Drug delivery compositions for improved stability of steroids

• US 5,780,050 A
• Filed: 07/20/1995
• Issued: 07/14/1998
• Est. Priority Date: 07/20/1995
• Status: Expired due to Term

• Current Assignee: Allergan Sales LLC (Abbvie Incorporated)
• Original Assignee: Theratech, Inc. (Dynatronics Corporation)
• Inventors: Jain, Uday, Venkateshwaran, Srinivasan, Ebert, Charles D.
• Primary Examiner(s): Phelan, D. Gabrielle
• Application Number:
  US08/504,430
• Time in Patent Office: 1,090 Days
• Field of Search: 424/448, 424/449
• US Class Current: 424/449
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/569 substituted in position 17 alpha, e.g. ethisterone
• 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 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: A61P 5/38 of the suprarenal hormones

Abstract

A stabilized patch device for transdermal drug delivery of steroid drugs containing a 3-keto-4-en functional group is described, wherein the patch comprises an effective amount of the steroid drug and a carrier that is free of acid functional groups. The device can further contain additives such as a penetration enhancer or excipient, so long as such additives are also free of acid functional groups. The device can be either a matrix patch or a liquid reservoir patch. In a matrix patch, the carrier is a biocompatible polymeric adhesive with which the steroid drug is intimately admixed. The adhesive is preferably an acrylic polymer or copolymer. In a liquid reservoir patch, the carrier is a controlled-viscosity composition containing a thinner or thickener. Preferred steroid drugs include certain corticosteroids and sex hormones, such as progestins and androgens. A method of stabilizing such steroid drugs during storage in transdermal patches is also disclosed.

Claims

1. A stabilized patch device for transdermal delivery of a steroid drug containing a 3-keto-4-en functional group, wherein said steroid drug is stable upon storage of said device, comprising an effective amount of said steroid drug and a biocompatible polymeric adhesive with which said steroid drug is intimately admixed, wherein said polymeric adhesive is a block copolymer of N-vinyl pyrrolidone and 2-ethyl-hexyl acrylate.

2. The stabilized patch device of claim 1 wherein said steroid drug is selected from the group consisting of sex hormones and corticosteroids that have said 3-keto-4-en functional group.

3. The stabilized patch device of claim 2 wherein said steroid drug is a sex hormone selected from the group consisting of progestins that have said 3-keto-4-en functional group, androgens that have said 3-keto-4-en functional group, and mixtures thereof.

4. The stabilized patch device of claim 3 wherein said sex hormone is a progestin that has said 3-keto-4-en functional group and said progestin is a member selected from the group consisting of progesterone, ethisterone (17α

-ethinyltestosterone), medroxyprogesterone, hydroxyprogesterone, norethindrone (17α

-ethinyl-19-nortestosterone), norethindrone acetate (17α

-ethinyl-19-nortestosterone acetate), dydrogesterone (9β

,10α

-pregna-4,6-diene-3,20-dione), dimethisterone (6α

-methyl-17α

- 1-propynyl!-testosterone), chlormadinone acetate (6-chloro-6-dehydro-17α

-acetoxyprogesterone), norgestrel (13β

-ethyl-17α

-ethinyl-17β

-hydroxygon-4-en-3-one), and esters and mixtures thereof.

5. The stabilized patch device of claim 4 wherein said progestin is norethindrone acetate.

6. The stabilized patch device of claim 4 wherein said progestin is norethindrone.

7. The stabilized patch device of claim 4 wherein said progestin is levonorgestrel.

8. The stabilized patch device of claim 3 wherein said sex hormone is an androgen that has said 3-keto-4-en functional group and said androgen is a member selected from the group consisting of testosterone, methyltestosterone, fluoxymesterone, methandrostenolone, nandrolone, norethandrolone, and esters and mixtures thereof.

9. The stabilized patch device of claim 8 wherein said androgen is a member selected from the group consisting of testosterone and esters thereof.

10. The stabilized patch device of claim 2 wherein said steroid drug is a corticosteroid that has said 3-keto-4-en functional group and said corticosteroid is a member selected from the group consisting of hydroxycortisone, cortisone, desoxycorticosterone, fludrocortisone, betamethasone, dexamethasone, prednisolone, prednisone, methylprednisolone, paramethasone, triamcinolone, flumethasone, fluocinolone, fluocinonide, fluprednisolone, halcinonide, flurandrenolide, meprednisone, medrysone, and esters and mixtures thereof.

11. The stabilized patch device of claim 1 further comprising a penetration enhancer selected from the group consisting of envelope disordering compounds, solvents, and mixtures thereof.

12. The stabilized patch device of claim 11 wherein said cell envelope disordering compounds are selected from the group consisting of isopropyl myristate, methyl laurate, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate, and sorbitan esters and mixtures thereof, and said solvents are selected from the group consisting of water, diols, mono-alcohols, DMSO, dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, azones, and mixtures thereof.

13. The stabilized patch device of claim 2 further comprising a steroid not containing a 3-keto-4-en functional group selected from the group consisting of estrogens, progestins not containing a 3-keto-4-en functional group, androgens not containing a 3-keto-4-en functional group, and corticosteroids not containing a 3-keto-4-en functional group.

14. The stabilized patch device of claim 13 wherein said steroid not containing a 3-keto-4-en functional group in an estrogen.

15. The stabilized patch device of claim 14 wherein said estrogen is an estradiol.

16. A method of stabilizing a steroid drug containing a 3-keto-4-en functional group during storage of a transdermal drug delivery patch device containing said steroid drug comprising the steps of (a) first intimately admixing an effective amount of said steroid drug with an effective amount of a block copolymer of N-vinyl pyrrolidone and 2-ethyl-hexyl acrylate, and (b) then incorporating said admixed steroid drug and block copolymer of N-vinyl pyrrolidone and 2-ethyl-hexyl acrylate into said delivery patch device as a source of said steroid drug.

17. The method of claim 16 wherein said steroid drug is selected from the group consisting of sex hormones and corticosteroids that have a 3-keto-4-en functional group.

18. The method of claim 17 wherein said steroid drug is a sex hormone selected from the group consisting of progestins that have a 3-keto-4-en functional group, androgens that have a 3-keto-4-en functional group, and mixtures thereof.

19. The method of claim 18 wherein said sex hormone is a progestin that has said 3-keto-4-en functional group and said progestin is a member selected from the group consisting of progesterone, ethisterone (17α

-ethinyltestosterone), medroxyprogesterone, hydroxyprogesterone, norethindrone (17α

-ethinyl-19-nortestosterone), norethindrone acetate (17α

-ethinyl-19-nortestosterone acetate), dydrogesterone (9β

,10α

-pregna-4,6-diene-3,20-dione), dimethisterone (6α

-methyl-17α

- 1-propynyl!-testosterone), chlormadinone acetate (6-chloro-6-dehydro-17α

-acetoxyprogesterone), norgestrel (13β

-ethyl-17α

-ethinyl-17β

-hydroxygon-4-en-3-one), and esters and mixtures thereof.

20. The method of claim 19 wherein said progestin is norethindrone acetate.

21. The method of claim 19 wherein said progestin is norethindrone.

22. The method of claim 19 wherein said progestin is levonorgestrel.

23. The method of claim 18 wherein said sex hormone is an androgen that has said 3-keto-4-en functional group and said androgen is a member selected from the group consisting of testosterone, methyltestosterone, fluoxymesterone, methandrostenolone, nandrolone, norethandrolone, and esters and mixtures thereof.

24. The method of claim 23 wherein said androgen is a member selected from the group consisting of testosterone and esters thereof.

25. The method of claim 17 wherein said steroid drug is a corticosteroid that has said 3-keto-4-en functional group and said corticosteroid is a member selected from the group consisting of hydroxycortisone, cortisone, desoxycorticosterone, fludrocortisone, betamethasone, dexamethasone, prednisolone, prednisone, methylprednisolone, paramethasone, triamcinolone, flumethasone, fluocinolone, fluocinonide, fluprednisolone, halcinonide, flurandrenolide, meprednisone, medrysone, and esters and mixtures thereof.

26. The method of claim 16 further comprising a penetration enhancer selected from the group consisting of cell envelope disordering compounds, solvents, and mixtures thereof.

27. The method of claim 26 wherein said cell envelope disordering compounds are selected from the group consisting of isopropyl myristate, methyl laurate, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate, and sorbitan esters and mixtures thereof, and said solvents are selected from the group consisting of water, diols, mono- alcohols, DMSO, dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, azones, and mixtures thereof.

28. The method of claim 17 further comprising a steroid not containing a 3-keto-4-en functional group selected from the group consisting of estrogens, progestins not containing a 3-keto-4-en functional group, androgens not containing a 3-keto-4-en functional group, and corticosteroids not containing a 3-keto-4-en functional group.

29. The method of claim 28 wherein said steroid not containing a 3-keto-4-en functional group in an estrogen.

30. The method of claim 29 wherein said estrogen is estradiol.