Prolonged Release Formulations Comprising an 2-Oxo-1-Pyrrolidine Derivative

Abstract

The present invention relates to a pharmaceutical composition comprising Levetiracetam, Brivaracetam or Seletracetam as active ingredient, the invention relates specifically to a prolonged release formulation.

1 . A pharmaceutical composition comprising a granulate containing an inert core which is coated by a first layer comprising an active ingredient and at least one excipient, this first layer being coated by a controlled release layer, and the active ingredient being an 2-oxo-1-pyrrolidine derivative of formula (I), 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is H, C 1-10  alkyl or C 2-6  alkenyl; 
         R 2  is C 1-10  alkyl or C 2-6  alkenyl; 
         X is —CONR 4 R 5 , —COOH, —COOR 3  or —CN; 
         R 3  is C 1-10  alkyl; 
         R 4  is hydrogen or C 1-10  alkyl; 
         R 5  is hydrogen or C 1-10  alkyl. 
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein R 1  is hydrogen, n-propyl or 2,2-diflurorovinyl; R 2  is ethyl; and X is —CONH 2 . 
     
     
         3 . The pharmaceutical composition according to  claim 1  or  2 , wherein the weight percentage of the controlled release layer is comprised between 1.0% and 60%, relative to the weight of the pharmaceutical composition. 
     
     
         4 . The pharmaceutical composition according to  claim 1 ,  2  or  3 , wherein the controlled release layer contains at least a polymer consisting in ammonioalkyl methacrylate ethyl acrylate copolymers, or in ethylacrylate methyl methacrylate copolymer, or in ethylcellulose, or in cellulose acetate having a level of acetyl group comprised between 32% and 44%, or in a mix of thereof. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the controlled release polymer is chosen among a copolymer of ammonioalkyl methacrylate and ethyl acrylate, having an average molecular weight comprised between 75000 and 200.000 da, and having a level of ammonioalkyl methacrylate moieties comprised between 6% and 14%; or a copolymer of ethyl acrylate and methyl methacrylate in a molar ratio of 2:1 of the two monomers and having an average molecular weight comprised between 500000 and 1000000. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the controlled release layer contains at least an excipient, such as co-binders, anti-sticking agents, antifoams, flavoring agents, pigments, processing aid agents, like plasticizers, emulsifier or stabilizer. 
     
     
         7 . The pharmaceutical composition according to any of the  claims 1  to  6 , wherein the inert core is a sphere having a sphericity degree higher than 0.75 and having a density comprised between 0.5 and 1.5. 
     
     
         8 . The pharmaceutical composition according to any of the  claims 1  to  7 , wherein the inert core consists essentially in microcrystalline cellulose. 
     
     
         9 . The pharmaceutical composition according to any of the  claims 1  to  8 , wherein the average particle size of the inert core is between 75 and 1400 μm. 
     
     
         10 . The pharmaceutical composition according to any of the  claims 1  to  9 , wherein the excipients of the first layer comprise hydroxylpropylmethylcellulose and talc. 
     
     
         11 . The pharmaceutical composition according to any of the preceding claims, wherein the granulate is coated with an intermediate layer. 
     
     
         12 . The pharmaceutical composition according to any of the preceding claims, wherein the granulate coated with the controlled release layer is further coated with the final layer. 
     
     
         13 . The pharmaceutical composition according to any of the preceding claims, wherein an external phase is added.