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.

1 . An encapsulated liquid pharmaceutical formulation for intra-vaginal delivery of estradiol, said formulation comprising estradiol that is solubilized in one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol or one or more other glycols. 
     
     
         2 . The formulation of  claim 1  wherein the estradiol is fully solubilized, the formulation further comprising a thickening agent, and wherein the fatty acids comprise predominantly (>50 wt %) the following:
 C6 to C12 fatty acids, 
 C6 to C10 fatty acids, 
 C8 to C12 fatty acids, or 
 C8 to C10 fatty acids. 
 
     
     
         3 . The formulation of  claim 1  wherein the estradiol is solubilized in:
 one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol; or 
 one or more C6 to C12 fatty acid mono-, di-, or triesters of glycerol; or 
 one or more C6 to C14 fatty acid triesters of glycerol; or 
 one or more C6 to C12 fatty acid triesters of glycerol; or 
 one or more C8 to Cl 0 fatty acid triesters of glycerol. 
 
     
     
         4 . The formulation of any of  claim 1 ,  2 , or  3  comprising a thickening agent that is a non-ionic surfactant. 
     
     
         5 . The formulation of  claim 4  wherein the non-ionic surfactant comprises a polyethylene glycol fatty acid ester. 
     
     
         6 . The formulation of  claim 4  wherein the non-ionic surfactant has a HLB value of 9 to 10. 
     
     
         7 . The formulation of  claim 5  wherein the non-ionic surfactant comprises a polyethylene glycol long chain fatty acid ester and further comprises an ethylene glycol long chain fatty acid ester. 
     
     
         8 . The formulation of  claim 7  wherein the non-ionic surfactant comprises PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. 
     
     
         9 . The formulation of  claim 5  wherein the non-ionic surfactant comprises C8 to C18 fatty acid esters of glycerol and polyethylene glycol. 
     
     
         10 . The formulation of any of the preceding claims having a viscosity of less than 10,000 cP. 
     
     
         11 . The formulation of  claim 9  having a viscosity of less than 5000 cP. 
     
     
         12 . The formulation of  claim 11  having a viscosity of 50 to 1000 cP. 
     
     
         13 . The formulation of any of the preceding claims wherein the non-ionic surfactant comprises a polyethylene glycol fatty acid ester and has a HLB value of 9 to 10. 
     
     
         14 . The formulation of any of the preceding claims wherein the capsule is a soft gelatin capsule or other soft capsule. 
     
     
         15 . The formulation of any of the preceding claims that does not comprise at least one of a bioadhesive agent, a gelling agent, or a dispersing agent. 
     
     
         16 . The formulation of  claim 1 , providing said formulation does not include a hydrophilic gel-forming bioadhesive agent. 
     
     
         17 . The formulation of  claim 16 , providing said formulation does not include at least one of carboxyvinylic acids, hydroxypropylcellulose, carboxymethylcellulose, gelatin, xanthane gum, guar gum, aluminum silicate or mixtures thereof as a hydrophilic gel-forming bioadhesive agent. 
     
     
         18 . The formulation of  claim 1 , providing said formulation does not include a gelling agent. 
     
     
         19 . An encapsulated pharmaceutical formulation of  claim 18 , providing said formulation does not include hydrophobic colloidal silica as a gelling agent. 
     
     
         20 . The formulation of  claim 1 , providing said formulation does not include a hydrophilic gel-forming bioadhesive agent or a gelling agent. 
     
     
         21 . The formulation of  claim 1 , wherein a soft capsule is used for said encapsulation. 
     
     
         22 . The formulation of  claim 21 , wherein said capsule is a soft gelatin capsule. 
     
     
         23 . The formulation of  claim 22 , wherein said estradiol has a dosage strength from about 1 microgram to about 25 micrograms. 
     
     
         24 . The formulation of  claim 23 , wherein said estradiol dosage strength is from about 10 micrograms to about 25 micrograms. 
     
     
         25 . The formulation of  claim 23 , wherein the AUC of circulating blood level concentrations of estradiol following intra-vaginal administration is bioequivalent to the AUC of circulating blood level concentrations following administration of a reference drug. 
     
     
         26 . A method of treating vulvovaginal atrophy, said method comprising administering to a female in need of treatment an effective dose of a pharmaceutical formulation of any one of  claims 1  through  25 . 
     
     
         27 . A method of treating estrogen-deficient urinary states, said method comprising administering to a female in need of treatment an effective dose of a pharmaceutical formulation of any one of  claims 1  through  25 . 
     
     
         28 . A method of minimizing vaginal discharge occurring following administration of a vaginal suppository when compared to the vaginal discharge occurring following administration of a reference drug, said method comprising administering to a female in need of treatment an effective dose of a pharmaceutical formulation of any one of  claims 1  through  25 . 
     
     
         29 . A method of minimizing tears to the vaginal fornix following digital vaginal insertion of a vaginal suppository when compared to tears to the vaginal fornix following vaginal administration of a reference drug using an applicator, said method comprising administering to a female in need of treatment an effective dose of a pharmaceutical formulation of any one of  claims 1  through  25 . 
     
     
         30 . A method of minimizing vaginal itching following vaginal administration of a suppository, said method comprising administering to a female in need of treatment an effective dose of a pharmaceutical formulation of any one of  claims 1  through  25 . 
     
     
         31 . A method of minimizing back pain following vaginal administration of a suppository, said method comprising administering to a female in need of treatment an effective dose of a pharmaceutical formulation of any one of  claims 1  through  25 .