Microgranules containing cisplatin

Abstract

The invention concerns an oral formulation of cisplatin, in the form of controlled-release microgranules, and its method of formulation by grossing in an aqueous medium. The invention also concerns a pharmaceutical preparation containing controlled-release cisplatin microgranules, optionally combined with an anticancer agent, to be used in anticancer therapy. The invention further provides a use for these microgranules for making orally administered medicaments for polychemotherapy or in combination with radiotherapy.

1 . Controlled-release microgranules for oral administration containing cisplatin, the mean particle size of which is between 0.4 and 1.5 mm, in particular between 1 and 1.25 mm.  
     
     
         2 . Microgranules according to  claim 1 , characterized in that each microgranule comprises an immediate microgranule to which is fixed a coating containing a coating agent which makes possible the controlled release of cisplatin and/or of other active principles, the said immediate microgranule being composed either a mixture of excipients, of cisplatin and optionally of other active principles or of a neutral support grain coated with a mixture of excipients, of cisplatin and optionally of other active principles.  
     
     
         3 . Microgranules according to  claim 2 , characterized in that the coating agent which makes possible the controlled release of cisplatin or optionally of other active principles is a cellulose polymer or a methacrylic acid copolymer.  
     
     
         4 . Microgranules according to  claim 3 , characterized in that the coating agent is a poly(ethyl acrylate, methyl methacrylate).  
     
     
         5 . Microgranules according to one of  claims 2  to  4 , characterized in that the coating containing the coating agent is composed of a single polymer or of a mixture of polymers and/or of a sequence of polymer layers.  
     
     
         6 . Microgranules according to one of  claims 3  to  5 , characterized in that the coating agent is combined with a lubricating agent, such as talc, and/or a plasticizing agent, such as triethyl citrate, and/or a surface-active agent, such as polysorbate 80.  
     
     
         7 . Microgranules according to one of  claims 2  to  6 , characterized in that a protective coating layer is fixed between the immediate microgranule and the coating containing the coating agent.  
     
     
         8 . Microgranules according to, one of  claims 2  to  7 , characterized in that the mixture of excipients comprises sodium chloride.  
     
     
         9 . Microgranules according to one of  claims 2  to  8 , characterized in that their cisplatin content is between 25 and 350 mg/g.  
     
     
         10 . Microgranules according to  claim 9 , characterized in that their cisplatin content is between 50 and 60 mg/g.  
     
     
         11 . Process for the preparation of microgranules according to one of  claims 2  to  10 , characterized in that fixing cisplatin to neutral support grains is carried out by spraying a fixing suspension of cisplatin in aqueous/alcoholic or alcoholic medium or in aqueous medium.  
     
     
         12 . Process for the preparation of microgranules according to  claim 11 , characterized in that the fixing suspension is aqueous in nature and contains a stabilizing agent, such as sodium chloride, one or more binding agents, such as hydroxypropylmethylcellulose and polyethylene glycol, and a surface-active agent.  
     
     
         13 . Process for the preparation of microgranules according to  claim 11  or  12 , characterized in that the immediate microgranules coated with the coating agent are lubricated with talc.  
     
     
         14 . Pharmaceutical preparation, characterized in that it contains microgranules according to one of  claims 1  to  10  or obtained by the process according to  claims 11  to  13  in an amount which makes it possible to obtain a unit dose of between 10 and 50 mg of cisplatin.  
     
     
         15 . Pharmaceutical preparation according to  claim 14 , characterized in that it contains a mixture of cisplatin and of an anticancer agent as combination product for a use in anticancer therapy which is simultaneous, separate or spread out over time.  
     
     
         16 . Pharmaceutical preparation according to  claim 15 , characterized in that the anticancer agent is fluorouracil, S1, the combination of vinblastine with bleomycin, the combination of etoposide with bleomycin, or paclitaxel.  
     
     
         17 . Use of the microgranules according to  claims 1  to  10  or obtained by the process according to claims  11  to  13  in manufacturing a medicament, to be administered by the oral route, intended to be used at low doses, in particular less than or equal to approximately 20 mg/m 2 /day.  
     
     
         18 . Use according to  claim 17 , characterized in that the medicament is used in polychemotherapy or in combination with a radiotherapy.  
     
     
         19 . Use according to  claim 17  or  claim 18  in order to obtain an average cisplatin blood concentration of between 0.5 and 1.0 μg/ml.