Dpp-iv inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation

Abstract

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.

1 . A pharmaceutical composition comprising or made from a DPP-4 inhibitor, a partner drug, and one or more pharmaceutical excipients, and a nucleophilic and/or basic agent for stabilizing said DPP-4 inhibitor against degradation. 
     
     
         2 . The pharmaceutical composition according to  claim 1  further comprising a buffering agent for stabilizing said DPP-4 inhibitor against degradation. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein said DPP-4 inhibitor is stabilized against chemical degradation. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the partner drug is selected from the group consisting of biguanides, thiazolidinones, statins, and Angiotensin II receptor blockers (ARBs). 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the nucleophilic and/or basic agent or the buffering agent is a basic amino acid having an intramolecular amino group and alkaline characteristics. 
     
     
         6 . The pharmaceutical composition according to  claim 5 , wherein the basic amino acid having an intramolecular amino group and alkaline characteristics is selected from the group consisting of L-arginine, L-lysine and L-histidine. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the DPP-4 inhibitor has an intramolecular free primary or secondary amino group. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the DPP-4 inhibitor is selected from the group consisting of vildagliptin, saxagliptin alogliptin, and 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the DPP-4 inhibitor is present in a dosage range from about 0.5 mg to about 20 mg, or from about 0.5 mg to about 10 mg; or wherein the DPP-4 inhibitor is present in a dosage strength of 0.5, 1, 2.5, 5 or 10 mg; or wherein the DPP-4 inhibitor is present in a dosage strength of 2.5 mg. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the partner drug is metformin hydrochloride. 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein the metformin hydrochloride is present in a dosage range from about 100 mg to about 1500 mg; or wherein the metformin hydrochloride is present in a dosage strength of 250, 500, 625, 750, 850 or 1000 mg; or wherein the metformin hydrochloride is present in a dosage strength of 500 mg, 850 mg or 1000 mg. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the nucleophilic and/or basic agent or the buffering agent is L-arginine. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein L-arginine is present from about 1 mg to about 50 mg, or from about 1 mg to about 25 mg. 
     
     
         14 . The pharmaceutical composition according to  claim 12 , wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio from about 1:20 to about 10:1, or from about 1:15 to about 10:1, or from about 1:10 to about 10:1. 
     
     
         15 . The pharmaceutical composition according to  claim 1 , wherein the excipients are selected from the group consisting of:
 one or more fillers selected from the group consisting of D-mannitol, corn starch and pregelatinized starch;   a binder which is copovidone;   a lubricant which is magnesium stearate; and   a glidant which is colloidal anhydrous silica.   
     
     
         16 . The pharmaceutical composition according to  claim 1  comprising copovidone as binder; and, optionally one or more of the following: a filler which is corn starch, a lubricant which is magnesium stearate, and a glidant which is colloidal anhydrous silica. 
     
     
         17 . The pharmaceutical composition according to  claim 1  in the dosage form of a tablet; wherein the tablet is selected from the group consisting of a mono-layer tablet, a bi-layer tablet, a press-coated tablet, and a tablet which is film-coated for drug-loading. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the tablet comprises a film-coat. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the film-coat comprises:
 a film-coating agent;   a plasticizer;   optionally a glidant, and   optionally one or more pigments.   
     
     
         20 . The pharmaceutical composition according to  claim 1 , in which the pharmaceutical composition is a mono-layer tablet, wherein:
 the percentage of metformin hydrochloride is about 85% by weight of total tablet core,   the percentage of DPP-4 inhibitor is about 0.2% -0.4% by weight of total tablet core,   the percentage of L-arginine is about 2% by weight of total tablet core,   the tablet crushing strength is higher than or equal to 100 N,   the tablet friability is lower than or equal to 0.5%,   the tablet thickness is from about 5.7 to about 8.4 mm,   the tablet core weight is from about 590 to about 1180 mg, and/or   the tablet disintegration time is lower than or equal 15 min.   
     
     
         21 . The pharmaceutical composition according to  claim 17 , which is an immediate release dosage form, characterized in that in a dissolution test after 45 minutes at least 75% by weight of each of the DPP-4 inhibitor and partner drug is dissolved. 
     
     
         22 . A solid pharmaceutical composition comprising or made from
 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,   metformin hydrochloride,   L-arginine,   and one or more fillers, one or more binders, one or more glidants and/or one or more lubricants;   optionally wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine has a particle size distribution of X90<200 μm.   
     
     
         23 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is in the dosage form of a coated tablet, which comprises one or more of the following amounts (% by weight of total coated tablet mass): 
       
         
           
                 
                 
               
                     
                 
                   0.1-0.5% 
                   DPP-4 inhibitor, 
                 
                   47-85% 
                   metformin HCl, 
                 
                   0.07-2.2%  
                   L-arginine, 
                 
                   3.9-8.1% 
                   binder, 
                 
                   2.3-5.9% 
                   first filler, 
                 
                     0-4.4% 
                   second filler, 
                 
                    0-33% 
                   third filler, 
                 
                   0.7-1.5% 
                   lubricant, and 
                 
                   0.1-0.5% 
                   glidant. 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         24 . Granules comprising a DPP-4 inhibitor which has a free or primary amino group, metformin hydrochloride, L-arginine, a binder and a filler; optionally said granules prepared by fluid bed granulation.