Transdermal administration of steroid drugs using hydroxide-releasing agents as permeation enhancers

• US 20030157157A1
• Filed: 02/20/2003
• Published: 08/21/2003
• Est. Priority Date: 12/16/1999
• Status: Abandoned Application

• Current Assignee: Eric C. Luo, Tsung-Min Hsu
• Original Assignee: Eric C. Luo, Tsung-Min Hsu
• Inventors: Luo, Eric C., Hsu, Tsung-Min
• Application Number:
  US10/371,538
• Publication Number:
  US 20030157157A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene

Abstract

A method is provided for increasing the permeability of skin or mucosal tissue to transdermally administered steroid drugs. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the drug through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Formulations and drug delivery systems for co-administering a hydroxide-releasing agent with a steroid drug are provided as well. Optimally, the steroid drugs are a combination of an estrogen and progestin that may be administered in female hormone replacement therapy, to provide female contraception, and the like

Claims

1. A composition of matter useful for the delivery of a steroid drug through a body surface, comprising:

(a) a therapeutically effective amount of a steroid drug;

(b) a hydroxide-releasing agent in an amount effective to enhance the flux of the drug through the body surface without causing damage thereto and effective to provide a pH in the range of approximately 8.0 to 13 at the body surface during drug administration, and wherein the amount of hydroxide-releasing agent in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.25 wt % to 25.0 wt % of the composition; and

(c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration.

2. The composition of claim 1, wherein the pH is within the range of approximately 8.0 to 11.5.

3. The composition of claim 2, wherein the pH is within the range of approximately 8.5 to 11.5.

4. The composition of claim 1, which is substantially free of organic solvents.

5. The composition of claim 1, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.

6. The composition of claim 5, wherein the hydroxide-releasing agent is an inorganic hydroxide.

7. The composition of claim 6, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.

8. The composition of claim 7, wherein the inorganic hydroxide is sodium hydroxide.

9. The composition of claim 7, wherein the inorganic hydroxide is potassium hydroxide.

10. The composition of claim 6, wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt % to 4.0 wt % of the composition.

11. The composition of claim 10, wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.75 wt % to 2.0 wt % of the composition.

12. The composition of claim 5, wherein the hydroxide-releasing agent is an inorganic oxide.

13. The composition of claim 12, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.

14. The composition of claim, 12, which contains up to approximately 20 wt % of the hydroxide-releasing agent.

15. The composition of claim 5, wherein the hydroxide-releasing agent is a metal salt of a weak acid.

16. The composition of claim 15, wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic ammonium phosphate, and mixtures thereof.

17. The composition of claim 15, which contains up to approximately 20 wt % of the hydroxide-releasing agent.

18. The composition of claim 1, which is an aqueous formulation.

19. The composition of claim 18, wherein the formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.

20. The composition of claim 19, wherein the formulation is a cream.

21. The composition of claim 19, wherein the formulation is a gel.

22. The composition of claim 1, which is a nonaqueous formulation.

23. The composition of claim 22, wherein the formulation is an ointment.

24. The composition of claim 1, wherein the steroid is a progestin selected from the group consisting of acetoxypregneno lone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone, hydroxymethyl-progesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrol acetate, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, d,1-norgestrel, 1-norgestrel, norgestrienone, normethisterone, progesterone, and combinations thereof.

25. The composition of claim 24, wherein the progestin is selected from the group consisting of progesterone, medroxyprogesterone acetate, norethindrone, norethynodrel, d,1-norgestrel and 1-norgestrel.

26. The composition of claim 25, wherein the progestin is progesterone.

27. The composition of claim 1, wherein the steroid is an estrogen selected from the group consisting of 17α

-estradiol, 17β

-estradiol, ethinyl estradiol, pharmaceutically acceptable esters and ethers of 17α

-estradiol, 17β

-estradiol and ethinyl estradiol, estriol, estriol succinate, polyestrol phosphate, estrone, estrone acetate, estrone sulfate, piperazine estrone sulfate, quinestrol, mestranol and conjugated equine estrogens.

28. The composition of claim 27, wherein the estrogen is 17β

-estradiol, ethinyl estradiol, or mestranol.

29. The composition of claim 27, which further comprises an androgenic agent.

30. The composition of claim 29, wherein the androgenic agent is testosterone or an ester thereof.

31. The composition of claim 27, which further comprises a progestin.

32. A system for the topical or transdermal administration of a steroidal drug through a body surface, comprising:

(a) at least one reservoir containing the drug and a hydroxide-releasing agent in an amount effective to enhance the flux of the drug through the body surface without causing damage thereto and effective to provide a pH in the range of approximately 8.0 to 13 at the body surface during drug administration, and wherein the amount of hydroxide-releasing agent in the reservoir applied to the body surface is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.25 wt % to 25.0 wt % of the reservoir;

(b) a means for maintaining the system in drug and enhancer transmitting relationship to the body surface; and

(c) a backing layer that serves as the outer surface of the system during use.

33. The system of claim 32, wherein the pH is within the range of approximately 8.0 to 11.5.

34. The system of claim 33, wherein the pH is within the range of approximately 8.5 to 11.5.

35. The system of claim 32, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.

36. The system of claim 35, wherein the hydroxide-releasing agent is an inorganic hydroxide.

37. The system of claim 36, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.

38. The system of claim 37, wherein the inorganic hydroxide is sodium hydroxide.

39. The system of claim 37, wherein the inorganic hydroxide is potassium hydroxide.

40. The system of claim 36, wherein the amount of inorganic hydroxide in the reservoir is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.5 wt % to 4.0 wt % of the reservoir.

41. The system of claim 40, wherein the amount of inorganic hydroxide in the reservoir is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.75 wt % to 2.0 wt % of the reservoir.

42. The system of claim 35, wherein the hydroxide-releasing agent is an inorganic oxide.

43. The system of claim 42, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.

44. The system of claim 42, wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.

45. The system of claim 35, wherein the hydroxide-releasing agent is a metal salt of a weak acid.

46. The system of claim 45, wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic ammonium phosphate, and mixtures thereof.

47. The system of claim 45, wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.

48. The system of claim 32, wherein the backing layer is occlusive.

49. The system of claim 32, wherein the reservoir is comprised of a polymeric adhesive.

50. The system of claim 49, wherein the polymeric adhesive serves as the means for maintaining the system in drug and enhancer transmitting relationship to the body surface.

51. The system of claim 32, wherein the reservoir is comprised of a hydrogel.

52. The system of claim 32, wherein the reservoir is comprised of a sealed pouch containing the drug and hydroxide-releasing agent in a liquid or semi-solid formulation.

53. The system of claim 32, wherein the steroid is a progestin selected from the group consisting of acetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone, hydroxymethyl-progesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrol acetate, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, d,1-norgestrel, 1-norgestrel, norgestrienone, normethisterone, progesterone, and combinations thereof.

54. The system of claim 53, wherein the progestin is selected from the group consisting of progesterone, medroxyprogesterone acetate, norethindrone, norethynodrel, d,1-norgestrel and 1-norgestrel.

55. The system of claim 54, wherein the progestin is progesterone.

56. The system of claim 32, wherein the steroid is an estrogen selected from the group consisting of 17α

-estradiol, 17β

-estradiol, ethinyl estradiol, pharmaceutically acceptable esters and ethers of 17α

-estradiol, 17β

-estradiol and ethinyl estradiol, estriol, estriol succinate, polyestrol phosphate, estrone, estrone acetate, estrone sulfate, piperazine estrone sulfate, quinestrol, mestranol and conjugated equine estrogens.

57. The system of claim 56, wherein the estrogen is 17β

-estradiol, ethinyl estradiol, or mestranol.

58. The system of claim 56, which further comprises an androgenic agent.

59. The system of claim 58, wherein the androgenic agent is testosterone or an ester thereof.

60. The system of claim 56, which further comprises a progestin.