# US 11,110,099 B2 · Natural combination hormone replacement formulations and therapies > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,110,099 B2 - Document ID: US11110099B2 - Status: Granted - Kind: B2 - Application number: 16/885,066 - Filed: 2020-05-27 - Published: 2020-09-10 - Granted: 2021-09-07 - Earliest claimed: 2012-06-18 - Assignees: TherapeuticsMD, Inc. - Applicants: TherapeuticsMD, Inc. - Inventors: Brian A. Bernick; Janice Louise Cacace; Peter H. R. Persicaner; Neda Irani; Julia M. Amadio - Web page: https://patentgrep.com/patent/US11110099B2 ## CPC - A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone - A61K 9/0034: {Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants} - A61K 9/02: Suppositories; Bougies; Bases therefor; {Ovules}(apparatus for making A61J3/08; devices for introducing into the body A61M31/00) - A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)} - A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)} - A61K 9/4858: {Organic compounds} - A61K 9/4866: {Organic macromolecular compounds} - A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters - 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) - A61P 5/24: of the sex hormones - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - A61P 15/12: for climacteric disorders - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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 ### Claim 1 A pharmaceutical composition comprising: a fill material encapsulated in a capsule, the fill material comprising: a. two active pharmaceutical ingredients, the active pharmaceutical ingredients being about 1 mg of 17β-estradiol and about 100 mg of progesterone, wherein at least about 90% of the 17β-estradiol is solubilized, and wherein a first portion of the progesterone is solubilized and a second portion of the progesterone is micronized; b. a solubilizing agent for the active pharmaceutical ingredients, the solubilizing agent comprising: i. a medium chain oil comprising mono- and diglycerides; and ii. at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides; wherein the 17β-estradiol and the progesterone in the capsule are present in the solubilizing agent; wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the progesterone has a solubility in the solubilizing agent of at least about 73 mg/g, and the 17β-estradiol has a solubility in the solubilizing agent of at least about 10 mg/g; and wherein the progesterone comprises about 30% to about 35% by weight of the fill material, and the 17β-estradiol comprises about 0.1% to about 0.4% by weight of the fill material. ### Claim 2 (depends on 1) The pharmaceutical composition of claim 1, wherein the medium chain oil comprises mono- and diglycerides of capric and caprylic acid. ### Claim 3 (depends on 1) The pharmaceutical composition of claim 1, wherein the medium chain oil comprises greater than about 75% caprylic monoglycerides and caprylic diglycerides. ### Claim 4 (depends on 1) The pharmaceutical composition of claim 1, wherein the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides comprises less than about 10% by weight of the fill material. ### Claim 5 (depends on 1) The pharmaceutical composition of claim 1, wherein the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides comprises about 1% to about 2% by weight of the fill material. ### Claim 6 (depends on 2) The pharmaceutical composition of claim 2, wherein the solubilizing agent comprises about 65 parts by weight of the medium chain oil and about one part by weight of the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides. ### Claim 7 (depends on 2) The pharmaceutical composition of claim 2, wherein the solubilizing agent comprises about 196 mg of the mono- and diglycerides of capric and caprylic acid and about 3 mg of the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides. ### Claim 8 (depends on 2) The pharmaceutical composition of claim 2, wherein the solubilizing agent consists of about 196 mg of the mono- and diglycerides of capric and caprylic acid and about 3 mg of the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides. ### Claim 9 (depends on 1) The pharmaceutical composition of claim 1, wherein the solubility of the 17β-estradiol in the solubilizing agent is at least about 12 mg/g. ### Claim 10 (depends on 1) The pharmaceutical composition of claim 1, wherein the 17β-estradiol is fully solubilized in the solubilizing agent. ### Claim 11 (depends on 1) The pharmaceutical composition of claim 1, wherein the 17β-estradiol does not precipitate for at least about 14 days. ### Claim 12 (depends on 1) The pharmaceutical composition of claim 1, wherein at least about 14% by weight of the progesterone is solubilized in the solubilizing agent. ### Claim 13 (depends on 1) The pharmaceutical composition of claim 1, wherein the micronized progesterone has an X50 particle size value below about 15 microns, an X90 particle size value below about 25 microns, or both. ### Claim 14 (depends on 1) The pharmaceutical composition of claim 1, wherein the fill material has a total weight of less than about 400 mg. ### Claim 15 A pharmaceutical composition comprising: a fill material encapsulated in a capsule, the fill material comprising: a. two active pharmaceutical ingredients, the active pharmaceutical ingredients being about 1 mg of 17β-estradiol and about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized and a second portion of the progesterone is micronized, and the 17β-estradiol is fully solubilized; b. a solubilizing agent for the active pharmaceutical ingredients, the solubilizing agent comprising: i. a medium chain oil comprises mono- and diglycerides of capric and caprylic acid; and ii. at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides that is about 1% to about 2% by weight of the fill material; wherein the 17β-estradiol and the progesterone in the capsule are present in the solubilizing agent wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the progesterone has a solubility in the solubilizing agent of at least about 73 mg/g, and the 17β-estradiol has a solubility in the solubilizing agent of at least about 10 mg/g; and wherein the progesterone is about 30% to about 35% by weight of the fill material, and the 17β-estradiol is about 0.1% to about 0.4% by weight of the fill material. ### Claim 16 (depends on 15) The pharmaceutical composition of claim 15, wherein the 17β-estradiol does not precipitate for at least about 14 days. ### Claim 17 (depends on 15) The pharmaceutical composition of claim 15, wherein the micronized progesterone has an X50 particle size value below about 15 microns, an X90 particle size value below about 25 microns, or both. ### Claim 18 (depends on 15) The pharmaceutical composition of claim 15, wherein at least about 14% by weight of the progesterone is solubilized in the solubilizing agent. ### Claim 19 (depends on 15) The pharmaceutical composition of claim 15, wherein the fill material has a total weight of less than about 400 mg. ### Claim 20 A pharmaceutical composition comprising: a fill material encapsulated in a capsule, the fill material comprising: a. two active pharmaceutical ingredients, the active pharmaceutical ingredients being about 1 mg of 17β-estradiol and about 100 mg of progesterone, wherein a first portion of the progesterone is solubilized and a second portion of the progesterone is micronized, and the 17β-estradiol is fully solubilized; b. a solubilizing agent for the active pharmaceutical ingredients, the solubilizing agent comprising: i. about 196 mg of mono- and diglycerides of caprylic and capric acid; and ii. about 3 mg of at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides; wherein the 17β-estradiol and the progesterone in the capsule are present in the solubilizing agent wherein the second portion of the progesterone is uniformly dispersed in the solubilizing agent; wherein the progesterone has a solubility in the solubilizing agent of at least about 73 mg/g, and the 17β-estradiol has a solubility in the solubilizing agent of at least about 10 mg/g; and wherein the progesterone is about 30% to about 35% by weight of the fill material and the 17β-estradiol is about 0.1% to about 0.4% by weight of the fill material. ### Claim 21 (depends on 20) The pharmaceutical composition of claim 20, wherein the 17β-estradiol does not precipitate for at least about 14 days. ### Claim 22 (depends on 20) The pharmaceutical composition of claim 20, wherein the micronized progesterone has an X50 particle size value below about 15 microns, an X90 particle size value below about 25 microns, or both. ### Claim 23 (depends on 20) The pharmaceutical composition of claim 20, wherein at least about 14% by weight of the progesterone is solubilized in the solubilizing agent. ### Claim 24 (depends on 1) A method for manufacturing the pharmaceutical composition of claim 1, the method comprising the steps of: a. mixing the medium chain oil and the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides at a temperature of about 30° C. to about 50° C. until the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides is dissolved in the medium chain oil to form a first mixture; b. adding 17β-estradiol to the first mixture to form a second mixture; c. adding micronized progesterone to the second mixture to form a fill material; d. encapsulating the fill material in a capsule. ### Claim 25 (depends on 24) The method of claim 24, wherein the mixing the medium chain oil and the at least one of lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides takes place at a temperature of about 40° C.±5° C. ### Claim 26 (depends on 24) The method of claim 24, wherein the medium chain oil comprises mono- and diglycerides of capric and caprylic acid. ### Claim 27 (depends on 24) The method of claim 24, wherein the fill material has a total weight of less than about 400 mg. ### Claim 28 (depends on 1) The pharmaceutical composition of claim 1, wherein up to about 14% by weight of the progesterone is solubilized in the solubilizing agent. ### Claim 29 (depends on 15) The pharmaceutical composition of claim 15, wherein up to about 14% by weight of the progesterone is solubilized in the solubilizing agent. ### Claim 30 (depends on 20) The pharmaceutical composition of claim 20, wherein up to about 14% by weight of the progesterone is solubilized in the solubilizing agent.