdermally administering levonorgestrel and ethinyl estradiol to a subject, comprising applying a transdermal delivery system of claim 1 to the skin of the subject.
32. A method of controlling fertility in a female subject, comprising applying a transdermal delivery system of claim 1 to the skin of the female subject.
33. The method of claim 32 , wherein the transdermal delivery system is replaced once each week for at least three successive weeks.