Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters

Abstract

The present invention is concerned with a pharmaceutical composition suitable as a depot formulation for administration via intramuscular or subcutaneous injection, comprising: (1) as an active ingredient a therapeutically effective amount of a 9-hydroxy-risperidone fatty acid ester or a salt, or a stereoisomer or a stereoisomeric mixture thereof in submicron form and (2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein and with a process of preparing such a composition. The invention further concerns such a pharmaceutical composition for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette's syndrome, bipolar mania, depression, anxiety.

1 . A pharmaceutical composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection, comprising a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester having the formula  
       
         
           
           
               
               
           
         
       
       or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R represents a straight C 9-19 alkyl radical; having a surfactant adsorbed to the surface thereof in an amount effective in maintaining a specific surface area>4 m 2 /g (corresponding to an effective average particle size of less than 2,000 nm) in a pharmaceutically acceptable carrier comprising water.  
     
     
         2 . A composition according to  claim 1  wherein R represents a straight C 15  (penta-decyl) chain and the active ingredient is 9-hydroxyrisperidone palmitate ester.  
     
     
         3 . A composition according to  claim 1  wherein the composition further comprises a suspending agent, and optionally one or more of a preservative, a buffer and an isotonizing agent.  
     
     
         4 . A composition according to  claim 3  wherein the suspending agent is sodium carboxymethyl cellulose and the surfactant is polysorbate 20.  
     
     
         5 . A composition according to  claim 4  wherein the preservative is benzyl alcohol and the isotonizing agent is mannitol or a phosphate buffer.  
     
     
         6 . A composition according to  claim 1  having a viscosity of less than 75 mPa.s.  
     
     
         7 . A composition according to  claim 1  comprising by weight based on the total volume of the composition: 
 (a) from 3 to 20% (w/v) of the prodrug;  
 (b) from 0.5 to 2% (w/v) of a wetting agent;  
 (c) one or more buffering agents sufficient to render the composition neutral to very slightly basic (up to pH 8.5);  
 (d) from 0.5 to 2% (w/v) of a suspending agent;  
 (e) up to 2% (w/v) preservatives; and  
 (f) water q.s. ad 100%.  
 
     
     
         8 . A pharmaceutical composition as claimed in any one of  claims 1  to  7  for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette's syndrome, bipolar mania, depression, anxiety.  
     
     
         9 . The use of a composition as claimed in any one of  claims 1  to  7  for the preparation of a medicament for treating psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette's syndrome, bipolar mania, depression, anxiety.