Sustained release pharmaceutical compositions

Abstract

The present invention provides controlled release dosage formulations of compounds having the Formula: or pharmaceutically acceptable salts thereof, and in particular, aplindore. The dosage forms are useful, inter alia, for reducing side effects from administration of such compounds.

1 . A controlled release oral dosage formulation comprising:
 about 0.05 mg to about 10 mg aplindore, or a pharmaceutically acceptable salt thereof;   about 0% to about 1.4% lubricant;   about 10% to 40% saccharide-based diluent;   one or more release-rate controlling polymers or release-retarding materials selected from the group consisting of:
 about 10% to about 60% wax matrix; 
 about 5% to about 40% polyethylene oxide matrix; 
 about 15% to about 80% hydroxypropyl methyl cellulose; 
   wherein the aplindore, or the pharmaceutically acceptable salt thereof, is released at a rate effective to provide:   a C max  that about 4,000 pg/mL to about 14,000 pg/mL;   a T max  of about 1.5 hours to about 6.3 hours;   an AUC 0-12  of about 36,000 pg*h/mL to about 109,000 pg*h/mL; and   wherein the controlled release oral dosage formulation comprises a tablet, an encapsulated dosage form, one or more microparticles, powder, or a combination thereof.   
     
     
         2 . The controlled release oral dosage formulation of  claim 1 , wherein the aplindore, or the pharmaceutically acceptable salt thereof, is released at a rate effective to provide a C max  that is less than about 0.60 times a C max  of an instant release formulation. 
     
     
         3 . The controlled release oral dosage formulation of  claim 1 , wherein the aplindore, or the pharmaceutically acceptable salt thereof, is released at a rate effective to provide a C max  that is less than about 0.50 times a C max  of an instant release formulation. 
     
     
         4 . The controlled release oral dosage formulation of  claim 1 , wherein the aplindore, or the pharmaceutically acceptable salt thereof, is released at a rate effective to provide a C max  that is less than about 0.40 times a C max  of an instant release formulation. 
     
     
         5 . The controlled release oral dosage formulation of  claim 1 , wherein the aplindore, or the pharmaceutically acceptable salt thereof, is released at a rate to provide an AUC 0-12  of at least about 1.05 times that of the instant release formulation. 
     
     
         6 . The controlled release oral dosage formulation of  claim 1 , wherein the aplindore, or the pharmaceutically acceptable salt thereof, is released at a rate to provide an AUC 0-12  of at least about 1.1 times that of the instant release formulation. 
     
     
         7 . The controlled release oral dosage formulation of  claim 1 , wherein the aplindore, or the pharmaceutically acceptable salt thereof, is released at a rate to provide an AUC 0-12  of at least about 1.2 times that of the instant release formulation. 
     
     
         8 . The controlled release oral dosage formulation of  claim 1 , wherein said about 15% to about 80% hydroxypropylmethyl cellulose is comprised of: about 30% to about 60% low-viscosity hydroxypropyl methyl cellulose, and about 30% to about 60% high-viscosity hydroxypropylmethyl cellulose. 
     
     
         9 . The controlled release oral dosage formulation of  claim 8 , wherein said high viscosity hydroxypropylmethyl cellulose has a viscosity of about 2,663 mPa·s to about 4,970 mPa·S; and wherein said low viscosity hydroxypropylmethyl cellulose has a viscosity of about 80 mPa·S to about 120 mPa·s·s. 
     
     
         10 . The controlled release oral dosage formulation of  claim 1 , containing about 5 mg of aplindore, or a pharmaceutically acceptable salt thereof, which provides a Cmax from about 4000 pg/mL to about 14000 pg/mL. 
     
     
         11 . The controlled release oral dosage formulation of  claim 10 , wherein said C max  is from about 6000 pg/mL to about 12000 pg/mL. 
     
     
         12 . The controlled release oral dosage formulation of  claim 5 , containing about 5 mg of aplindore, or a pharmaceutically acceptable salt thereof, which provides an AUC 0-12  from about 36000 pg*h/mL to about 109000 pg*h/mL. 
     
     
         13 . The controlled release oral dosage formulation of  claim 12 , wherein said AUC 0-12  is from about 36000 pg*h/mL to about 75000 pg*h/mL. 
     
     
         14 . The controlled release oral dosage formulation of  claim 1 , wherein the pharmaceutically acceptable salt is aplindore fumarate. 
     
     
         15 . The controlled release oral dosage formulation of  claim 1 , containing from about 0.05 mg to about 10 mg of aplindore free base added as fumarate salt. 
     
     
         16 . The controlled release oral dosage formulation of  claim 15 , containing 0.05, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, or 10 milligrams of aplindore free base, added as fumarate salt. 
     
     
         17 . The controlled release oral dosage formulation of  claim 15 , containing 0.05, 0.2, 0.5, 2, or 5 milligrams of aplindore free base, added as fumarate salt. 
     
     
         18 . A method of treating a disorder of the dopaminergic system comprising administering to a patient in need of such treatment an effective amount of a controlled release oral dosage formulation according to  claim 1 . 
     
     
         19 . A method of treating a disorder of the dopaminergic system comprising administering to a patient in need of such treatment the unit dosage form of  claim 15 . 
     
     
         20 . A method of treating a disorder of the dopaminergic system comprising administering to a patient in need of such treatment the unit dosage form of  claim 17 . 
     
     
         21 .- 41 . (canceled)