Morphine sulfate microgranules, manufacturing process and pharmaceutical preparations

Abstract

The present invention relates to a novel oral immediate-release morphine sulfate formulation in the form of microgranules. Each microgranule comprises a neutral support grain coated with a mixture of morphine sulfate and of a binder, such as hydroxypropylmethylcellulose, which represents 10 to 50% by weight of the morphine sulfate/binder mixture. The present invention also relates to a process for the preparation of these microgranules which is carried out entirely in aqueous medium on neutral support grains. The present invention finally relates to the pharmaceutical preparations comprising the microgranules according to the invention.

1 . An immediate-release microgranule, each microgranule comprising a neutral support grain coated with a mixture of morphine sulfate and of a pharmaceutically acceptable binder, said binder representing 10 to 50% by weight of the morphine sulfate/binder mixture.  
     
     
         2 . The microgranule as claimed in  claim 1 , wherein the binder represents 15 to 40% by weight of the morphine sulfate/binder mixture.  
     
     
         3 . The microgranule as claimed in  claim 1  or  2 , which is coated with an outer protective layer comprising a film-forming agent and optionally a lubricating agent.  
     
     
         4 . The microgranule as claimed in  claim 3 , wherein the lubricating agent represents 10 to 60% by weight of the binder/lubricating agent mixture.  
     
     
         5 . The microgranule according to  claim 3  or 4, wherein the lubricating agent is talc.  
     
     
         6 . The microgranule as claimed in one of  claims 3  to  5 , wherein the outer layer represents 1 to 5% by weight of the total mass of the microgranule before coating.  
     
     
         7 . The microgranule as claimed in one of the preceding claims, wherein the binder and/or the film-forming agent is hydroxypropylmethylcellulose.  
     
     
         8 . The microgranule as claimed in one of the preceding claims, wherein its content of morphine sulfate is between 50 and 200 mg/g.  
     
     
         9 . The microgranule as claimed in one of the preceding claims, which has a dissolution profile in water, buffered at a pH approximately equal to 7 and at a temperature of 37° C., by the dissolution method with a paddle at 100 revolutions/min, such that: 
 more than 70% by weight of active principle is dissolved after 30 minutes,  
 more than 90% by weight of active principle is dissolved after 60 minutes.  
 
     
     
         10 . The microgranule as claimed in one of the preceding claims, which has a mean particle size of between 0.5 and 2 mm.  
     
     
         11 . A process for the preparation of the microgranule as claimed in one of  claims 1  to  10 , which is carried out entirely in aqueous medium.  
     
     
         12 . The process as claimed in  claim 11 , which comprises a stage of emplacing an aqueous suspension comprising morphine sulfate and a binder on neutral support grains in a pan or in a fluidized air bed.  
     
     
         13 . The process as claimed in  claim 12 , wherein the microgranule obtained on conclusion of the emplacing stage is coated with an aqueous suspension of a film-forming agent, such as hydroxypropylmethylcellulose.  
     
     
         14 . A pharmaceutical preparation, which comprises the microgranule as claimed in one of  claims 1  to  10  or obtained by the process as claimed in one of  claims 11  to  13  in an amount equivalent to a unit dose of between 1 and 100 mg of morphine sulfate.