Natural combination hormone replacement formulations and therapies

• US 10,206,932 B2
• Filed: 05/22/2015
• Issued: 02/19/2019
• 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.
• Primary Examiner(s): Barsky, Jared
• Application Number:
  US14/719,933
• Publication Number:
  US 20150342963A1
• Time in Patent Office: 1,369 Days
• Field of Search: None
• 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 method of treating a subject having vasomotor symptoms associated with estrogen deficiency, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising:

about 0.25 mg estradiol, wherein at least 80% of the estradiol in the composition is solubilized estradiol;

progesterone, wherein the progesterone comprises suspended progesterone; and

a medium-chain oil comprising medium chain fatty acid esters of glycerol, polyethylene glycol, or propylene glycol, or mixtures thereof, wherein the medium chain fatty acid esters are predominantly esters of C6 to C12 fatty acids, and wherein the entire amount of the estradiol and the progesterone in the composition is present in the 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; and

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

2. The method of claim 1, wherein the subject is female.

3. The method of claim 1, wherein the subject is a woman having a uterus.

4. The method 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.

5. The method 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 progesterone that is from 24.0174 ng·

hr/ml to 37.5272 ng·

hr/ml; and

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

6. The method 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.

7. The method 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.

17. The method of claim 1, wherein the composition comprises about 0.25 mg estradiol and about 50 mg progesterone.

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

about 0.5 mg estradiol, wherein at least 80% of the estradiol in the composition is solubilized estradiol;

progesterone, wherein the progesterone comprises suspended progesterone; and

a medium-chain oil comprising medium chain fatty acid esters of glycerol, polyethylene glycol, or propylene glycol, or mixtures thereof, wherein the medium chain fatty acid esters are predominantly esters of C6 to C12 fatty acids, and wherein the entire amount of the estradiol and the progesterone in the composition is present in the 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; and

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

9. The method 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.

10. The method 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.

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

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

hr/ml to 75.0543 ng·

hr/ml; and

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

15. The method 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 progesterone that is from 24.0174 ng·

hr/ml to 37.5272 ng·

hr/ml; and

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

18. The method of claim 8, wherein the composition comprises about 0.5 mg estradiol and about 50 mg progesterone.

19. The method of claim 8, wherein the composition comprises about 0.5 mg estradiol and about 100 mg progesterone.

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

about 1 mg estradiol, wherein at least 80% of the estradiol in the composition is solubilized estradiol;

progesterone, wherein the progesterone comprises suspended progesterone; and

a medium-chain (C6-C12) oil comprising medium chain fatty acid esters of glycerol, polyethylene glycol, or propylene glycol, or mixtures thereof, wherein the medium chain fatty acid esters are predominantly esters of C6 to C12 fatty acids, and wherein the entire amount of the estradiol and the progesterone in the composition is present in the 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; and

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

13. The method of claim 12, 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.

14. The method of claim 12, 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.

16. The method of claim 12, 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 progesterone that is from 48.0348 ng·

hr/ml to 75.0543 ng·

hr/ml; and

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

20. The method of claim 12, wherein the composition comprises about 1 mg estradiol and about 100 mg progesterone.