Antipsychotic Injectable Depot Composition

Abstract

The present invention is directed to a composition that can be used to deliver an antipsychotic drug such as risperidone, paliperidone or a combination thereof, as an injectable in-situ forming biodegradable implant for extended release providing therapeutic plasma levels from the first day. The composition is in the form of drug suspension on a biodegradable and biocompatible copolymer or copolymers solution using water miscible solvents that is administered in liquid form. Once the composition contacts the body fluids, the polymer matrix hardens retaining the drug, forming a solid or semisolid implant that releases the drug in a continuous manner. Therapeutic plasma levels of the drug can be achieved from the first day up to at least 14 days or more even up to at least four weeks.

1 ) A method of treating schizophrenia or bipolar disorder in a human subject, the method comprising intramuscularly administering to said subject an extended release injectable suspension comprising risperidone particles suspended in polymeric solution, wherein after said administering said composition forms an implant in said subject, and said implant provides therapeutically effective levels of active moiety, which is risperidone and/or 9-hydroxyrisperidone, from the first day up to at least 28 days after said administering. 
     
     
         2 ) The method of  claim 1 , wherein said suspension consists essentially of mg of particles of risperidone suspended in a polymeric solution of DMSO and PLGA copolymer. 
     
     
         3 ) The method of  claim 1 , wherein said administering is done every 4 to 5 weeks or every 4 weeks. 
     
     
         4 ) A method of treating schizophrenia or bipolar disorder, the method comprising administering by intramuscular injection to a human subject in need thereof a dose of extended release injectable suspension consisting essentially of 25-150 mg of risperidone, wherein in said suspension, particles of risperidone are suspended in a polymeric solution of DMSO and PLGA copolymer, wherein after said administering said composition forms an implant in said subject, wherein said implant provides therapeutically effective levels of active moiety, which is risperidone and/or 9-hydroxyrisperidone, from the first day up to at least 28 days after said administering, wherein ≥1% wt and ≤20% wt of the risperidone is dissolved in said DMSO or said polymeric solution prior to administration, and wherein said administering is done every 4 to 5 weeks or every 4 weeks. 
     
     
         5 ) The method of  claim 4  further comprising providing a pharmaceutical kit comprising a) risperidone in a container and said PLGA copolymer in another container; or b) risperidone and said PLGA copolymer in a container and DMSO in another container. 
     
     
         6 ) The method of  claim 4  further comprising a) dissolving said copolymer in said DMSO to form said polymeric solution and mixing risperidone with said polymeric solution to form said injectable suspension; or b) mixing said copolymer and said risperidone with said DMSO to form said injectable suspension. 
     
     
         7 ) A method of treating schizophrenia or bipolar disorder, the method comprising
 providing a kit comprising a) a first container containing PLGA copolymer and risperidone; and b) a second container containing DMSO;   mixing the contents of said first container and said second container to form an extended release injectable suspension consisting essentially of particles of risperidone suspended in a polymeric solution of said DMSO and said PLGA copolymer, wherein ≥1% wt and ≤20% wt of the risperidone is dissolved in said DMSO or said polymeric solution; and   administering to said subject by intramuscular injection a dose of said suspension comprising 25-150 mg of said risperidone; wherein   after said administering said composition forms an implant in said subject, wherein said implant provides therapeutically effective levels of active moiety, which is risperidone and/or 9-hydroxyrisperidone, from the first day up to at least 28 days after said administering, and wherein said administering is done every 4 to 5 weeks or every 4 weeks.   
     
     
         8 ) The method of  claim 4 , wherein following said administering, supplementary oral daily therapy with risperidone is excluded. 
     
     
         9 ) The method of  claim 4 , wherein 0.5% wt up to 20% wt of said risperidone is released from said implant within 24 hours after said administering. 
     
     
         10 ) The method of  claim 4 , wherein in said subject a substantially level plasma concentration profile for active moiety within ±20% of the average or mean plasma concentration is achieved during a period of at least 14 days following said administering. 
     
     
         11 ) The method of  claim 4 , wherein in said subject a plasma concentration profile for active moiety a) exhibits one, two or more maxima; b) exhibits one, two or more minima; c) exhibits a maximum during the initial one to six days, one to three days, or one to two days after said administering; d) exhibits a maximum during 11 to 13 days or 12 to 14 days after said administering; e) exhibits a maximum during 14 to 24 days of a 4-week dosing period; or f) is within ±20% of the average or mean plasma concentration during the at least 28-day period following said administering. 
     
     
         12 ) The method of  claim 4 , wherein a) an average daily plasma concentration of active moiety that ranges from about 5 ng/ml to about 80 ng/ml is achieved in said subject when about 116 mg to about 700 mg, respectively, of said suspension is administered; or b) an average daily plasma concentration of active moiety that ranges from about 5 ng/ml to about 150 ng/ml or from about 10 ng/ml to about 100 ng/ml in the steady state is achieved in said subject when about 116 to about 700 mg, respectively, of said suspension is administered. 
     
     
         13 ) The method of  claim 4 , wherein a) an average daily Cmin of active moiety in the range of about 1-80 ng/ml, about 5-50 ng/ml, or about 5-40 ng/ml is achieved in said subject when an amount of said suspension equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of risperidone is administered; and/or b) an average daily Cmax of active moiety in the range of about 8-300 ng/ml, about 10-150 ng/ml, or 10-120 ng/ml is achieved in said subject when an amount of said suspension equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of risperidone is administered. 
     
     
         14 ) The method of  claim 4 , wherein following said administering, plasma levels of active moiety in the subject are defined as follows 
       
         
           
                 
                 
                 
               
                     
                 
                   Cmin  
                   Cavg  
                   Cmax  
                 
                   (ng/ml) 
                   (ng/ml) 
                   (ng/ml) 
                 
                     
                 
                   1-80 
                   3-200 
                   8-300 
                 
                     
                 
             
                
                
                
                
               
               
                
                
               
            
           
         
       
     
     
         15 ) The method of  claim 1 , wherein ≥1% wt and ≤20% wt of the risperidone is dissolved in said DMSO or said polymeric solution prior to administration. 
     
     
         16 ) The method of  claim 4 , wherein
 the DMSO to risperidone mass ratio is about 4:1 to 5:1;   the polymeric solution to risperidone mass ratio is about 6.5:1 to 7:1;   the polymeric solution has a viscosity in the range of about 0.7 Pa·s to about 7.0 Pa·s; and   the PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25.   
     
     
         17 ) The method of  claim 4 , wherein a) 0.5% wt up to no more than 8% wt of said risperidone is released within 24 hour; or b) no more than 20% wt, no more than 12% wt, or no more than 8% wt of said risperidone is released within 24 hours, and at least 0.5% wt., at least 2% wt, or at least 3% wt of said risperidone is released within 24 hours. 
     
     
         18 ) The method of  claim 4 , wherein in said subject the plasma concentration profile for said active moiety is within ±15% of the average or mean plasma concentration during the period of at least 14 days following administration of said suspension. 
     
     
         19 ) The method of  claim 1 , wherein 0.5% wt up to 20% wt of said risperidone is released from said implant within 24 hours after said administering. 
     
     
         20 ) The method of  claim 1 , wherein in said subject a substantially level plasma concentration profile for active moiety within ±20% of the average or mean plasma concentration is achieved during a period of at least 14 days following said administering 
     
     
         21 ) The method of  claim 2 , wherein
 the DMSO to risperidone mass ratio is about 4:1 to 5:1;   the polymeric solution to risperidone mass ratio is about 6.5:1 to 7:1;   the polymeric solution has a viscosity in the range of about 0.7 Pa·s to about 7.0 Pa·s; and   the PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25.