Dpp iv inhibitor formulations

Abstract

The present invention relates to pharmaceutical compositions of DPP IV inhibitors with an amino group, their preparation and their use to treat diabetes mellitus.

1 . A pharmaceutical composition comprising as an active ingredient a DPP IV inhibitor compound of formula 
       
         
           
           
               
               
           
         
       
       in an amount of 0.5 mg, 1 mg, 2.5 mg, 5 mg or 10 mg, or a salt thereof, a first diluent, a second diluent, a binder, a disintegrant and a lubricant, wherein the first diluent is mannitol, the second diluent is pregelatinized starch, the binder is copovidone, the disintegrant is corn starch, and the lubricant is magnesium stearate; and wherein the DPP IV inhibitor compound is present in an amount 0.5-20% based on the total weight of DPP IV inhibitor compound, first diluent, second diluent, binder, disintegrant and lubricant. 
     
     
         2 . The pharmaceutical composition of  claim 1  further comprising an additional disintegrant. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the additional disintegrant is crospovidone. 
     
     
         4 . The pharmaceutical composition of  claim 1  further comprising a glidant. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the glidant is colloidal silicon dioxide. 
     
     
         6 . The pharmaceutical composition of  claim 1  comprising 
       
         
           
                 
                 
               
                     
                 
                   40-88% 
                   diluent 1, 
                 
                    3-40% 
                   diluent 2, 
                 
                   1-5% 
                   binder, 
                 
                    5-15% 
                   disintegrant, and 
                 
                   0.1-4%   
                   lubricant 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         7 . The pharmaceutical composition of  claim 1  comprising 
       
         
           
                 
                 
               
                     
                 
                   0.5-7%   
                   active ingredient 
                 
                   50-75% 
                   diluent 1, 
                 
                    5-15% 
                   diluent 2, 
                 
                   2-4% 
                   binder, 
                 
                    8-12% 
                   disintegrant, and 
                 
                   0.5-2%   
                   lubricant 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         8 . The pharmaceutical composition according to  claim 1  in the dosage form of a capsule, a tablet, or a film-coated tablet. 
     
     
         9 . The pharmaceutical composition of  claim 8  comprising 2-4% film coat. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the film coat comprises a film-forming agent, a plasticizer, a glidant and optionally one or more pigments. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the film coat comprises hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide. 
     
     
         12 . A process for the preparation of a pharmaceutical composition according to  claim 1  comprising
 a. dissolving the binder in a solvent to produce a granulation liquid; 
 b. blending the DPP-IV inhibitor, a diluent, and the disintegrant to produce a pre-mix; 
 c. moistening the pre-mix with the granulation liquid and subsequently granulating the moistened pre-mix; 
 d. optionally sieving the granulated pre-mix through a sieve with a mesh size of at least 1.0 mm; 
 e. drying the granulate at about 40-75° C. until the desired loss on drying value in the range of 1-5% is obtained; 
 f. sieving the dried granulate through a sieve with a mesh size of at least 0.6 mm; 
 g. adding the lubricant to the granulate for final blending. 
 
     
     
         13 . The process according to  claim 12  further comprising
 h. compressing the final blend into tablet cores; 
 i. preparing a coating suspension; 
 j. coating the tablet cores with the coating suspension to a weight gain of about 2-4% to produce film-coated tablets. 
 
     
     
         14 . The process according to  claim 12 , wherein part of the excipients are added extragranular prior to the final blending of step g. 
     
     
         15 . The process according to  claim 12 , wherein the granulate produced in steps a-e is produced in a one pot high shear granulation process and subsequent drying in a one pot granulator. 
     
     
         16 . The pharmaceutical composition according to  claim 1 , wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is comprised in an amount of 5 mg. 
     
     
         17 . The pharmaceutical composition according to  claim 16  in the form of a capsule, a tablet, or a film-coated tablet. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein the composition is in the form of a film-coated tablet, and wherein the film coat comprise 2-4% wt % based the weight of the uncoated tablet. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the film coat comprises a film-forming agent, a plasticizer, a glidant and optionally one or more pigments. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the film coat comprises hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide. 
     
     
         21 . The pharmaceutical composition according to  claim 16 , which is an oral dosage form in the form of a tablet. 
     
     
         22 . The pharmaceutical composition according to  claim 16 , which is an oral dosage form in form of a film-coated tablet.