Claims for Patent: 11,497,709

Summary for Patent: 11,497,709

Title:	Vaginal inserted estradiol pharmaceutical compositions and methods
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.
Inventor(s):	Brian A. Bernick, Julia Amadio, Peter H.R. Persicaner
Assignee:	TherapeuticsMD Inc
Application Number:	US16/834,780
Patent Claims:	1. A method of treating a female patient with a symptom of vulvovaginal atrophy comprising administering to the patient in need thereof, an intravaginal softgel insert, the insert consisting essentially of: a. 10 mcg of estradiol, the estradiol being the only active pharmaceutical ingredient in the softgel insert; b. a liquid solvent system having a viscosity between about 50 cP and about 1000 cP at 25° C., the solvent system consisting of a 9:1 ratio of (i) one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol and (ii) a nonionic surfactant consisting of PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate; and c. a soft gelatin capsule encapsulating the estradiol and the solvent system; wherein after a single administration of the softgel insert to the female patient in need thereof, the female patient achieves at least one of: a peak plasma concentration (Cmax) of 17β-estradiol of about 15.7176±7.9179 pg/ml; a mean area under the curve (AUC0-24) of 17β-estradiol of about 53.01±19.5629 pg*hr/ml; or a Tmax of 1.98±1.29 hr. 2. The method of claim 1, wherein after the single administration of the softgel insert to the female patient in need thereof, the female patient achieves at least two of the following parameters: a. a peak plasma concentration (Cmax) of 17β-estradiol of about 15.7176±7.9179 pg/ml; b. a mean area under the curve (AUC0-24) of 17β-estradiol of about 53.01±19.5629 pg*hr/ml; or c. a Tmax of 1.98±1.29 hr. 3. The method of claim 2, wherein, after the single administration of the softgel insert to the female patient in need thereof, the female patient achieves at least one of: a. a peak plasma concentration (Cmax) of estrone of about 6.8485±6.5824 pg/ml; b. a mean area under the curve (AUC0-24) of estrone of about 34.7051±27.9541 pg*hr/ml; or c. a Tmax of 9.12±8.83 hr. 4. The method of claim 3, wherein, after the single administration of the softgel insert to the female patient in need thereof, the female patient achieves at least two of the following parameters: a. a peak plasma concentration (Cmax) of estrone of about 6.8485±6.5824 pg/ml; b. a mean area under the curve (AUC0-24) of estrone of about 34.7051±27.9541 pg*hr/ml; or c. a Tmax of 9.12±8.83 hr. 5. A method of treating a female patient with a symptom of vulvovaginal atrophy comprising administering to the patient in need thereof, an intravaginal softgel insert, the insert consisting essentially of: a. 10 mcg of estradiol, the estradiol being the only active pharmaceutical ingredient in the softgel insert; b. a liquid solvent system having a viscosity between about 50 cP and about 1000 cP at 25° C., the solvent system consisting of a 9:1 ratio of (i) one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol and (ii) a nonionic surfactant consisting of PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate; and c. a soft gelatin capsule encapsulating the estradiol and the solvent system; wherein after a single administration of the softgel insert to the female patient in need thereof, the female patient achieves at least one of: a plasma estradiol concentration of about 28.7±5.89 pg/ml one hour post administration; a plasma estradiol concentration of about 25.7±5.71 pg/ml three hours post administration; or a plasma estradiol concentration of about 23.4±7.91 pg/ml six hours post administration. 6. A method of administering an effective amount of estradiol to the proximal region of a vagina, the method comprising inserting into the vagina of a female patient in need thereof, an intravaginal softgel insert, the insert comprising: a. 10 mcg of estradiol, the estradiol being the only active pharmaceutical ingredient in the softgel insert; and b. a liquid solvent system having a viscosity between about 50 cP and about 1000 cP at 25° C., the solvent system consisting of a 9:1 ratio of (i) one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol and (ii) a nonionic surfactant consisting of PEG-6 stearate, PEG-32 stearate, and ethylene glycol palmitostearate, wherein after a single administration of the softgel insert to the female patient in need thereof, the patient achieves at least one of: i. peak plasma concentration (Cmax) of 17β-estradiol of about 12 pg/ml to about 18 pg/ml; or ii. a mean area under the curve (AUC0-24) of 17β-estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml; further wherein the AUC0-24 achieved after a single intravaginal administration is not statistically different from the AUC0-24 achieved after administration of a placebo. 7. A method of treating a female patient with a symptom of vulvovaginal atrophy, the method comprising administering to a female patient in need thereof, an intravaginal softgel insert, the insert comprising: 10 mcg of estradiol, the estradiol being the only active pharmaceutical ingredient in the softgel insert; and a liquid estradiol delivery means having a viscosity between about 50 cP and about 1000 cP at 25° C. for providing, after a single administration of the softgel insert to the female patient in need thereof, at least one pharmacokinetic parameter selected from the group consisting of: a peak plasma concentration (Cmax) of 17β-estradiol of about 12 pg/ml to about 18 pg/ml; and a mean area under the curve (AUC0-24) of 17β-estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml. 8. The method of claim 7, wherein the liquid estradiol delivery means provides a peak plasma concentration (Cmax) of 17β-estradiol of about 12 pg/ml to about 18 pg/ml. 9. The method of claim 7, wherein the liquid estradiol delivery means provides a mean area under the curve (AUC0-24) of 17β-estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml. 10. The method of claim 1, wherein after a single administration of the softgel insert to the female patient in need thereof, the female patient achieves at least one of: a peak plasma concentration (Cmax) of 17β-estradiol of about 15.7176±7.9179 pg/ml; or a Tmax of 1.98±1.29 hr. 11. The method of claim 9, wherein after a single administration of the softgel insert to the female patient in need thereof, the female patient achieves a peak plasma concentration (Cmax) of 17β-estradiol of about 15.7176±7.9179 pg/ml; and a Tmax of 1.98±1.29 hr. 12. The method of claim 3, wherein after a single administration of the softgel insert to the female patient in need thereof, the female patient achieves at least one of: a. a peak plasma concentration (Cmax) of estrone of about 6.8485±6.5824 pg/ml; or b. a Tmax of 9.12±8.83 hr. 13. The method of claim 10, wherein after a single administration of the softgel insert to the female patient in need thereof, the female patient achieves a. a peak plasma concentration (Cmax) of estrone of about 6.8485±6.5824 pg/ml; and b. a Tmax of 9.12±8.83 hr. 14. The method of claim 6, wherein after a single administration of the softgel insert to the female patient in need thereof, the patient achieves a peak plasma concentration (Cmax) of 17β-estradiol of about 12 pg/ml to about 18 pg/ml. 15. The method of claim 7, wherein the estradiol delivery means provides, after a single administration of the softgel insert to the female patient in need thereof, a peak plasma concentration (Cmax) of 17β-estradiol of about 12 pg/ml to about 18 pg/ml.