Claims for Patent: 10,888,516

Summary for Patent: 10,888,516

Title:	Soluble estradiol capsule for vaginal insertion
Abstract:	According to various embodiments of this disclosure, pharmaceutical formulations comprising solubilized estradiol are provided. In various embodiments, such formulations are encapsulated in soft capsules which may be vaginally inserted for the treatment of vulvovaginal atrophy.
Inventor(s):	Bernick; Brian A. (Boca Raton, FL), Amadio; Julia M. (Boca Raton, FL), Persicaner; Peter H. R. (Boca Raton, FL), Thorsteinsson; Thorsteinn (Boynton Beach, FL), Cacace; Janice Louise (St. Petersburg, FL), Sancilio; Frederick D. (Stuart, FL), Irani; Neda (Palm Beach Gardens, FL)
Assignee:	TherapeuticsMD, Inc. (Boca Raton, FL)
Application Number:	16/833,213
Patent Claims:	1. A method of treating a symptom of vulvovaginal atrophy in a female human patient in need thereof, the method comprising administering to the female human an estradiol-containing soft gelatin capsule intravaginally once daily for 14 days and one capsule twice weekly thereafter, the estradiol-containing soft gelatin capsule comprising a gelatin shell surrounding an estradiol-containing liquid fill material, the estradiol-containing liquid fill material comprising one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol and 1 to 10 mcg of estradiol, wherein the estradiol-containing liquid fill material has a viscosity of between 50 to 1000 cP as measured at 25.degree. C. wherein: administering the estradiol-containing soft gelatin capsule intravaginally to the female human in need thereof provides an estradiol AUC and estradiol C.sub.max that are each 80% to 125% of the estradiol AUC and estradiol C.sub.max obtained upon intravaginal administration of a reference soft gelatin capsule in a reference human female patient, the reference soft gelatin capsule consisting of a soft gelatin shell and a reference liquid fill material within the soft gelatin shell, wherein the reference liquid fill material consists of approximately 270 mg of a C8 to C10 triglyceride composition containing at least about 80 percent by weight of a mixture of caprylic acid and capric acid; approximately 30 mg of a surfactant containing a mixture of PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate; and 1 to 10 mcg of estradiol further wherein the reference liquid fill material has a viscosity of between 50 to 1000 cP as measured at 25.degree. C. 2. The method of claim 1, wherein the estradiol-containing fill material further comprises a nonionic surfactant. 3. The method of claim 2, wherein the nonionic surfactant comprises a mixture of PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate. 4. The method of claim 1, wherein the symptom of vulvovaginal atrophy is dyspareunia. 5. The method of claim 1 wherein each capsule disintegrates in the patient's vagina leaving no capsule residue. 6. The method of claim 1, wherein the estradiol-containing soft gelatin capsule and the reference soft gelatin capsule have substantially similar shapes and sizes. 7. The method of claim 6, wherein the estradiol-containing soft gelatin capsule and the reference soft gelatin capsule have identical shapes and sizes. 8. The method of claim 7, wherein the estradiol-containing soft gelatin capsule is shaped with a wider bottom portion and a narrower top portion. 9. The method of claim 7, wherein the estradiol-containing soft gelatin capsule is in the shape of a tear drop, a cone with a frustoconical end, or a cylinder with a wider cap portion. 10. The method of claim 2, wherein the nonionic surfactant has an HLB value of or less than about 10. 11. The method of claim 2, wherein the nonionic surfactant has an HLB value of about 9 to about 10. 12. The method of claim 2, wherein the nonionic surfactant comprises PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate. 13. The method of claim 1, wherein the gelatin shell of the estradiol-containing soft gelatin capsule comprises 150 bloom, Type B gelatin, hydrolyzed collagen, and glycerin. 14. The method of claim 13, wherein the gelatin shell further comprises a sorbitan-sorbitol based soft gel plasticizer. 15. The method of claim 1, wherein the estradiol-fill containing material has a mass of about 300 mg. 16. The method of claim 1, wherein the estradiol-containing soft gelatin capsule has an interior wall surface defining an inner space, wherein a maximal length defined by two points on opposing sides of the interior wall surface is about 0.69 inches. 17. The method of claim 1, wherein the estradiol-containing soft gelatin capsule has an interior wall surface defining an inner space and an exterior wall surface disposed over the interior wall surface defining a thickness, wherein the thickness measured perpendicular to the interior wall surface and the exterior wall surface is about 0.108 inches. 18. The method of claim 2, wherein the estradiol-containing fill material comprises a 9:1 ratio of one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol to nonionic surfactant. 19. The method of claim 1, wherein administering the reference soft gelatin capsule does not substantially raise circulating estradiol blood levels of the patient following administration.