Vaginal inserted estradiol pharmaceutical compositions and methods

Abstract

Disclosed herein is, among other things, a soft gel vaginal pharmaceutical composition and dosage form containing solubilized estradiol for the treatment of vulvovaginal atrophy (VVA) and female sexual dysfunction (FSD).

What is claimed is: 
     
         1 . A pharmaceutical composition comprising 4 μg of estradiol, wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted average concentration (C avg ) of estradiol ranging from 1.82 pg/mL to 5.38 pg/mL; and/or 
 (b) an unadjusted peak plasma concentration (C max ) of estradiol ranging from 2.49 pg/mL to 7.11 pg/mL. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol of about 3.6 pg/mL; and/or   (b) an unadjusted C max  of estradiol of about 4.8 pg/mL.   
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA further produces, in a plasma sample from the patient,
 (c) an unadjusted area under the curve (AUC) 0-24  of estradiol ranging from 44.43 pg*hr/mL to 129.97 pg*hr/mL.   
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol of about 87.2 pg*hr/mL.   
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein estradiol is the only active hormone in the composition. 
     
     
         6 . A method of treating moderate to severe dyspareunia, comprising intravaginally administering a pharmaceutical composition comprising 4 μg of estradiol to a patient having VVA once daily for two weeks, wherein administration of the composition once daily for two weeks to the patient produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol ranging from 1.82 pg/mL to 5.38 pg/mL; and/or 
 (b) an unadjusted C max  of estradiol ranging from 2.49 pg/mL to 7.11 pg/mL. 
 
     
     
         7 . The method of  claim 6 , wherein administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol of about 3.6 pg/mL; and/or   (b) an unadjusted C max  of estradiol of about 4.8 pg/mL.   
     
     
         8 . The method of  claim 6 , wherein administration of the composition once daily for two weeks to a patient having VVA further produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol ranging from 44.43 pg*hr/mL to 129.97 pg*hr/mL.   
     
     
         9 . The method of  claim 8 , wherein administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol of about 87.2 pg*hr/mL.   
     
     
         10 . A pharmaceutical composition comprising 10 μg of estradiol, wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol ranging from 2.33 pg/mL to 6.87 pg/mL; and/or 
 (b) an unadjusted C max  of estradiol ranging from 4.94 pg/mL to 9.66 pg/mL. 
 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol of about 4.6 pg/mL; and/or   (b) an unadjusted C max  of estradiol of about 7.3 pg/mL.   
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA further produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol ranging from 55.53 pg*hr/mL to 164.67 pg*hr/mL.   
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol of about 110.1 pg*hr/mL.   
     
     
         14 . The pharmaceutical composition of  claim 10 , wherein estradiol is the only active hormone in the composition. 
     
     
         15 . A method of treating moderate to severe dyspareunia, comprising intravaginally administering a pharmaceutical composition comprising 10 μg of estradiol to a patient having VVA once daily for two weeks, wherein administration of the composition once daily for two weeks to the patient produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol ranging from 2.33 pg/mL to 6.87 pg/mL; and/or 
 (b) an unadjusted C max  of estradiol ranging from 4.94 pg/mL to 9.66 pg/mL. 
 
     
     
         16 . The method of  claim 15 , wherein administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol of about 4.6 pg/mL; and/or   (b) an unadjusted C max  of estradiol of about 7.3 pg/mL.   
     
     
         17 . The method of  claim 15 , wherein administration of the composition once daily for two weeks to a patient having VVA further produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol ranging from 55.53 pg*hr/mL to 164.67 pg*hr/mL.   
     
     
         18 . The method of  claim 17 , wherein administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol of about 110.1 pg*hr/mL.   
     
     
         19 . A pharmaceutical composition comprising 25 μg of estradiol, wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol ranging from 3.76 pg/mL to 10.44 pg/mL; and/or 
 (b) an unadjusted C max  of estradiol ranging from 8.09 pg/mL to 23.31 pg/mL. 
 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol of about 7.1 pg/mL; and/or   (b) an unadjusted C max  of estradiol of about 15.7 pg/mL.   
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA further produces, in a plasma sample from the patient,
 (c) an unadjusted AUC-24 of estradiol ranging from 91.47 pg*hr/mL to 251.73 pg*hr/mL.   
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein intravaginal administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (c) an unadjusted AUC-24 of estradiol of about 171.6 pg*hr/mL.   
     
     
         23 . The pharmaceutical composition of  claim 19 , wherein estradiol is the only active hormone in the composition. 
     
     
         24 . A method of treating moderate to severe dyspareunia, comprising intravaginally administering a pharmaceutical composition comprising 25 μg of estradiol to a patient having VVA once daily for two weeks, wherein administration of the composition once daily for two weeks to the patient produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol ranging from 3.76 pg/mL to 10.44 pg/mL; and/or 
 (b) an unadjusted C max  of estradiol ranging from 8.09 pg/mL 23.31 pg/mL. 
 
     
     
         25 . The method of  claim 24 , wherein administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (a) an unadjusted C avg  of estradiol of about 7.1 pg/mL; and/or   (b) an unadjusted C max  of estradiol of about 15.7 pg/mL.   
     
     
         26 . The method of  claim 24 , wherein administration of the composition once daily for two weeks to a patient having VVA further produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol ranging from 91.47 pg*hr/mL to 251.73 pg*hr/mL.   
     
     
         27 . The method of  claim 26 , wherein administration of the composition once daily for two weeks to a patient having VVA produces, in a plasma sample from the patient,
 (c) an unadjusted AUC 0-24  of estradiol of about 171.6 pg*hr/mL.