Natural combination hormone replacement formulations and therapies

• US 10,675,288 B2
• Filed: 04/04/2016
• Issued: 06/09/2020
• Est. Priority Date: 11/23/2011
• Status: Active Grant

• Current Assignee: TherapeuticsMD Inc.
• Original Assignee: TherapeuticsMD Inc.
• Inventors: Bernick, Brian A., Cacace, Janice Louise, Persicaner, Peter H. R., Irani, Neda, Amadio, Julia M.
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US15/090,493
• Publication Number:
  US 20160213685A1
• Time in Patent Office: 1,527 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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

Abstract

Estrogen and progesterone replacement therapies are provided herein. Among others, the following formulations are provided herein: solubilized estradiol without progesterone; micronized progesterone without estradiol; micronized progesterone with partially solubilized progesterone; solubilized estradiol with micronized progesterone; solubilized estradiol with micronized progesterone in combination with partially solubilized progesterone; and solubilized estradiol with solubilized progesterone.

Claims

1. A method of treating an estrogen-deficient state in a female subject in need of treatment, the method comprising administering to the subject a capsule containing an effective amount of a pharmaceutical formulation comprising:

0.17 to 0.35 wt % solubilized estradiol,

30 to 35 wt % progesterone, comprising suspended micronized progesterone and solubilized progesterone,

55 to 75 wt % of an oil, wherein the oil is predominantly medium chain fatty acid mono- and diglycerides comprising esters of C6 to C12 fatty acids, and

0.5 to 10 wt % nonionic surfactant;

wherein the solubilized estradiol, the suspended micronized progesterone, and the solubilized progesterone are present in the oil.

2. The method of claim 1, wherein the oil is predominantly medium chain fatty acid mono- and diglycerides comprising esters of C6 to C10 fatty acids.

3. The method of claim 1, wherein the oil is predominantly medium chain fatty acid mono- and diglycerides comprising esters of C8 to C12 fatty acids.

4. The method of claim 1, wherein the oil is predominantly medium chain fatty acid mono- and diglycerides comprising esters of C8 to C10 fatty acids.

5. The method of claim 1, wherein at least 90% of the total estradiol is solubilized.

6. The method of claim 1, wherein the non-ionic surfactant is lauroyl polyoxyl-32-glycerides.

7. The method of claim 1 wherein the capsule is a gelatin capsule.

8. The method of claim 1, wherein the progesterone is released more rapidly from the pharmaceutical composition than progesterone in peanut oil.

9. The method of claim 1, wherein the estrogen-deficient state is selected from the group consisting of a vasomotor symptom of menopause, sleep disturbances, mood changes, vulvovaginal atrophy, and osteoporosis.

10. The method of claim 1, wherein the estrogen-deficient state is a vasomotor symptom of menopause.

11. The method of claim 1, wherein the vasomotor symptom of menopause is selected from the group consisting of hot flashes and night sweats.

12. The method of claim 1, wherein the female subject is a post-menopausal woman.

13. A method of treating a vasomotor symptom of menopause in a female subject in need of treatment, the method comprising administering to the subject a capsule containing an effective amount of a pharmaceutical formulation comprising:

0.17 to 0.35 wt % solubilized estradiol,

30 to 35 wt % progesterone, comprising suspended micronized progesterone and solubilized progesterone,

55 to 75 wt % of an oil, wherein the oil is predominantly medium chain fatty acid mono- and diglycerides comprising predominantly esters of C6 to C12 fatty acids, and

0.5 to 10 wt % nonionic surfactant;

wherein the solubilized estradiol, the suspended micronized progesterone, and the solubilized progesterone are present in the oil.

14. The method of claim 13, wherein the vasomotor symptom of menopause is selected from the group consisting of hot flashes and night sweats.

15. The method of claim 13, wherein the mammal is a post-menopausal woman.

16. A method of treating vulvovaginal atrophy in a female subject in need of treatment, the method comprising administering to the subject a capsule containing an effective amount of a pharmaceutical formulation comprising:

0.17 to 0.35 wt % solubilized estradiol,

30 to 35 wt % progesterone, comprising suspended micronized progesterone and solubilized progesterone,

55 to 75 wt % of an oil, wherein the oil is predominantly medium chain fatty acid mono- and diglycerides comprising predominantly esters of C6 to C12 fatty acids, and

0.5 to 10 wt % nonionic surfactant;

wherein the solubilized estradiol, the suspended micronized progesterone, and the solubilized progesterone are present in the oil.