Vaginal inserted estradiol pharmaceutical compositions and methods

• US 9,289,382 B2
• Filed: 02/17/2015
• Issued: 03/22/2016
• Est. Priority Date: 06/18/2012
• Status: Active Grant

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Bernick, Brian A., Amadio, Julia M.
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US14/624,051
• Publication Number:
  US 20150164789A1
• Time in Patent Office: 399 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• 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 9/0036 Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• CPC Class Codes: A61K 9/4858 Organic compounds

Abstract

According to various embodiments of this disclosure, pharmaceutical compositions comprising solubilized estradiol are provided. In various embodiments, such compositions are encapsulated in soft capsules which may be vaginally inserted for the treatment of vulvovaginal atrophy.

Claims

1. A pessary comprising about 25 μ

g of 17β

-estradiol in a solubilizing agent comprising a medium chain oil, wherein after a single administration of the pessary to a patient provides, in a plasma sample from the patient;

1) a corrected geometric mean peak plasma concentration (C_max) of 17β

-estradiol of about 19 pg*hr/ml to about 29 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of 17β

-estradiol of about 75 pg*hr/ml to about 112 pg*hr/ml,

wherein 17β

-estradiol is the only active hormone in the pessary.

2. The pessary of claim 1, wherein administration of the pessary to a patient provides, in a plasma sample from the patient:

1) a corrected geometric mean peak plasma concentration (C_max) of estrone of about 9 pg*hr/ml to about 14 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of estrone of about 43 pg*hr/ml to about 65 pg*hr/ml.

3. The pessary of claim 1, wherein administration of the pessary to a patient provides, in a plasma sample from the patient:

1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 416 pg*hr/ml to about 613 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of estrone sulfate of about 3598 pg*hr/ml to about 5291 pg*hr/ml.

16. The pessary of claim 1, wherein the medium chain oil comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof.

17. The pessary of claim 1, wherein the medium chain oil comprises a monoglyceride, diglyceride, or triglyceride ester of the at least one C6-C12 fatty acid.

4. A pessary comprising about 10 μ

g of 17β

-estradiol in a solubilizing agent comprising a medium chain oil, wherein after a single administration of the pessary to a patient provides, in a plasma sample from the patient;

1) a corrected geometric mean peak plasma concentration (C_max) of 17β

-estradiol of about 12 pg*hr/ml to about 18 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of 17β

-estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml,

wherein 17β

-estradiol is the only active hormone in the pessary.

5. The pessary of claim 4, wherein the pessary further provides a corrected geometric mean time to peak plasma concentration (T_max) of 17β

-estradiol of about 1 hrs to about 3 hrs.

6. The pessary of claim 4, wherein administration of the pessary to a patient provides, in a plasma sample from the patient:

1) a corrected geometric mean peak plasma concentration (C_max) of estrone of about 4 pg*hr/ml to about 7 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of estrone of about 20 pg*hr/ml to about 31 pg*hr/ml.

7. The pessary of claim 6, wherein the pessary further provides a corrected geometric mean time to peak plasma concentration (T_max) of estrone of about 4 hrs to about 8 hrs.

8. The pessary of claim 4, wherein administration of the pessary to a patient provides, in a plasma sample from the patient:

1) a corrected geometric mean peak plasma concentration (C_max) of estrone sulfate of about 10 pg*hr/ml to about 16 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of estrone sulfate of about 56 pg*hr/ml to about 84 pg*hr/ml.

9. The pessary of claim 8, wherein the pessary further provides a corrected geometric mean time to peak plasma concentration (T_max) of estrone sulfate of about 4 hrs to about 7 hrs.

18. The pessary of claim 4, wherein the medium chain oil comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof.

19. The pessary of claim 4, wherein the medium chain oil comprises a monoglyceride, diglyceride, or triglyceride ester of the at least one C6-C12 fatty acid.

10. A pessary comprising about 4 μ

g of 17β

-estradiol in a solubilizing agent comprising a medium chain oil, wherein after a single administration of the pessary to a patient provides, in a plasma sample from the patient;

1) a corrected geometric mean peak plasma concentration (Cmax) of 17β

-estradiol of about 4 pg*hr/ml to about 8 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of 17β

-estradiol of about 16 pg*hr/ml to about 26 pg*hr/ml, wherein 17β

-estradiol is the only active hormone in the pessary.

11. The pessary of claim 10, wherein the pessary further provides a corrected geometric mean time to peak plasma concentration (T_max) of 17β

-estradiol of about 0.25 hrs to about 2 hrs.

12. The pessary of claim 10, wherein administration of the pessary to a patient provides, in a plasma sample from the patient:

1) a corrected geometric mean peak plasma concentration (C_max) of estrone of about 1 pg*hr/ml to about 3 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of estrone of about 8 pg*hr/ml to about 13 pg*hr/ml.

13. The pessary of claim 12, wherein the pessary further provides a corrected geometric mean time to peak plasma concentration (T_max) of estrone of about 1 hrs to about 4 hrs.

14. The pessary of claim 10, wherein administration of the pessary to a patient provides, in a plasma sample from the patient:

1) a corrected geometric mean peak plasma concentration (C_max) of estrone sulfate of about 4 pg*hr/ml to about 7 pg*hr/ml; and

2) a corrected geometric mean area under the curve (AUC)_0-24 of estrone sulfate of about 22 pg*hr/ml to about 34 pg*hr/ml.

15. The pessary of claim 14, wherein the pessary further provides a corrected geometric mean time to peak plasma concentration (T_max) of estrone sulfate of about 1 hrs to about 3 hrs.

20. The pessary of claim 10, wherein the medium chain oil comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof.

21. The pessary of claim 10, wherein the medium chain oil comprises a monoglyceride, diglyceride, or triglyceride ester of the at least one C6-C12 fatty acid.