Multiparticulate controlled release selective serotonin reuptake inhibitor formulations

Abstract

A multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) formulation for oral administration comprises particles of said SSRI or a pharmaceutically acceptable salt thereof coated with rate-controlling polymer which allows controlled release of said SSRI, over a period of not less than about 12 hours following oral administration. The formulation, which contains for example fluvoxamine or a pharmaceutically acceptable salt thereof, is suitable for once or twice daily administration. The formulation can comprise a blend of two or more populations of particles, pellets or mini-tablets having different in vitro and/or in vivo release characteristics.

1 - 19 . (canceled) 
     
     
         20 . A multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising particles, each of the particles comprising:
 (i) an inert non-pareil core,   (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and   (iii) a rate-controlling membrane coating disposed over the SSRI layer,   wherein the fluvoxamine is released over a period of about 12 hours or more following oral administration.   
     
     
         21 . The composition according to  claim 20 , wherein the particles comprise a first and a second quantity of particles. 
     
     
         22 . The composition of  claim 21 , wherein the first quantity of particles is defined by a first amount of rate-controlling membrane coating disposed over the SSRI layer and the second quantity of particles is defined by a second amount of rate-controlling membrane coating disposed over the SSRI layer, wherein the first amount is different from the second amount. 
     
     
         23 . The composition according to  claim 21 , wherein the rate-controlling membrane coating comprises a mixture of pharmaceutically acceptable film-forming, water-insoluble polymers in a selected ratio effective to permit the controlled release of the fluvoxamine over a period of about 12 hours or more following oral administration. 
     
     
         24 . The composition according to  claim 21 , wherein the rate-controlling membrane coating is an acrylic resin comprising copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, or the rate-controlling membrane coating is a polymeric lacquer substances based on acrylate and/or methacrylates. 
     
     
         25 . The composition according to  claim 24 , wherein the rate-controlling membrane coating is a polymeric lacquer. 
     
     
         26 . The composition according to  claim 24 , wherein the rate-controlling membrane coating is a mixture of the acrylic resin and the polymeric lacquer. 
     
     
         27 . The composition according to  claim 21 , wherein the SSRI layer further comprises an organic acid, and the fluvoxamine and the organic acid are present in a ratio of about 50:1 to about 1:50. 
     
     
         28 . The composition according to  claim 21 , wherein the rate-controlling membrane coating is fluvoxamine-permeable. 
     
     
         29 . The composition according to  claim 21 , wherein the rate-controlling membrane coating is fluvoxamine-permeable and water soluble. 
     
     
         30 . The composition according to  claim 21 , wherein the rate controlling membrane coating is fluvoxamine-permeable and water insoluble. 
     
     
         31 . The composition according to  claim 21 , wherein the composition for oral administration is in a form of a multiparticulate-filled capsule or a tablet. 
     
     
         32 . A composition according to  claim 21 , wherein the rate-controlling membrane coating comprises an acrylic resin copolymer of acrylic and methacrylic acid esters with quaternary ammonium groups having 12.5% polymer solids and dibutyl sebacate. 
     
     
         33 . The composition of  claim 20 , wherein following a single oral administration of the composition to a patient, the composition releases the fluvoxamine over a period of about 12 hours or more and achieves an (AUC 0-4 ) of about 128 to about 1,175 ng/ml.h, of fluvoxamine in the blood serum of the patient. 
     
     
         34 . The composition of  claim 20 , wherein the rate-controlling membrane coating comprises the polymeric lacquer and a plasticizer, the combined amount of the polymeric lacquer and the plasticizer in the coating is from about 4% to about 15% of the weight of the particle. 
     
     
         35 . The composition of  claim 34 , wherein the combined amount of the polymeric lacquer and plasticizer in the coating of the first and/or second quantity of particles is in an amount of about 4%, 6%, 8%, 10%, 12%, or 15% of the weight of the particle. 
     
     
         36 . A method for the treatment of depression or obsessive compulsive disorder treatable with an SSRI, comprising administering to a patient suffering from one of the conditions a therapeutically effective amount of a multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising particles, each of the particles comprising:
 (i) an inert non-pareil core,   (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and   (iii) a coating of a rate-controlling acrylic resin, a rate-controlling methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine,   wherein the fluvoxamine is released over a period of not less than about 12 hours following oral administration.   
     
     
         37 . A fluvoxamine containing unit dose formulation comprising particles, each of the particles comprising:
 (i) an inert non-pareil core,   (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and   (iii) a rate-controlling membrane coating disposed over the SSRI layer,
 wherein following a single oral administration of the unit dose to the patient, the formulation releases the fluvoxamine over a period of about 12 hours or more and achieves an (AUCO 4 ) of about 128 to about 1,175 ng/ml.h, of fluvoxamine in the blood serum of the patient.