Pharmaceutical composition and the process for its preparation

Abstract

The present invention provides a new stable pharmaceutical composition containing 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione as active ingredient.

1 . A pharmaceutical composition comprising (i) a compound selected from the group consisting of 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione and a pharmaceutically acceptable salt thereof, and (ii) one or more of a a pharmaceutically acceptable carrier or excipient, wherein said mixture has a water content below about 1%(w/w).  
     
     
         2 . The composition of  claim 1  in the form of a tablet, a powder or a capsule.  
     
     
         3 . The composition of  claim 1 , further comprising an antioxidant.  
     
     
         4 . The composition of  claim 3 , wherein said antioxidant comprises between 1 and 100 parts by weight and the pharmaceutically acceptable excipient is selected from the group consisting of: 
 between 100 and 400,000 parts by weight of anhydrous lactose,    between 1 and 100 parts by weight of an antioxidant,    between 50 and 500 parts by weight of pregelatinized starch,    between 1000 and 10,000 parts by weight of microcrystalline cellulose,    between 10 and 500 parts by weight of crospovidone,    between 10 and 500 parts by weight of silicon dioxide,    between 10 and 500 parts by weight of hydrogenated vegetable oil,    between 10 and 500 parts by weight of magnesium stearate,    between 10 and 500 parts by weight of hydroxypropyl methylcellulose,    between 10 and 500 parts by weight of hydroxypropyl cellulose,    between 1000 and 10,000 parts by weight of mannitol,    between 10 and 500 parts by weight of stearic acid, or    between 10 and 500 parts by weight of titanium dioxide.    
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the water content is below about 0.5% (w/w).  
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the water content is below about 0.1% (w/w).  
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein water content is below about 0.05% (w/w).  
     
     
         8 . The composition of  claim 3 , wherein the antioxidant is selected from group consisting of: α-tocopherol, γ-tocopherol, δ-tocopherol, extracts of natural origin rich in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate (PG), octyl gallate, dodecyl gallate, butylated hydroxy anisole (BHA), and butylated hydroxy toluene (BHT).  
     
     
         9 . The composition of  claim 8 , wherein the antioxidant is α-tocopherol.  
     
     
         10 . The pharmaceutical composition of  claim 1 , further comprising at least one customary additive selected from the group consisting of sweeteners, flavouring agents, colours and lubricants.  
     
     
         11 . The composition of  claim 1  comprising (i) a compound selected from the group consisting of 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiadiazolidine-2,4-dione and a pharmaceutically acceptable salt thereof, and (ii) pharmaceutically acceptable excipients comprising anhydrous lactose, microcrystalline cellulose, magnesium stearate, and talc.  
     
     
         12 . The composition of  claim 11 , wherein the pharmaceutically acceptable excipients are: 
 between 100 and 400,000 parts by weight of anhydrous lactose,    between 1000 and 10,000 parts by weight of microcrystalline cellulose, and    between 10 and 500 parts by weight of magnesium stearate,    expressed in parts by weight per 100 parts of 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiadiazolidine-2,4-dione, or of one of its pharmaceutically acceptable salts.    
     
     
         13 . The composition of  claim 12 , wherein the amount of talc is 0-10% (weight/weight).  
     
     
         14 . The composition of  claim 1 , comprising:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   5-[[4-[3-methyl-4-oxo-3,4-dihydro-2- 
                     9% 
                 
                     
                   quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- 
                 
                     
                   dione, potassium salt 
                 
                     
                   cellulose microcrystallline 
                    20% 
                 
                     
                   lactose 
                    66% 
                 
                     
                   magnesium Stearate 
                   0.5% 
                 
                     
                   talc 
                   4.5% 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         15 . The composition of  claim 1 , comprising:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   dione, potassium salt 
                   18% 
                 
                     
                   cellulose microcrystalline 
                   20% 
                 
                     
                   mannitol 
                   57% 
                 
                     
                   magnesium stearate 
                   0.5%  
                 
                     
                   talc 
                   4.5%  
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         16 . The composition of  claim 1 , comprising:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   dione, potassium salt 
                     18% 
                 
                     
                   lactose 
                   81.5% 
                 
                     
                   magnesium stearate 
                    0.5% 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
               
            
           
         
       
     
     
         17 . The composition of  claim 1 , comprising:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   dione, potassium salt 
                   0.09% 
                 
                     
                   mannitol 
                     98% 
                 
                     
                   magnesium stearate 
                     2% 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
               
            
           
         
       
     
     
         18 . The composition of  claim 1 , comprising:  
       
         
           
                 
                 
               
                     
                 
                     
                 
                   dione, potassium salt 
                   0.09% 
                 
                   hydrogenated vegetable oil 
                   6.25% 
                 
                   talc 
                     5% 
                 
                   α-tocopherol 
                     50% of 5-[[4-[3-methyl-4-oxo-3,4-dihydro- 
                 
                     
                   2-quinazolinyl]methoxy]phenylmethyl] 
                 
                     
                   thiazolidine-2,4-dione, potassium salt 
                 
                   lactose DCL21/mannitol 
                   Up to 200 g. 
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         19 . The composition of  claim 1 , comprising:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   dione, potassium salt 
                   0.09% 
                 
                     
                   povidone 
                    7.5% 
                 
                     
                   hydroxypropylmethyl cellulose 
                    1.5% 
                 
                     
                   croscarmelose sodium 
                   1.56% 
                 
                     
                   talc 
                    1.1% 
                 
                     
                   magnesium stearate 
                    0.5% 
                 
                     
                   lactose 300 mesh 
                   up to 200 g. 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         20 . The composition of  claim 1 , comprising the following:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   dione, potassium salt 
                   0.1096 
                   g 
                 
                     
                   mannitol 
                   2.5 
                   g 
                 
                     
                   hydroxypropyl-β-cyclodextrin 
                   10 
                   g 
                 
                     
                   and diluted with 92 mL water before use. 
                 
                     
                     
                 
                     
                     
                 
             
                
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         21 . The composition of  claim 1 , comprising:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   dione, potassium salt 
                   1.096 
                   g 
                 
                     
                   mannitol 
                   2.5 
                   g 
                 
                     
                   hydroxypropyl-β-cyclodextrin 
                   10 
                   g 
                 
                     
                   sodium carbonate, anhydrous, 
                   15 
                   mg 
                 
                     
                   Na 2 CO 3   
                 
                     
                   and diluted with 92 mL water before use.