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, the first layer being coated by a controlled release layer, wherein the active ingredient is Brivaracetam. 
     
     
         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 , wherein the weight percentage of the controlled release layer is between 1.0% and 60%, relative to the weight of the pharmaceutical composition. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the controlled release layer comprises ammonioalkyl methacrylate ethyl acrylate copolymers, ethylacrylate methyl methacrylate copolymer, ethylcellulose, or cellulose acetate having a level of acetyl group comprised between 32% and 44%, or a combination thereof. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the controlled release polymer is 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 of 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 of between 500000 and 1000000. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the controlled release layer comprises an excipient. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the inert core is a sphere having a sphericity degree greater than 0.75 and having a density of between 0.5 and 1.5. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the inert core consists essentially of microcrystalline cellulose. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the average particle size of the inert core is between 75 and 1400 μm. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the excipients of the first layer comprise hydroxylpropylmethylcellulose and talc. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the granulate is coated with an intermediate layer. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the granulate coated with the controlled release layer is further coated with the final layer. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein an external phase is added. 
     
     
         14 . The pharmaceutical composition according to  claim 6 , wherein the excipient is a co-binder, an anti-sticking agent, and antifoam agent, a flavoring agent, a pigment, a plasticizer, an emulsifier, or a stabilizer. 
     
     
         15 . A pharmaceutical composition comprising a granulate wherein the granulate comprises
 (a) an inert core;   (b) a first layer coating on the core, wherein the first layer comprises Brivaracetam and hydroxypropylmethylcellulose; and   (c) a controlled release layer coating the first layer, wherein the controlled release layer comprises an acrylate copolymer and hydroxypropylmethylcellulose.   
     
     
         16 . A pharmaceutical composition according to  claim 15 , wherein the acrylate copolymer is a copolymer of ethyl acrylate and methyl methacrylate. 
     
     
         17 . A pharmaceutical composition according to  claim 15 , wherein the amount of Brivaracetam is about 20% by weight of the combined weights of the inert core and the first layer. 
     
     
         18 . A pharmaceutical composition according to  claim 15 , wherein the amount of the acrylate copolymer is about 11% by weight of the combined weights of the inert core, the first layer, and the controlled release layer.