Formulations and methods for providing progestin-only contraception while minimizing adverse side effects associated therewith

• US 20070037780A1
• Filed: 08/15/2005
• Published: 02/15/2007
• Est. Priority Date: 08/15/2005
• Status: Active Grant

• Current Assignee: Allergan Sales LLC (Abbvie Incorporated)
• Original Assignee: Allergan Sales LLC (Abbvie Incorporated)
• Inventors: Ebert, Charles, Anigbogu, Angela, Roy, Samir, Hoel, Gary
• Granted Patent: US 10,137,135 B2
• Time in Patent Office: Days
• US Class Current: 514/170
• 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 9/7061 Polyacrylates
• CPC Class Codes: A61P 15/18 Feminine contraceptives

Abstract

Formulations and methods for providing progestin-only contraception to a woman while minimizing various side effects, such as breakthrough bleeding, that are normally associated with progestin-only contraception are disclosed and described. In one aspect, the method can include transdermally administering a formulation having a contraceptively effective amount of a single progestin as the sole active hormonal agent to the woman as part of a contraceptive regimen.

Claims

1. A method of providing progestin-only contraception to a woman while minimizing adverse side effects associated with the progestin-only contraception, comprising:

transdermally administering a formulation having either norethindrone or norethindrone acetate as the sole active hormonal agent to the woman, at a rate and an amount that provides a minimum norethindrone serum level of at least about 160 pg/ml in order to cause and sustain physiologic events in the woman resulting in contraception, and also provides a maximum norethindrone serum level of less than about 2400 pg/ml in order to avoid a significant incidence of adverse side effects.

2. The method of claim 1, wherein the sole active hormonal agent is norethindrone.

3. The method of claim 1, wherein the sole active hormonal agent is norethindrone acetate.

4. The method of claim 1, wherein the formulation includes a permeation enhancer.

5. The method of claim 4, wherein the permeation enhancer includes a sorbitan ester-type enhancer.

6. The method of claim 5, wherein the sorbitan ester-type enhancer is sorbitan monooleate.

7. The method of claim 4, wherein the permeation enhancer includes a lauryl-type enhancer.

8. The method of claim 7, wherein the lauryl-type enhancer is a member selected from the group consisting of lauryl alcohol, 1-lauryl-2-pyrrolidone, and mixtures thereof.

9. The method of claim 4, wherein the permeation enhancer is a combination of lauryl alcohol and isopropyl myristate.

10. The method of claim 4, wherein the permeation enhancer includes a polyol-type enhancer.

11. The method of claim 10, wherein the polyol-type enhancer is dipropylene glycerol.

12. The method of claim 4, wherein concentration of the permeation enhancer is from about 0.01% w/w to about 50% w/w of the formulation.

13. The method of claim 12, wherein the concentration of the permeation enhancer is from about 3% w/w to about 15% w/w of the formulation.

14. The method of claim 1, wherein the transdermal formulation includes a polymeric adhesive.

17. The method of claim 14, wherein the polymeric adhesive is an acrylic polymer.

18. The method of claim 1, wherein the physiologic events are sustained for a period from about 24 to about 168 hours.

19. The method of claim 18, wherein the physiologic events include prevention of ovulation.

20. The method of claim 18, wherein the physiologic events include a thickening of cervical mucus.

21. The method of claim 18, wherein the physiologic events include both prevention of ovulation and a thickening of cervical mucus.

22. The method of claim 1, wherein the adverse side effect is a member selected from the group consisting of strokes, myocardial infarctions, embolisms, breakthrough bleeding, and combinations thereof.

23. The method of claim 22, wherein the adverse side effect is breakthrough bleeding.

24. The method of claim 1, wherein the maximum norethindrone serum level is from about 240 pg/ml to about 1920 pg/ml.

25. The method of claim 1, wherein the maximum norethindrone serum level is from about 300 pg/ml to about 1200 pg/ml.

26. The method of claim 1, wherein the maximum norethindrone serum level is from about 400 pg/ml to about 1100 pg/ml.

27. The method of claim 1, wherein the minimum norethindrone serum level is at least about 300 pg/ml.

28. The method of claim 1, wherein the minimum norethindrone serum level is at least about 350 pg/ml.

29. The method of claim 1, wherein the formulation is in a dosage form selected from the group consisting of transdermal patches, ointments, lotions, gels, pastes, mousses, aerosols, creams, sprays, vaginal rings, and combinations thereof.

30. The method of claim 29, wherein the formulation is a transdermal patch.

31. The method of claim 1, wherein the norethindrone or norethindrone acetate is administered in an amount of about 0.3 mg/day.

48. A kit for use in accordance with any of claims 1, 32, 43, or 47, comprising:

a transdermally administrable formulation including;

norethindrone acetate as the sole active hormonal agent in an amount of from about 5% w/w to about 25% w/w of the transdermal formulation; and

a permeation enhancer in an amount from about 0.01% w/w to about 50% w/w of the transdermal formulation;

the formulation being administered at a rate and an amount that provides a minimum norethindrone serum level of at least 160 pg/ml in order to cause and sustain physiologic events in the woman resulting in contraception for a period of from about 24 to about 168 hours, and also provides a maximum norethindrone serum level of less than about 2400 pg/mi, which is obtained from about 24 to about 96 hours following administration, in order to avoid a significant incidence of adverse side effects; and

instructions describing a method of using the transdermally administrable formulation.

49. The kit of claim 48, wherein the formulation is in a dosage form selected from the group consisting of transdermal patches, ointments, lotions, gels, pastes, mousses, aerosols, creams, sprays, vaginal rings, and combinations thereof.

50. The kit of claim 49, wherein the dosage form is a transdermal patch.

51. The kit of claim 50, wherein transdermal patch is administered for up to about 168 hours and the kit contains at least three transdermal patches and optionally a placebo patch.

32. A method of providing progestin-only contraception to a woman while minimizing adverse side effects associated with the progestin-only contraception, comprising:

transdermally administering a formulation having either norethindrone or norethindrone acetate as the sole active hormonal agent to the woman, at a rate and an amount that provides a minimum norethindrone serum level sufficient to cause and sustain contraception for a period of from about 24 to about 168 hours and which avoids a significant incidence of adverse side effects by attaining a maximum norethindrone serum level that is less than about 2400 pg/mi.

33. The method of claim 32, wherein the sole active hormonal agent is norethindrone.

34. The method of claim 32, wherein the sole active hormonal agent is norethindrone acetate.

35. The method of claim 32, wherein the minimum norethindrone serum level is at least about 160 pg/ml.

36. The method of claim 32, wherein the minimum norethindrone serum level is at least about 300 pg/ml.

37. The method of claim 32, wherein the minimum norethindrone serum level is at least about 350 pg/ml.

38. The method of claim 32, wherein contraception is sustained for a period of from about 24 to about 96 hours.

39. The method of claim 32, wherein contraception is sustained for a period of from about 48 to about 168 hours.

40. The method of claim 32, wherein the maximum norethindrone serum level is obtained during a period from about 24 to about 96 hours after administering the formulation.

41. The method of claim 32, wherein the formulation is in a dosage form selected from the group consisting of transdermal patches, ointments, lotions, gels, pastes, mousses, aerosols, creams, sprays, vaginal rings, and combinations thereof.

42. The method of claim 41, wherein the formulation is a transdermal patch.

43. A method of providing progestin-only contraception to a woman while minimizing adverse side effects associated with the progestin-only contraception, comprising:

transdermally administering a formulation having either norethindrone or norethindrone acetate as the sole active hormonal agent to the woman, at a rate and an amount that provides a minimum norethindrone serum level sufficient to cause and sustain contraception for a period of from about 24 to about 168 hours and which maintains a maximum norethindrone serum level that is up to about 15 times greater than the minimum norethindrone serum level.

44. The method of claim 43, wherein the maximum norethindrone serum level is up to about 8 times greater than the minimum norethindrone serum level.

45. The method of claim 43, wherein the maximum norethindrone serum level is up to about 4 times greater than the minimum norethindrone serum level.

46. The method of claim 43, wherein the maximum norethindrone serum level is up to about 2.75 times greater than the minimum norethindrone serum level.

47. A method of providing progestin-only contraception to a woman while minimizing adverse side effects associated with progestin-only contraception, comprising:

transdermally administering a formulation having;

norethindrone acetate as the sole active hormonal agent in an amount of from about 5% w/w to about 25% w/w of the transdermal formulation; and

a permeation enhancer in an amount from about 0.01% w/w to about 50% w/w of the transdermal formulation,

the formulation being administered at a rate and an amount that provides a minimum norethindrone serum level of at least 160 pg/ml in order to cause and sustain physiologic events in the woman resulting in contraception for a period of from about 24 to about 168 hours, and also provides a maximum norethindrone serum level of less than about 2400 pg/ml, which is obtained from about 24 to about 96 hours following administration, in order to avoid a significant incidence of adverse side effects.