Formulations and methods for vaginal delivery of antiprogestins

Abstract

The subject matter of the present invention is pertinent to the field of vaginal delivery of pharmaceutically active agents. Embodiments of the instant invention disclose methods for treating a variety of progesterone related disorders by vaginal administration of a pullulan capsule and a fill formulation comprising one or more antiprogestins dispersed in a mixture of isopropyl palmitate or isopropyl myristate and a polyethylene glycol.

1 .- 22 . (canceled) 
     
     
         23 . A formulation for vaginal use, comprising a mucoadhesive capsule comprising pullulan and a capsule fill formulation comprising a SPRM or a pharmaceutically acceptable salt thereof dispersed in an excipient mixture comprising (a) isopropyl myristate or isopropyl palmitate and (b) a polyethylene glycol, wherein the capsule fill formulation produces an increased AUC with vaginal administration as compared to a capsule fill formulation lacking isopropyl myristate or isopropyl palmitate. 
     
     
         24 . The formulation of  claim 23 , wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 1% to 15% (w/w) of the excipient mixture and polyethylene glycol is present in an amount ranging from 99% to 85% (w/w) of the excipient mixture. 
     
     
         25 . The formulation of  claim 24 , wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 2% to 8% (w/w) of the excipient mixture and polyethylene glycol is present in an amount ranging from 98% to 92% (w/w) of the excipient mixture. 
     
     
         26 . The formulation of  claim 24 , wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 3% to 5% (w/w) and polyethylene glycol is present in an amount ranging from 97% to 95% (w/w) of the excipient mixture. 
     
     
         27 . The formulation of  claim 23 , wherein the SPRM or the pharmaceutically acceptable salt thereof is present in an amount ranging from 2 to 80 mg. 
     
     
         28 . The formulation of  claim 27 , wherein the SPRM or the pharmaceutically acceptable salt thereof is present in an amount selected from 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg and 20 mg. 
     
     
         29 . The formulation of  claim 28 , wherein the formulation comprises 12 mg of the SPRM or the pharmaceutically acceptable salt thereof. 
     
     
         30 . The formulation of  claim 23 , wherein the excipient mixture further comprises BHT in an amount between 0.01% w/w and 0.03% w/w of the excipient mixture. 
     
     
         31 . The formulation of  claim 23 , comprising a mucoadhesive capsule comprising pullulan and capsule fill formulation comprising about 12 mg of the SPRM or a pharmaceutically acceptable salt thereof dispersed in an excipient mixture of (a) about 4% (w/w) isopropyl myristate; (b) about 95.98% (w/) PEG 1000 and (c) about 0.02% BHT. 
     
     
         32 . The formulation of  claim 23 , wherein the capsule comprises about 85 to 90 wt % pullulan. 
     
     
         33 . The formulation of  claim 31 , wherein the capsule comprises pullulan in an amount of 86.3% by weight, potassium chloride in an amount of 1.32% by weight, carrageenan in an amount of 0.27% by weight, surfactants selected from sugar esters, sorbitan monolaurate and combinations thereof in an amount of 0.15% by weight and water. 
     
     
         34 . A method of treating a progesterone-dependent condition in a subject in need thereof, the method comprising: administering a mucoadhesive capsule comprising pullulan and a capsule fill formulation to the vaginal mucosa of the subject,
 wherein the capsule fill formulation comprises a SPRM or a pharmaceutically acceptable salt thereof dispersed in an excipient mixture comprising (a) isopropyl myristate or isopropyl palmitate and (b) a polyethylene glycol, wherein the capsule fill formulation produces an increased AUC with vaginal administration as compared to a capsule fill formulation lacking isopropyl myristate or isopropyl palmitate to the vaginal mucosa of the patient, and   wherein the progesterone-dependent condition is selected from the group consisting of endometriosis, adenomyosis, endometriomas of the ovary, dysmenorrhea, uterine fibroids, endometrial hyperproliferation, ovarian cancer, and cervical cancer.   
     
     
         35 . The method of  claim 34 , wherein the progesterone-dependent condition is endometriosis. 
     
     
         36 . The method of  claim 34 , wherein the progesterone-dependent condition is uterine fibroids. 
     
     
         37 . The method of  claim 34 , wherein the progesterone-dependent condition is endometrial hyperproliferation. 
     
     
         38 . The method of  claim 34 , wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 1% to 15% (w/w) of the excipient mixture and polyethylene glycol is present in an amount ranging from 99% to 85% (w/w) of the excipient mixture. 
     
     
         39 . The method of  claim 34 , wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 2% to 8% (w/w) of the excipient mixture and polyethylene glycol is present in an amount ranging from 98% to 92% (w/w) of the excipient mixture. 
     
     
         40 . The method of  claim 34 , wherein the isopropyl myristate or isopropyl palmitate is present in an amount ranging from 3% to 5% (w/w) and polyethylene glycol is present in an amount ranging from 97% to 95% (w/w) of the excipient mixture. 
     
     
         41 . The method of  claim 34 , wherein the SPRM or the pharmaceutically acceptable salt thereof is present in an amount ranging from 2 to 80 mg. 
     
     
         42 . The method of  claim 34 , wherein the mucoadhesive capsule is administered once per day.