NATURAL COMBINATION HORMONE REPLACEMENT FORMULATIONS AND THERAPIES

• US 20150342963A1
• Filed: 05/22/2015
• Published: 12/03/2015
• Est. Priority Date: 05/22/2014
• Status: Active Grant

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Bernick, Brian A., Persicaner, Peter H.R., Amadio, Julia M.
• Granted Patent: US 10,206,932 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 5/34 Gestagens

Abstract

Pharmaceutical compositions for co-administering estradiol and progesterone to a human subject in need thereof are provided. In some embodiments, the pharmaceutical composition comprises solubilized estradiol, suspended progesterone, and a solubilizing agent comprising a medium chain (C6-C12) oil.

Claims

1. A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising:

solubilized estradiol, suspended progesterone, and a solubilizing agent, the solubilizing agent comprising a medium chain (C6-C12) oil;

wherein administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from;

(i) an area under the curve (AUC)_(0-t) for estradiol that is from 140.3733 pg·

hr/ml to 219.3333 pg·

hr/ml;

(ii) a C_max for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml;

(iii) an AUC_(0-t) for progesterone that is from 24.0174 ng·

hr/ml to 37.5272 ng·

hr/ml; and

(iv) a C_max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.

2. The pharmaceutical composition of claim 1, wherein administration of the composition to the subject produces both an AUC_(0-t) for estradiol that is from 140.3733 pg·

hr/ml to 219.3333 pg·

hr/ml and a C_max for estradiol that is from 6.4790 pg/ml to 10.1235 pg/ml.

3. The pharmaceutical composition of claim 1, wherein administration of the composition to the subject produces both an AUC_(0-t) for progesterone that is from 24.0174 ng·

hr/ml to 37.5272 ng·

hr/ml and a C_max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.

4. The pharmaceutical composition of claim 1, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for estrone that is from 909.6091 pg·

hr/ml to 1421.2642 pg·

hr/ml; and

(ii) a C_max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml.

5. The pharmaceutical composition of claim 4, wherein administration of the composition to the subject produces both an AUC_(0-t) for estrone that is from 909.6091 pg·

hr/ml to 1421.2642 pg·

hr/ml and a C_max for estrone that is from 42.6549 pg/ml to 66.6483 pg/ml.

6. The pharmaceutical composition of claim 1, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for total estrone that is from 20.1752 ng·

hr/ml to 31.5238 ng·

hr/ml; and

(ii) a C_max for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.

7. The pharmaceutical composition of claim 6, wherein administration of the composition to the subject produces both an AUC_(0-t) for total estrone that is from 20.1752 ng·

hr/ml to 31.5238 ng·

hr/ml and a C_max for total estrone that is from 3.5429 ng/ml to 5.5358 ng/ml.

29. A method of treating a subject having vasomotor symptoms associated with estrogen deficiency, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 1.

30. The method of claim 29, wherein the subject is female.

31. The method of claim 29, wherein the subject is a woman having a uterus.

8. A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising:

solubilized estradiol, suspended progesterone, and a solubilizing agent, the solubilizing agent comprising a medium chain (C6-C12) oil;

wherein administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from;

(i) an area under the curve (AUC)_(0-t) for estradiol that is from 280.7467 pg·

hr/ml to 438.6667 pg·

hr/ml;

(ii) a C_max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml;

(iii) an AUC_(0-t) for progesterone that is from 24.0174 ng·

hr/ml to 37.5272 ng·

hr/ml; and

(iv) a C_max for progesterone that is from 17.8444 ng/ml to 27.8819 ng/ml.

11. The pharmaceutical composition of claim 8, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for estrone that is from 1819.2181 pg·

hr/ml to 2842.5283 pg·

hr/ml; and

(ii) a C_max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.

13. The pharmaceutical composition of claim 8, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for total estrone that is from 40.3505 ng·

hr/ml to 63.0476 ng·

hr/ml; and

(ii) a C_max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.

9-10. -10. (canceled)

12. (canceled)

14. (canceled)

15. A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising:

solubilized estradiol, suspended progesterone, and a solubilizing agent, the solubilizing agent comprising a medium chain (C6-C12) oil;

wherein administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from;

(i) an area under the curve (AUC)_(0-t) for estradiol that is from 280.7467 pg·

hr/ml to 438.6667 pg·

hr/ml;

(ii) a C_max for estradiol that is from 12.9580 pg/ml to 20.2469 pg/ml;

(iii) an AUC_(0-t) for progesterone that is from 48.0348 ng·

hr/ml to 75.0543 ng·

hr/ml; and

(iv) a C_max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml.

18. The pharmaceutical composition of claim 15, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for estrone that is from 1819.2181 pg·

hr/ml to 2842.5283 pg·

hr/ml; and

(ii) a C_max for estrone that is from 85.3098 pg/ml to 133.2966 pg/ml.

20. The pharmaceutical composition of claim 15, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for total estrone that is from 40.3505 ng·

hr/ml to 63.0476 ng·

hr/ml; and

(ii) a C_max for total estrone that is from 7.0858 ng/ml to 11.0715 ng/ml.

16-17. -17. (canceled)

19. (canceled)

21. (canceled)

22. A pharmaceutical composition for co-administering estradiol and progesterone to a human subject having vasomotor symptoms associated with estrogen deficiency comprising:

solubilized estradiol, suspended progesterone, and a solubilizing agent, the solubilizing agent comprising a medium chain (C6-C12) oil;

wherein administration of the composition to the subject produces, in a plasma sample from the subject, one or more parameters selected from;

(i) an area under the curve (AUC)_(0-t) for estradiol that is from 561.4933 pg·

hr/ml to 877.3333 pg·

hr/ml;

(ii) a C_max for estradiol that is from 25.9161 pg/ml to 40.4939 pg/ml;

(iii) an AUC_(0-t) for progesterone that is from 48.0348 ng·

hr/ml to 75.0543 ng·

hr/ml; and

(iv) a C_max for progesterone that is from 35.6889 ng/ml to 55.7639 ng/ml.

25. The pharmaceutical composition of claim 22, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for estrone that is from 3638.4363 pg·

hr/ml to 5685.0567 pg·

hr/ml; and

(i) a C_max for estrone that is from 170.6197 pg/ml to 266.5933 pg/ml.

27. The pharmaceutical composition of claim 22, wherein administration of the composition to the subject further produces, in a plasma sample from the subject, one or both parameters selected from:

(i) an AUC_(0-t) for total estrone that is from 80.7010 ng·

hr/ml to 126.0953 ng·

hr/ml; and

(ii) a C_max for total estrone that is from 14.1716 ng/ml to 22.1431 ng/ml.

23-24. -24. (canceled)

26. (canceled)

28. (canceled)

32. A method of treating a subject having vasomotor symptoms associated with estrogen deficiency with a pharmaceutical composition for co-administering estradiol and progesterone, the method comprising:

administering to the subject a pharmaceutical composition comprising solubilized estradiol, suspended progesterone, and a solubilizing agent, wherein the solubilizing agent comprises a medium chain (C6-C12) oil;

obtaining a plasma sample from the subject about 24 hours to 36 hours after administration of a single dose or a first dose of the pharmaceutical composition; and

measuring one or more pharmacokinetic parameters selected from an area under the curve (AUC)_(0-t) for estradiol, a C_max for estradiol, an AUC_(0-t) for progesterone, a C_max for progesterone, an AUC_(0-t) for estrone, a C_max for estrone, an AUC_(0-t) for total estrone, and a C_max for total estrone to determine the pharmacokinetic values for the one or more pharmacokinetic parameters;

wherein the presence of one or more pharmacokinetic values disclosed in any one of Tables 18-21 is indicative of a therapeutically effective dose for the pharmaceutical composition.

33-36. -36. (canceled)