Progesterone formulations having a desirable PK profile

• US 10,471,148 B2
• Filed: 03/09/2017
• Issued: 11/12/2019
• Est. Priority Date: 06/18/2012
• Status: Expired due to Fees

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Cacace, Janice, Persicaner, Peter H. R., Thorsteinsson, Thorsteinn, Sancilio, Frederick, Amadio, Julia, Bernick, Brian
• Primary Examiner(s): Wang, Shengjun
• Application Number:
  US15/454,898
• Publication Number:
  US 20170340739A1
• Time in Patent Office: 978 Days
• Field of Search: 424400, 424456, 514177
• 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 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/4825 Proteins, e.g. gelatin gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816
• CPC Class Codes: A61K 9/4858 Organic compounds

Abstract

This disclosure provides progesterone formulations, methods of using these formulations, and their related pharmacokinetic parameters. In particular embodiments, the formulations disclosed herein allow for a reduction in the amount of progesterone administered to a patient in need thereof, while still providing the benefits of a larger dosage amount.

Claims

1. A pharmaceutical composition for orally administering progesterone to a subject in need thereof, the composition comprising:

progesterone;

a solubilizing agent; and

a nonionic surfactant;

wherein the solubilizing agent comprises predominantly C₆-C₁₂ fatty acid tri-esters of glycerol;

wherein the progesterone is present from about 20 to about 50 weight percent of the composition; and

wherein the composition provides increased progesterone bioavailability compared to micronized progesterone suspended in peanut oil.

2. The pharmaceutical composition of claim 1, wherein the solubilizing agent further comprises a C₆-C₁₂ fatty acid mono-ester of glycerol.

3. The pharmaceutical composition of claim 2, wherein the solubilizing agent further comprises a C₆-C₁₂ fatty acid di-ester of glycerol.

4. The pharmaceutical composition of claim 1, wherein the tri-ester of glycerol comprises predominantly esters of caprylic fatty acid (C₈) and capric fatty acid (C₁₀).

5. The pharmaceutical composition of claim 1, wherein the nonionic surfactant is lauroyl polyoxyl-32 glycerides.

6. The pharmaceutical composition of claim 1, wherein the nonionic surfactant is lauroyl macrogol-32 EP.

7. The pharmaceutical composition of claim 1, wherein the nonionic surfactant is caprylocaproyl macrogol-8 glyceride EP.

8. The pharmaceutical composition of claim 1, wherein the amount of progesterone is from 25 mg to 200 mg.

9. The pharmaceutical composition of claim 1, wherein the amount of progesterone is 75 mg or 150 mg.

10. The pharmaceutical composition of claim 1, wherein the progesterone includes solubilized progesterone and suspended progesterone.

11. The pharmaceutical composition of claim 1, wherein the composition is provided in a gelatin capsule.

12. The pharmaceutical composition of claim 1, wherein the composition has a total mass of less than 500 mg.

13. The pharmaceutical composition of claim 1, wherein the composition provides a 25% increase in progesterone bioavailability compared to micronized progesterone suspended in peanut oil.

14. The pharmaceutical composition of claim 1, wherein the amount of progesterone comprises about 33% by weight of the composition;

the solubilizing agent comprises about 65% by weight of the composition, the non-ionic surfactant comprises about 1.7% by weight of the composition.

15. The pharmaceutical composition of claim 1, wherein the amount of progesterone comprises about 33.33% by weight of the composition;

the solubilizing agent comprises about 64.93% by weight of the composition, the non-ionic surfactant comprises about 1.67% by weight of the composition.

16. The pharmaceutical composition of claim 14, further comprising an antioxidant.

17. The pharmaceutical composition of claim 16, wherein the antioxidant is butylated hydroxy toluene.

18. The pharmaceutical composition of claim 17, wherein the solubilizing agent is medium chain triglycerides of caprylic fatty acid (C₈) and capric fatty acid (C₁₀).

19. The pharmaceutical composition of claim 18, wherein the non-ionic surfactant is lauroyl polyoxyl-32 glycerides.

20. The pharmaceutical composition of claim 19, wherein the amount of progesterone is 200 mg.

21. The pharmaceutical composition of claim 19, wherein the amount of progesterone is 150 mg.

22. The pharmaceutical composition of claim 19, wherein the progesterone is ultra-micronized and has an X50 of less than or equal to 15 microns.

23. The pharmaceutical composition of claim 1, wherein the progesterone is ultra-micronized and has an X90 of less than or equal to 25 microns.

24. The pharmaceutical composition of claim 1, wherein the progesterone is the sole active ingredient in the composition.

27. A method of treating a progesterone-deficient state in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 1.

28. The method of claim 27, wherein the progesterone-deficient state is endometrial hyperplasia, secondary amenorrhea, preterm birth, shortened cervix, or another disease states or condition treated with supplemental progesterone.

29. The method of claim 28, wherein the progesterone-deficient state is secondary amenorrhea.

25. A pharmaceutical composition for orally administering progesterone to a subject in need thereof, the composition comprising:

progesterone;

a solubilizing agent; and

a nonionic surfactant;

wherein the solubilizing agent comprises predominantly C₆-C₁₂ fatty acid tri-esters of glycerol;

wherein the progesterone is present from about 20 to about 50 weight percent of the composition and wherein less than 6 percent of the progesterone is soluble in the solubilizing agent; and

wherein the composition provides increased progesterone bioavailability compared to micronized progesterone suspended in peanut oil.

26. The pharmaceutical composition of claim 25, wherein more than 5 percent of the progesterone is soluble in the solubilizing agent.

30. A method of treating a progesterone-deficient state in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 25.

31. The method of claim 30, wherein the progesterone-deficient state is endometrial hyperplasia, secondary amenorrhea, preterm birth, shortened cervix, or another disease states or condition treated with supplemental progesterone.

32. The method of claim 31, wherein the progesterone-deficient state is secondary amenorrhea.