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, the 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, wherein the formulation further comprises a thickening agent, and wherein the fatty acids comprise predominantly (>50 wt %) one of the following:
 a) C6 to C12 fatty acids,   b) C6 to C10 fatty acids,   c) C8 to C 12 fatty acids, or   d) C8 to C10 fatty acids.   
     
     
         3 . The formulation of  claim 1 , wherein the estradiol is solubilized in one of the following:
 a) one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol; or   b) one or more C6 to C12 fatty acid mono-, di-, or triesters of glycerol; or   c) one or more C6 to C14 fatty acid triesters of glycerol; or   d) one or more C6 to C12 fatty acid triesters of glycerol; or   e) one or more C8 to C10 fatty acid triesters of glycerol.   
     
     
         4 . The formulation of any one of  claim 1 ,  2 , or  3  further 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 41 , 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, or 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 one of the preceding claims, wherein the formulation has a viscosity of less than 10,000 cP. 
     
     
         11 . The formulation of  claim 9 , wherein the formulation has a viscosity of less than 5000 cP. 
     
     
         12 . The formulation of  claim 11 , wherein the formulation has a viscosity of 50 to 1000 cP. 
     
     
         13 . The formulation of any one 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 one of the preceding claims, wherein the formulation is encapsulated in a capsule, and wherein the capsule is a soft gelatin capsule or other soft capsule. 
     
     
         15 . The formulation of any one of the preceding claims, wherein the formulation does not comprise at least one of a bioadhesive agent, a gelling agent, or a dispersing agent. 
     
     
         16 . The formulation of  claim 1 , providing the formulation does not include a hydrophilic gel-forming bioadhesive agent. 
     
     
         17 . The formulation of  claim 16 , wherein the formulation does not include at least one of carboxyvinylic acids, hydroxypropylcellulose, carboxymethylcellulose, gelatin, xanthane gum, guar gum, aluminum silicate or mixtures thereof as the hydrophilic gel-forming bioadhesive agent. 
     
     
         18 . The formulation of  claim 1 , wherein the formulation does not include a gelling agent. 
     
     
         19 . An encapsulated pharmaceutical formulation of  claim 18 , providing the formulation does not include hydrophobic colloidal silica as the gelling agent. 
     
     
         20 . The formulation of  claim 1 , providing the 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 the encapsulation. 
     
     
         22 . The formulation of  claim 21 , wherein the capsule is a soft gelatin capsule. 
     
     
         23 . The formulation of  claim 22 , wherein the estradiol has a dosage strength from about 1 microgram to about 25 micrograms. 
     
     
         24 . The formulation of  claim 23 , wherein the 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 .- 31 . (canceled)