Vaginal inserted estradiol pharmaceutical compositions and methods

• US 10,537,581 B2
• Filed: 10/22/2014
• Issued: 01/21/2020
• Est. Priority Date: 12/21/2012
• Status: Active Grant

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Bernick, Brian A., Thorsteinsson, Thorsteinn, Persicaner, Peter H. R., Cacace, Janice Louise, Sancilio, Frederick D., Irani, Neda, Amadio, Julia
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US14/521,230
• Publication Number:
  US 20150045335A1
• Time in Patent Office: 1,917 Days
• Field of Search: 424452, 514182
• 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 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular 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 consisting of:

a) a liquid pharmaceutical composition comprising;

about 1 μ

g to about 25 μ

g of estradiol; and

a solubilizing agent comprising a medium chain oil;

wherein the viscosity of the liquid pharmaceutical composition ranges from about 50 cP to about 1000 cP at 25 °

C., and

wherein the liquid pharmaceutical composition does not include a hydrophilic gel-forming bioadhesive agent; and

b) a soft gelatin capsule encapsulating the liquid pharmaceutical composition;

wherein estradiol is the only active hormone in the pessary; and

wherein the pessary is for intravaginal administration.

2. The pessary of claim 1, wherein the liquid pharmaceutical composition comprises about 1 μ

g to about 10 μ

g of estradiol.

3. The pessary of claim 1, wherein the liquid pharmaceutical composition comprises about 10 μ

g to about 25 μ

g of estradiol.

4. The pessary of claim 1, wherein the estradiol is solubilized.

5. 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.

6. The pessary of claim 5, wherein each glycol, monoglyceride, diglyceride, or triglyceride ester of the C6-C12 fatty acid is independently an ester of caproic acid, an ester of caprylic acid, or an ester of capric acid.

7. The pessary of claim 6, wherein the triglyceride ester of the C6-C12 fatty acid is a caprylic/capric triglyceride.

10. A method of treating an estrogen-deficient state, the method comprising administering to a patient in need thereof a pessary according to claim 1.

8. A pessary consisting of:

a) a liquid pharmaceutical composition comprising;

about 1 μ

g to about 25 μ

g of estradiol;

a caprylic/capric triglyceride; and

a non-ionic surfactant comprising PEG-6 stearate and ethylene glycol palmitostearate;

wherein the viscosity of the liquid pharmaceutical composition ranges from about 50 cP to about 1000 cP at 25°

C., and

wherein the liquid pharmaceutical composition does not include a hydrophilic gel-forming bioadhesive agent; and

b) a soft gelatin capsule encapsulating the liquid pharmaceutical composition, wherein estradiol is the only active hormone in the pessary; and

wherein the pessary is for intravaginal administration.

11. A method of treating an estrogen-deficient state, the method comprising administering to a patient in need thereof, a pessary according to claim 8.

9. A pessary consisting of:

(a) a liquid pharmaceutical composition comprising;

about 1 μ

g to about 25 μ

g of estradiol and

a solubilizing agent comprising a medium chain oil,

wherein the viscosity of the liquid pharmaceutical composition ranges from about 50 cP to about 1000 cP at 25 °

C., and

wherein the liquid pharmaceutical composition does not include a hydrophilic gel-forming bioadhesive agent;

and

(b) a soft gelatin capsule encapsulating the liquid pharmaceutical composition;

wherein estradiol is the only active hormone in the pessary; and

wherein administration of the pessary to the proximal region of the vagina of a patient provides a therapeutically effective concentration of estradiol over 24 hours in the proximal region of the vagina.