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

• US 6,562,370 B2
• Filed: 12/14/2000
• Issued: 05/13/2003
• Est. Priority Date: 12/16/1999
• Status: Expired due to Fees

• Current Assignee: Technology Recovery Systems, LLC
• Original Assignee: Dermatrends, Inc.
• Inventors: Luo, Eric C., Hsu, Tsung-Min
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Ghali, Isis
• Application Number:
  US09/737,833
• Publication Number:
  US 20010033870A1
• Time in Patent Office: 880 Days
• Field of Search: 424/449, 424/443, 424/447, 424/448, 514/944, 514/946, 514/947
• 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 method for enhancing the flux of a steroid drug through a body surface, comprising administering the steroid drug to a localized region of a human patient'"'"'s body surface in combination with a hydroxide-releasing agent applied to the body surface in a predetermined amount effective to enhance the flux of the drug through the localized region of the body surface without causing damage thereto, and effective to provide a pH in the range of approximately 8.0 to 13 at the localized region of the body surface, during drug administration, wherein the steroid drug and hydroxide-releasing agent are present in a formulation and the amount of hydroxide-releasing agent in the formulation applied to the body surface is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.5 wt. % to 25.0 wt. % of the formulation.

2. The method of claim 1, wherein the body surface is skin.

3. The method of claim 1, wherein the body surface is mucosal tissue.

4. The method of claim 1, wherein the steroid is a progestin and is 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, hydroxymethylprogesterone 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.

5. The method of claim 4, wherein the progestin is selected from the group consisting of progesterone, medroxyprogesterone acetate, norethindrone, norethynodrel, d,1-norgestrel and 1-norgestrel.

6. The method of claim 5, wherein the progestin is progesterone.

7. The method of claim 1, wherein the steroid is a estrogen and is 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.

8. The method of claim 7, wherein the estrogen is 17β

-estradiol, ethinyl estradiol, or mestranol.

9. The method of claim 1, wherein the steroid is an androgenic agent and is testosterone or an ester thereof.

10. The method of claim 1, wherein the pH is in the range of approximately 8.0 to 11.5.

11. The method of claim 10, wherein the pH is in the range of approximately 8.5 to 11.5.

12. The method of claim 1, wherein the formulation is aqueous.

13. The method of claim 12, wherein the formulation has a pH in the range of approximately 8.0 to 13.

14. The method of claim 13, wherein the pH is in the range of approximately 8.0 to 11.5.

15. The method of claim 14, wherein the pH is in the range of approximately 8.5 to 11.5.

16. The method of claim 12, wherein the aqueous formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.

17. The method of claim 16, wherein the formulation is a cream.

18. The method of claim 16, wherein the formulation is a gel.

19. The method of claim 1, wherein the formulation is nonaqueous.

20. The method of claim 19, wherein the formulation is an ointment.

21. The method of claim 1, wherein the hydroxide-releasing agent releases free hydroxide ions in the presence of an aqueous fluid.

22. The method 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.

23. The method of claim 22, wherein the hydroxide-releasing agent is an inorganic hydroxide.

24. The method of claim 23, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.

25. The method of claim 24, wherein the inorganic hydroxide is sodium hydroxide.

26. The method of claim 24, wherein the inorganic hydroxide is potassium hydroxide.

27. The method of claim 22, wherein the hydroxide-releasing agent is an inorganic oxide.

28. The method of claim 27, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.

29. The method of claim 22, wherein the hydroxide-releasing agent is a metal salt of a weak acid.

30. The method of claim 29, 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.

31. The method of claim 29, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.5 wt. % to 4.0 wt. % of the formulation.

32. The method of claim 31, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.75 wt. % to 2.0 wt. % of the formulation.

33. The method of claim 32, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 1.0 wt. % of the formulation.

34. The method of claim 29, wherein the formulation contains up to approximately 25 wt. % of the hydroxide-releasing agent.

35. The method of claim 34, wherein the formulation contains up to approximately 20 wt. % of the hydroxide-releasing agent.

36. The method of claim 27, wherein the formulation contains up to approximately 25 wt. % of the hydroxide-releasing agent.

37. The method of claim 36, wherein the formulation contains up to approximately 20 wt. % of the hydroxide-releasing agent.

38. The method of claim 1, wherein the steroid drugs and the hydroxide-releasing agent are administered by applying a drug delivery device to the localized region of the patient'"'"'s body surface thereby forming a body surface-delivery device interface, the device comprising the drugs and the hydroxide-releasing agent, and having an outer backing layer that serves as the outer surface of the device during use.

39. The method of claim 38, wherein the steroid drugs and hydroxide-releasing agent are present in an adhesive, gel or liquid formulation contained within the device.

40. The method of claim 38, wherein the outer backing layer is occlusive.