Drug dosage unit for buccal administration of steroidal active agents

• US 6,117,446 A
• Filed: 01/26/1999
• Issued: 09/12/2000
• Est. Priority Date: 01/26/1999
• Status: Expired due to Fees

• Current Assignee: Virgil A. Place
• Original Assignee: Virgil A. Place
• Inventors: Place, Virgil A.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/237,713
• Time in Patent Office: 595 Days
• Field of Search: 424/430, 424/434, 424/435
• US Class Current: 424/435
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives

Abstract

A buccal dosage unit is provided for administering a combination of steroidal active agents to a female individual. The novel buccal drug delivery systems may be used in female hormone replacement therapy, in female contraception, to treat female sexual dysfunction, and to treat or prevent a variety of conditions and disorders which are responsive to the active agents discussed herein. The buccal dosage unit comprises a progestin, an estrogen and optionally an androgenic agent, as well as a polymeric carrier that bioerodes and provides for delivery of the active agents throughout a predetermined drug delivery period.

Claims

1. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of an androgenic agent selected from testosterone and pharmacologically acceptable esters thereof, a progestin and an estrogen.

2. The dosage unit of claim 1, wherein the androgenic agent is selected from the group consisting of androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3-acetate, androstenediol-17-acetate, androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate, androstenedione, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, methyl testosterone, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol, testosterone, 4-dihydrotestosterone, 5α

-dihydrotestosterone, testolactone, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.

3. The dosage unit of claim 2, wherein the androgenic agent is a testosterone ester.

4. The dosage unit of claim 3, wherein the testosterone ester is selected from the group consisting of testosterone enanthate, propionate, cypionate, phenylacetate, acetate, buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprate.

5. The dosage unit of claim 4, wherein the testosterone ester is selected from the group consisting of testosterone enanthate, propionate and cypionate.

6. The dosage unit of claim 2, wherein the androgenic agent is testosterone.

7. The dosage unit of claim 1, wherein the progestin 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, norgestrel, norgestrienone, normethisterone, progesterone, and combinations thereof.

8. The dosage unit of claim 7, wherein the progestin is selected from the group consisting of progesterone, cyproterone acetate, norethindrone, norethindrone acetate and levonorgestrel.

9. The dosage unit of claim 8, wherein the progestin is progesterone.

10. The dosage unit of claim 1, wherein the estrogen is selected from the group consisting of 17α

-estradiol, 17β

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

-estradiol, 17β

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

11. The dosage unit of claim 10, wherein the estrogen is 17β

-estradiol or ethynyl estradiol.

12. The dosage unit of claim 1, wherein the androgenic agent is testosterone, the progestin is progesterone, and the estrogen is 17β

-estradiol or ethynyl estradiol.

16. The dosage unit of claim 1, weighing in the range of approximately 5 mg to 20 mg.

17. The dosage unit of claim 16, weighing in the range of approximately 10 mg to 15 mg.

20. The dosage unit of claim 1, further including an effective amount of a lubricant.

21. The dosage unit of claim 20, wherein the lubricant represents approximately 0.01 wt. % to 2.0 wt. % of the dosage unit.

22. The dosage unit of claim 20, wherein the lubricant is magnesium stearate.

13. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of an androgenic agent, a progestin and an estrogen, wherein the carrier is selected such that upon sustained contact with the buccal mucosa the unit completely erodes within a predetermined drug delivery period in the range of approximately 4 to 24 hours.

14. The dosage unit of claim 13, wherein the carrier is selected from the group consisting of carbomers, hydrolyzed polyvinylalcohol, polyethylene oxide, polyacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and combinations thereof.

15. The dosage unit of claim 14, wherein the carrier is polyethylene oxide or a carbomer.

18. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and approximately 5 wt. % to 20 wt. % of an androgenic agent, 5 wt. % to 60 wt. % of a progestin, and 1 wt. % to 5 wt. % of an estrogen.

19. The dosage unit of claim 18, comprising approximately 10 wt. % to 20 wt. % androgenic agent, 30 wt. % to 60 wt. % progestin, and 2 wt. % to 5 wt. % estrogen.

23. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet having a concave surface for contacting the buccal mucosa and adhering thereto, comprising a bioerodible polymeric carrier and therapeutically effective amounts of an androgenic agent, a progestin and an estrogen.

24. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of a progestin and an estrogen, said tablet weighino approximately 5 mg to 20 mg.

25. The dosage unit of claim 24, wherein the progestin 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, norgestrel, norgestrienone, normethisterone, progesterone, and combinations thereof.

26. The dosage unit of claim 25, wherein the progestin is selected from the group consisting of progesterone, cyproterone acetate, norethindrone, norethindrone acetate and levonorgestrel.

27. The dosage unit of claim 26, wherein the progestin is progesterone.

28. The dosage unit of claim 24, wherein the estrogen is selected from the group consisting of 17α

-estradiol, 17β

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

-estradiol, 17β

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

29. The dosage unit of claim 28, wherein the estrogen is 17β

-estradiol or ethynyl estradiol.

34. The dosage unit of claim 24, weighing approximately 10 mg to 15 mg.

37. The dosage unit of claim 24, further including an effective amount of a lubricant.

38. The dosage unit of claim 37, wherein the lubricant represents approximately 0.01 wt. % to 2.0 wt. % of the dosage unit.

39. The dosage unit of claim 37, wherein the lubricant is magnesium stearate.

30. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of a progestin and an estrogen, wherein the progestin is progesterone and the estrogen is 17β

-estradiol or ethynyl estradiol.

31. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of a progestin and an estrogen, wherein the carrier is selected such that upon sustained contact with the buccal mucosa the unit completely erodes within a predetermined drug delivery period in the range of approximately 4 to 24 hours.

32. The dosage unit of claim 31, wherein the carrier is selected from the group consisting of carbomers, hydrolyzed polyvinylalcohol, polyethylene oxide, polyacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and combinations thereof.

33. The dosage unit of claim 32, wherein the carrier is polyethylene oxide or a carbomer.

35. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier comprising approximately 5 wt. % to 60 wt. % of a progestin and 1 wt. % to 5 wt. % of an estrogen.

36. The dosage unit of claim 35, comprising approximately 30 wt. % to 60 wt. % progestin, and 2 wt. % to 5 wt. % estrogen.

40. A buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet having a concave surface for contacting the buccal mucosa and adhering thereto, comprising a bioerodible polymeric carrier and therapeutically effective amounts of a progestin and an estrogen.

41. A method for administering a combination of steroidal active agents to a female individual to achieve therapeutic blood levels thereof, comprising affixing a dosage unit comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of an androgenic agent, a progestin and an estrogen to the buccal mucosa of the individual and allowing the dosage unit to remain in place until erosion thereof is complete.

42. A method for administering a combination of steroidal active agents to a female individual to achieve therapeutic blood levels thereof, comprising affixing a dosage unit comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of a progestin and an estrogen to the buccal mucosa of the individual and allowing the dosage unit to remain in place until erosion thereof is complete.