Transdermal administration of progesterone, estradiol esters, and mixtures thereof

• US 4,788,062 A
• Filed: 02/26/1987
• Issued: 11/29/1988
• Est. Priority Date: 02/26/1987
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Cheng, Yu-Ling, Gale, Robert M., Enscore, David J., Nedberge, Diane E., Nelson, Melinda, Libicki, Shari B.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): HORNE, LEON
• Application Number:
  US07/019,162
• Time in Patent Office: 642 Days
• Field of Search: 424/448, 424/449, 914/946, 914/947
• US Class Current: 424/449
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7076 the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
• CPC Class Codes: A61K 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Abstract

A transdermal delivery system for the administering of progesterone and an estradiol ester alone or in combination utilizing a polymer matrix having the drug(s) along with a permeation enhancer dispersed throughout.

Claims

1. A composition of matter for the transdermal administration of a drug selected from the group consisting of progesterone, an estradiol ester and mixtures thereof, comprising said drug and a skin permeation enhancer selected from the group consisting of sucrose monolaurate, glycerol monooleate, glycerol monolaurate, propylene glycol laurate, and neopentyl glycol dicaprate.

2. The composition of claim 1 wherein said drug is present in an amount in excess of its saturation concentration in said carrier.

3. The composition of claim 1 wherein said permeation enhancer is present at a predetermined concentration such that it has an activity within the range of about 0.1 to unit activity.

4. The composition of claim 1 wherein said drug is progesterone.

5. The composition of claim 1 wherein said drug is an estradiol ester.

6. The composition of claim 1 wherein said drug is a combination of progesterone and an estradiol ester.

7. The composition of claim 1 which further comprises an adhesive.

8. The composition of claim 7 wherein said adhesive is an adhesive mixture forming said matrix, selected from the group consisting of an elastomer and tackifier mix, and a high molecular weight polymer, low molecular weight polymer and oil mix.

9. The composition of claim 7 wherein said adhesive is an in-line contact adhesive.

10. The composition of claim 9 wherein said adhesive is further comprised of a permeation enhancer.

11. The composition of claim 9 wherein said adhesive controls the rate of release of drug from said composition.

12. The composition of claim 9 wherein said adhesive controls the rate of release of permeation enhancer from said composition.

36. The composition of claim 1 wherein said drug and skin permeation enhancer are dispersed within a carrier.

13. A method for the transdermal administration of a drug selected from the group consisting of progesterone, an estradiol ester and mixtures thereof which comprises placing a matrix containing said drug in drug transmitting relationship to the skin in the presence of a permeation enhancer selected from the group consisting of sucrose monolaurate, glycerol monooleate, glycerol monolaurate, propylene glycol laurate, and neopentyl glycol dicaprate.

14. The method of claim 13 wherein said drug is at unit activity.

15. The method of claim 13 wherein said permeation enhancer has an activity within the range of about 0.1 to unit activity.

16. The method of claim 13 wherein said drug is progesterone.

17. The method of claim 16 wherein said progesterone is delivered through the skin at a rate of up to about 24 mg/day.

18. The method of claim 13 wherein said drug is an estradiol ester.

19. The method of claim 18 wherein said estradiol ester is delivered through the skin at a rate of about 25-250 μ

g/day.

20. The method of claim 18 wherein said estradiol ester is delivered through the skin at a rate of about 50-150 μ

g/day.

21. The method of claim 13 wherein said drug is a combination of progesterone and an estradiol ester.

22. The method of claim 21 wherein said progesterone is delivered through the skin at a rate of about 24 mg/day and said estradiol ester is delivered through the skin at a rate of about 25-250 μ

g/day.

23. The method of claim 21 wherein said progesterone is delivered through the skin at a rate of about 24 mg/day and said estradiol ester is delivered through the skin at a rate of about 50-150 μ

g/day.

24. A medical device for the transdermal delivery of a drug for a predetermined time period selected from the group consisting of progesterone, an estradiol ester and mixtures thereof comprising in combination:

(a) a reservoir means containing said drug and a permeation enhancer selected from the group consisting of sucrose monolaurate, glycerol monooleate, glycerol monolaurate, propylene glycol laurate, propylene glycol dipelarginate and neopentyl glycol dicaprate;

(b) a means for maintaining said reservoir means in drug and permeation enhancer transmitting relationship to the skin at therapeutically effective rates;

(c) said drug being present in said reservoir means in amounts sufficient to deliver said drug at said therapeutically effective rates for said predetermined time period; and

(d) said permeation enhancer being present in said reservoir means in amounts sufficient to deliver said permeation enhancer at said therapeutically effective rates for said predetermined time period.

25. The medical device of claim 24 wherein said means for maintaining said reservoir in drug and permeation enhancer transmitting relationship to the skin is an adhesive overlay.

26. The medical device of claim 24 wherein said means for maintaining said reservoir in drug and permeation enhancer transmitting relationship to the skin is an in-line contact adhesive.

27. The medical device of claim 24 wherein said drug is progesterone.

28. The medical device of claim 24 wherein said drug is an estradiol ester.

29. The medical device of claim 24 wherein said drug is a combination of progesterone and an estradiol ester.

30. A method for the treatment of post-menopausal symptoms in the human female which comprises transdermally administering progesterone and an estradiol ester at therapeutically effective rates nd durations, said rates and durations defining a 28 day therapeutic regimen, and repeating said regimen at the expiration of the preceding 28 day regimen for so long as therapy is desired.

31. The method of claim 30 wherein said 28 day regimen comprises delivering an estradiol ester for 14 days, followed by delivering a mixture of an estradiol ester and progesterone for 14 days.

32. The method of claim 30 wherein said 28 day regimen comprises delivering an estradiol ester for 14 days, followed by delivering progesterone for 14 days.

33. The method of claim 30 wherein said 28 day regimen comprises delivering an estradiol ester for 7 days, followed by delivering a mixture of an estradiol ester and progesterone for 14 days, followed by delivering progesterone for 7 days.

34. The method of claim 30 wherein said 28 day regimen comprises delivering a mixture of an estradiol ester and progesterone for 28 days.

35. The method of claim 34 wherein the delivery ratio of said estradiol ester to said progesterone varies within the 28 day delivery period.

37. A 28 day transdermal dosage package for the treatment of post-menopausal symptoms comprising in combination, a container containing a plurality of transdermal systems for delivering progesterone and an estradiol ester at therapeutically effective rates and durations, said rates and durations defining a 28 day therapeutic regimen.

38. The package of claim 37 wherein a portion of said systems deliver said estradiol ester and the remainder of said systems deliver a mixture of said estradiol ester and progesterone, wherein said systems delivering the estradiol ester deliver said estradiol ester for the initial 14 day and systems delivering the estradiol ester and progesterone mixture deliver said mixture for the remaining 14 days.

39. The package of claim 37 wherein a portion of said systems deliver said estradiol ester and the remainder of said systems deliver progesterone, wherein said systems delivering the estradiol ester deliver said estradiol ester for the initial 14 days and systems delivering progesterone deliver said progesterone for the remaining 14 days.

40. The package of claim 37 wherein a first portion of said systems deliver said estradiol ester, a second portion of said systems deliver a mixture of said estradiol ester and progesterone and the remainder of said systems deliver progesterone, wherein said systems delivering the estradiol ester deliver said estradiol ester for the initial 7 days, systems delivering a mixture of the estradiol ester and progesterone deliver said mixture for the subsequent 14 days and systems delivering progesterone deliver said progesterone for the remaining 7 days.

41. The package of claim 37 wherein said systems deliver a mixture of said estradiol ester and progesterone.

42. The package of claim 41 wherein said systems have varying amounts of said estradiol ester and progesterone.