Micronized Tanaproget and Compositions Containing Same

Abstract

The present invention provides compositions, desirably pharmaceutical compositions, containing micronized tanaproget. The compositions can also contain microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, and magnesium stearate; or can contain microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, povidone, and magnesium stearate. The compositions are useful in contraception and hormone replacement therapy and in the treatment and/or prevention of uterine myometrial fibroids, benign prostatic hypertrophy, benign and malignant neoplastic disease, dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, and carcinomas and adenocarcinomas of the pituitary, endometrium, kidney, ovary, breast, colon, and prostate and other hormone-dependent tumors, and in the preparation of medicaments useful therefor. Additional uses include stimulation of food intake.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising micronized tanaproget, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, povidone, and magnesium stearate. 
     
     
         2 . The composition according to  claim 1 , wherein said tanaproget comprises about 0.10% wt/wt of said composition. 
     
     
         3 . A pharmaceutical composition for oral administration comprising about 0.10% wt/wt micronized tanaproget, about 90.15% wt/wt microcrystalline cellulose, about 6% wt/wt/croscarmellose sodium, about 2% wt/wt sodium lauryl sulfate, about 1.5% wt/wt povidone, and about 0.25% wt/wt magnesium stearate. 
     
     
         4 . A process for preparing a composition comprising micronized tanaproget, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, and magnesium stearate, said process comprising:
 (a) combining said micronized tanaproget, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, and magnesium stearate; and   (b) granulating the mixture of step (a).   
     
     
         5 . The process according to  claim 4 , wherein said composition is compacted and compressed into a tablet suitable for oral administration. 
     
     
         6 . The process according to  claim 5 , wherein said tablet is encapsulated in a capsule. 
     
     
         7 . The process according to  claim 4 , further comprising compacting said composition, milling the composition, or a combination thereof. 
     
     
         8 . The process according to  claim 4 , wherein about 86% to about 99% of said tanaproget is released from said composition after about 90 minutes. 
     
     
         9 . A process for preparing a composition of  claim 1 , said process comprising:
 (a) combining said micronized tanaproget, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, and magnesium stearate; and   (b) granulating the product of step (a).   
     
     
         10 . The process according to  claim 9 , further comprising adding said composition to a capsule. 
     
     
         11 . The process according to  claim 10 , wherein said capsule is a hard shell gelatin capsule. 
     
     
         12 . A capsule comprising the composition of  claim 1 . 
     
     
         13 . A pharmaceutical kit comprising a daily dosage unit of said capsule of  claim 12 . 
     
     
         14 . The pharmaceutical kit according to  claim 13 , comprising a single phase of a daily dosage of said composition over a 21, 28, 31, or 31-day cycle. 
     
     
         15 . The pharmaceutical kit according to  claim 14 , further comprising a placebo. 
     
     
         16 . The composition according to  claim 1 , comprising about 0.05 mg to about 1 mg of tanaproget. 
     
     
         17 . A tablet comprising the composition of  claim 1 . 
     
     
         18 . A method of contraception, said method comprising administering the composition of  claim 1  to a female patient. 
     
     
         19 . A method of hormone replacement therapy, said method comprising administering the composition of  claim 1  to a patient. 
     
     
         20 . A method of treating or preventing uterine myometrial fibroids, benign prostatic hypertrophy, benign and malignant neoplastic disease, dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, and carcinomas and adenocarcinomas of the pituitary, endometrium, kidney, ovary, breast, colon, and prostate, said method comprising administering the composition of  claim 1  to a patient. 
     
     
         21 . A pharmaceutical composition comprising micronized tanaproget, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, magnesium stearate, and a granulating agent. 
     
     
         22 . The composition according to  claim 21 , wherein said granulating agent is silicon dioxide. 
     
     
         23 . The composition according to  claim 21 , wherein said tanaproget comprises about 0.08% to about 0.4% wt/wt of said composition. 
     
     
         24 . The composition according to  claim 21  which degrades less than about 4% over a period of greater than 1 month at temperatures at or greater than about 25° C. and a relative humidity at or greater than about 60%. 
     
     
         25 . The composition according to  claim 21 , wherein the particles of said micronized tanaproget are less than about 10 μm. 
     
     
         26 . The composition according to  claim 21 , wherein the particles of said composition are less than about 125 μm. 
     
     
         27 . A pharmaceutical composition comprising micronized tanaproget, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, magnesium stearate, and silicon dioxide. 
     
     
         28 . The composition according to  claim 27 , wherein said tanaproget comprises about 0.08% to about 0.4% wt/wt of said composition. 
     
     
         29 . The composition according to  claim 27  which degrades less than about 4% over a period of greater than 1 month at temperatures at or greater than about 25° C. and a relative humidity at or greater than about 60%. 
     
     
         30 . The composition according to  claim 27 , wherein the particles of said micronized tanaproget are less than about 10 μm. 
     
     
         31 . The composition according to  claim 27 , wherein the particles of said composition are less than about 125 μm. 
     
     
         32 . A process for preparing a composition of  claim 21 , said process comprising:
 (a) combining said micronized tanaproget, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, magnesium stearate, and granulating agent; and   (b) granulating the mixture of step (a).   
     
     
         33 . The process according to  claim 32 , wherein said composition is compacted and directly compressed into a tablet suitable for oral administration. 
     
     
         34 . The process according to  claim 33 , wherein said tablet is encapsulated in a capsule. 
     
     
         35 . The process according to  claim 32 , further comprising compacting said composition, milling the composition, or a combination thereof. 
     
     
         36 . The process according to  claim 32 , wherein about 86% to about 99% of said tanaproget is released from said composition after about 90 minutes. 
     
     
         37 . A process for preparing a composition of  claim 27 , said process comprising:
 (a) combining said micronized tanaproget, microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, magnesium stearate, and silicon dioxide; and   (b) granulating the product of step (a).   
     
     
         38 . The process according to  claim 37 , wherein said composition is compacted and directly compressed into a tablet suitable for oral administration. 
     
     
         39 . The process according to  claim 38 , wherein said tablet is encapsulated in a capsule. 
     
     
         40 . The process according to  claim 37 , further comprising compacting said composition, milling the composition, or a combination thereof. 
     
     
         41 . The process according to  claim 37 , wherein about 86% to about 99% of said tanaproget is released from said composition after about 90 minutes. 
     
     
         42 . A tablet comprising the composition of  claim 21 . 
     
     
         43 . A tablet comprising the composition of  claim 27 . 
     
     
         44 . A pharmaceutical kit comprising a daily dosage unit of said tablet of  claim 42 . 
     
     
         45 . The pharmaceutical kit according to  claim 44 , wherein said daily dosage is about 0.05 mg to about 1 mg. 
     
     
         46 . The pharmaceutical kit according to  claim 45 , wherein said daily dosage is about 0.05 mg to about 0.3 mg. 
     
     
         47 . The pharmaceutical kit according to  claim 44 , which is for oral delivery of said tablet over 21 days. 
     
     
         48 . The pharmaceutical kit according to  claim 44 , which is for oral delivery of said tablet over 28 days. 
     
     
         49 . The pharmaceutical kit according to  claim 44 , which is for oral delivery of said tablet over 30 days. 
     
     
         50 . The pharmaceutical kit according to  claim 44 , which is for oral delivery of said tablet over 31 days. 
     
     
         51 . A pharmaceutical kit, comprising:
 (i) a first phase of 14 to 28 daily dosage units of said composition of  claim 1 ; and   (ii) a second phase of 1 to 11 daily dosage units of a progestational agent.   
     
     
         52 . The pharmaceutical kit according to  claim 51 , comprising a first phase of 14 to 21 daily dosage units of said composition. 
     
     
         53 . The pharmaceutical kit according to  claim 51 , comprising:
 (i) a first phase of 18 to 21 daily dosage units of said composition; and   (ii) a second phase of 1 to 7 daily dose units of said progestational agent.   
     
     
         54 . The pharmaceutical kit according to  claim 51 , comprising:
 (i) a first phase of 21 daily dosage units of said tablet; and   (ii) a second phase of 3 daily dosage units for days 22 to 24 of said progestational agent.   
     
     
         55 . A pharmaceutical kit, comprising:
 (i) a first phase of 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel; and   (ii) a second phase of 1 to 11 daily dosage units of said composition of  claim 1 .   
     
     
         56 . The pharmaceutical kit according to  claim 55 , wherein said progestational agent is equal in progestational activity to about 35 to about 100 μg levonorgestrel. 
     
     
         57 . A pharmaceutical kit comprising a daily dosage unit of said tablet of  claim 55 .