Antidiabetic Solid Pharmaceutical Compositions

Abstract

Provided are pharmaceutical compositions in solid form comprising a selective modulator of PPAR-γ suitable for oral dosage to treat subjects having PPAR-γ mediated conditions. Provided further are methods of manufacturing the compositions, and methods of treating a PPAR-γ mediated condition.

What is claimed is: 
     
         1 . A pharmaceutical composition, in solid form, suitable for oral administration to a subject, which comprises a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein the composition comprises granules comprising compound (I), diluent, disintegrant, and binder; wherein the mean particle size of the compound of formula (I) is less than 150 microns, and wherein after administration to a subject, is capable of providing in the subject a T max  of less than 4.0 hours. 
       
     
     
         2 . The composition of  claim 1 , wherein the solid pharmaceutical composition, after administration to a subject, is capable of providing in the subject an AUC 0→∞  for the compound (I) of about 150 to about 5000 ng*hr/mL. 
     
     
         3 . The solid pharmaceutical composition of  claim 1 , wherein the solid pharmaceutical composition, after administration to a subject, is capable of providing in the subject an AUC 0→∞  for the compound (I) from about 5000 to about 35,000 ng*hr/mL. 
     
     
         4 . The solid pharmaceutical composition of  claim 1 , wherein the mean particle size of the compound of formula (I) is selected from the group consisting of less than 100 microns, less than 50 microns, less than 20 microns, and about 1 to about 10 microns. 
     
     
         5 . The solid pharmaceutical composition of  claim 1  in the form of a tablet or powder. 
     
     
         6 . The solid pharmaceutical composition of  claim 1  provided as a unit dosage form. 
     
     
         7 . The solid pharmaceutical composition of  claim 4  wherein the compound of formula (I) is present in an amount of between about 0.1 to about 10.0 mg. 
     
     
         8 . The solid pharmaceutical composition of  claim 1 , wherein the compound is present as a salt thereof selected from the group consisting of benzenesulfonate salt, hydrochloride salt, hydrobromide salt, and p-toluenesulfonate salt. 
     
     
         9 . The solid pharmaceutical composition of  claim 8 , wherein the compound is present as the benzenesulfonate salt and wherein the benzenesulfonate salt is present in an amount of between about 0.1 to about 10.0 mg. 
     
     
         10 . The solid pharmaceutical composition of  claim 1  prepared by a process which comprises the steps of (a) micronizing the compound of formula (I); and (b) preparing a wet granulation of the micronized compound in combination with one or more pharmaceutically acceptable excipients comprising diluent, disintegrant, and binder. 
     
     
         11 . A method of making the solid pharmaceutical composition of  claim 1 , wherein said pharmaceutical composition is made by wet granulation. 
     
     
         12 . The method of  claim 11  comprising the steps of:
 (a) mixing micronized particles of the compound of formula (I) with one or more excipients to form a powder blend; 
 (b) adding a granulating solution to the powder blend obtained in step (a), and mixing the solution and powder blend to form wet granules; 
 (c) drying the wet granules obtained in step (b) to form dry granules; 
 (d) milling the dry granules obtained in step (c); 
 (e) blending the milled dry granules obtained in step (d) with one or more excipients to form a blend constituting the final composition of the solid pharmaceutical composition; and 
 (f) optionally, compressing the blend obtained in step (e) into a unit dosage form. 
 
     
     
         13 . A solid pharmaceutical composition suitable for unit dosage administration to a human, comprising the pharmaceutical composition prepared by the method of  claim 12 . 
     
     
         14 . A method of treating a PPARγ-mediated condition or disorder in a human, the method comprising administering to the subject a therapeutically effective amount of the solid pharmaceutical composition of  claim 1 .