Vaginally administrable progesterone containing tablets and method for preparing the same

Abstract

The present invention provides a method for preparing a tablet for the vaginal administration of progesterone for systemic use. The method comprises first mixing water with micronized progesterone, the total amount of water mixed with said micronized progesterone not exceeding the maximum wetting capacity of the micronized progesterone, drying the wetted, micronized progesterone; mixing the dry micronized progesterone with other pharmaceutically acceptable excipients or diluents; and; forming a tablet by direct compaction of the dry micronized progesterone. Tablets prepared by this method are also provided.

1 . A method for preparing a tablet for the vaginal administration of: progesterone for systemic use, comprising the steps of: 
 (i) preparing a mixture consisting of water and micronized progesterone to obtain wetted micronized progesterone;    (ii) drying the wetted micronized progesterone to obtain dry micronized progesterone;    (iii) mixing the dried micronized progesterone with at least one pharmaceutically acceptable excipient or diluent to form a second mixture; and    (iv) forming a tablet by direct compaction of the second mixture.    
     
     
         2 . The method of  claim 1 , wherein step (iii) comprises mixing the dry micronized progesterone with 
 (a) a pharmaceutically acceptable non-effervescent excipient or diluent; and    (b) an effervescent.    
     
     
         3 . The method of  claim 2 , wherein the micronized progesterone is present in from about 6% to about 20% by weight of the tablet.  
     
     
         4 . The method of  claim 2 , wherein the micronized progesterone is present in from about 8% to about 12% by weight of the tablet.  
     
     
         5 . The method of  claim 2 , wherein the effervescent is a mixture of a pharmaceutically acceptable carboxylic or dicarboxylic acid and a pharmaceutically acceptable salt of HCO 3   − .  
     
     
         6 . The method of  claim 5 , wherein the pharmaceutically acceptable salt of HCO 3   −  is sodium bicarbonate.  
     
     
         7 . The method of  claim 2 , wherein the pharmaceutically acceptable carboxylic or dicarboxylic acid is adipic acid or tartaric acid.  
     
     
         8 . The method of  claim 7 , wherein the pharmaceutically acceptable carboxylic or dicarboxylic acid and said bicarbonate are present in an amount providing a molar excess of —COOH groups.  
     
     
         9 . The method of  claim 2 , wherein the effervescent comprises a mixture ofadipic acid and sodium bicarbonate.  
     
     
         10 . The method of  claim 2 , wherein the effervescent comprises between about 5% and about 12% by weight of the tablet.  
     
     
         11 . The method of  claim 10 , wherein the effervescent comprises about 8% by weight of the tablet.  
     
     
         12 . The method of  claim 2 , wherein the amount of water mixed with the micronized progesterone is between about 25% and 28% by weight of the amount of micronized progesterone.  
     
     
         13 . The method of  claim 12 , wherein the amount of water mixed with the micronized progesterone is about 28% by weight of the amount of micronized progesterone.  
     
     
         14 . The method according to  claim 2 , wherein the dried micronized  
     
     
         15 . The method according to  claim 2 , wherein step (iii) comprises: 
 (i) sieving a first lubricant to obtain a sieved first lubricant;    (ii) mixing the dry micronized progesterone with the sieved first lubricant and a material selected from a first filler or a disintegrant to form a first mixture;    (iii) mixing a binder which binds dry particles with the first mixture to form a second mixture;    (iv) intimately mixing the effervescent and a first quantity of a second filler to form a third mixture;    (v) sieving the third mixture to obtain a sieved third mixture, and then intimately mixing the sieved third mixture and the second mixture to form a fourth mixture;    (vi) intimately mixing the fourth mixture with a second quantity of the second filler to form a fifth mixture;    (vii) sieving a second lubricant and a material selected from a saponificant or a third lubricant to obtain, respectively, sieved second lubricant and sieved third lubricant; and    (viii) intimately mixing the sieved second lubricant and said sieved third lubricant with said fifth mixture to form a sixth mixture.    
     
     
         16 . The method of  claim 15 , wherein said first lubricant is silicon dioxide.  
     
     
         17 . A method according to  claim 15 , wherein the material in step (ii) is a disintegrant, and wherein the disintegrant is a starch derived from corn, potatoes or wheat.  
     
     
         18 . The method of  claim 17 , wherein said starch is cornstarch.  
     
     
         19 . The method of  claim 15 , wherein the binder is polyvinylpyrrolidone.  
     
     
         20 . The method of  claim 15 , wherein the second filler is selected from lactose or a composition consisting essentially of lactose.  
     
     
         21 . A method according to  claim 15 , wherein the second lubricant is selected from the group consisting of magnesium stearate, talc, sodium lauryl sulfate, and phosphates.  
     
     
         22 . The method of  claim 15 , wherein the material selected from a saponificant or a third lubricant in step (vii) is sodium lauryl sulfate.  
     
     
         23 . A method for preparing a tablet useful for vaginal administration of progesterone which comprises (i) mixing water with micronized progesterone, prior to adding any other ingredients, to obtain wetted micronized progesterone; 
 (ii) drying the wetted micronized progesterone;    (iii) mixing a pharmaceutically acceptable excipient or diluent with the micronized progesterone after the drying step to form a tabletting mixture; and    (iv) directly compacting the tabletting mixture to form the tablet.    
     
     
         24 . The method of  claim 23  for preparing a tablet for the vaginal administration of progesterone for systemic use, wherein the mixture in step (i) consists essentially of water and micronized progesterone.  
     
     
         25 . A method for preparing a tablet for the vaginal administration of progesterone for systemic use, comprising the following sequential steps: 
 (i) first mixing water with micronized progesterone, in the absence of a pharmaceutically acceptable excipient or diluent, to obtain wetted micronized progesterone;    (ii) drying said wetted micronized progesterone to form dry micronized progesterone;    (iii) mixing said dry micronized progesterone with 
 (a) a pharmaceutically acceptable non effervescent excipient or diluent; and  
 (b) an effervescent to form a mixture; and  
   (iv) forming a tablet by direct compaction of said mixture.