Morphine sulfate microgranules, method for preparing same and compositions containing same

Abstract

The present invention relates to sustained-release morphine sulfate microgranules each comprising a neutral support grain coated with an active layer and with a sustained-release layer, wherein the sustained-release layer contains a copolymer of methacrylic acid, and a silica selected from hydrophobic fumed silica, as well as pharmaceutical compositions containing them.

1 . Sustained-release morphine sulfate microgranules each comprising a neutral support grain coated with an active layer and with a sustained-release layer, wherein the sustained-release layer contains a copolymer of methacrylic acid, and a silica selected from hydrophobic fumed silica.  
   
   
       2 . The microgranules according to  claim 1 , wherein the hydrophobic fumed silica is a hydrophobic fumed silica after treated with dimethyldichlorosilane based on a hydrophilic fumed silica with a specific surface area of 130 m 2 /g.  
   
   
       3 . The microgranules according to  claim 1 , wherein the hydrophobic fumed silica represents from 0.2 to 1% by weight of the microgranules.  
   
   
       4 . The microgranules according to  claim 1 , wherein the copolymer of methacrylic acid represents from 5 to 15% by weight of the total weight of the microgranules.  
   
   
       5 . The microgranules according to  claim 1 , wherein the copolymer of methacrylic acid is selected from the group consisting of fully polymerized copolymers of acrylic acid and methacrylic acid esters with low content of quaterny ammonium groups, or mixtures thereof.  
   
   
       6 . The microgranules according to  claim 1  wherein the copolymer of methacrylic acid is selected from the group consisting of poly(ethyl acrylate methyl methacrylate, trimethyamonioethyl methacrylate chloride) with a (1:2:0.1) ratio or with a (1:2:0.2) ratio, and mixtures thereof.  
   
   
       7 . The microgranules according to  claim 1 , wherein the sustained-release layer contains a mixture of two or more different grades of said copolymer of methacrylic acid.  
   
   
       8 . The microgranules according to  claim 1 , wherein the neutral support grain coated with the active layer contains 40% to 50% of morphine sulfate and 10 to 20% of at least one pharmaceutically acceptable binder.  
   
   
       9 . The microgranules according to  claim 1 , wherein the sustained-release layer contains a plasticizer and a lubricant.  
   
   
       10 . The microgranules according to  claim 1  whose composition is as follows:  
     
       
         
               
               
               
             
                   
                   
               
                   
                   
               
                   
                 Morphine sulfate: 
                 30 to 42% 
               
                   
                 Neutral support grain: 
                 30 to 40% 
               
                   
                 Binder: 
                 10 to 20% 
               
                   
                 Copolymer of methacrylic acid: 
                  5 to 15% 
               
                   
                 Plasticizer: 
                   1 to 2.5% 
               
                   
                 Lubricant: 
                 1 to 4% 
               
                   
                 Hydrophobic silica: 
                 0.2 to 1%   
               
                   
                   
               
                   
                   
               
           
              
              
             
             
              
              
              
              
              
              
              
              
              
             
          
         
       
     
   
   
       11 . The microgranules according to  claim 10  whose composition is as follows:  
     
       
         
               
               
               
             
                   
                   
               
                   
                   
               
                   
                 Morphine sulfate: 
                 30 to 40% 
               
                   
                 Neutral support grain: 
                 30 to 40% 
               
                   
                 Binder: 
                 10 to 20% 
               
                   
                 Copolymer of methacrylic acid: 
                  5 to 15% 
               
                   
                 Plasticizer: 
                   1 to 2.5% 
               
                   
                 Lubricant: 
                 2 to 4% 
               
                   
                 Hydrophobic silica: 
                 0.2 to 1%   
               
                   
                   
               
                   
                   
               
           
              
              
             
             
              
              
              
              
              
              
              
              
              
             
          
         
       
     
   
   
       12 . The microgranules according to  claim 1 , wherein the relative mass proportion of the morphine sulfate to the neutral support grain is between 40/60 and 60/40.  
   
   
       13 . The microgranules according to  claim 1 , wherein the morphine sulfate represents 30 to 40% by mass of the microgranules.  
   
   
       14 . The microgranules according to  claim 1 , whose composition is as follows:  
     
       
         
               
               
               
             
                   
                   
               
                   
                   
               
                   
                 Morphine sulphate 
                 37.56% 
               
                   
                 Neutral support grain (sugar sphere) 
                 38.03% 
               
                   
                 Binder (HPMC) 
                 13.18% 
               
                   
                 Methacrylic acid copolymer 
                 7.08% 
               
                   
                 (Eudragit ® RS 30D) 
               
                   
                 Plasticizer (Triethylcitrate) 
                 1.42% 
               
                   
                 Lubricant (Talc) 
                 2.38% 
               
                   
                 Hydrophobic fumed silica 
                 0.35% 
               
                   
                 (Aerosil ® R972) 
               
                   
                   
               
                   
                   
               
           
              
              
             
             
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
     
   
   
       15 . A process for preparing the microgranules according to  claim 1 , wherein the active layer and the sustained-release layer are applied onto the neutral grains by spraying.  
   
   
       16 . A pharmaceutical composition containing microgranules according to  claim 1 .  
   
   
       17 . The pharmaceutical composition according to  claim 16 , having substantially no food effect on the bioavailability of morphine sulfate.  
   
   
       18 . The pharmaceutical composition according to  claim 16 , in the form of capsules or tablets.