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 dosage formulation comprising a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  and R 2  are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl;  
 or R 1  and R 2 , taken together, are benzylidene optionally substituted with R 3  as defined below or alkylidene of up to 6 carbon atoms;  
 or R 1  and R 2 , taken together with the carbon to which they are attached, form a carbonyl moiety or a cycloalkyl group having three to 6 carbon atoms;  
 R 3  is hydrogen, hydroxy, halo, trifluoromethyl, trifluoromethoxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, arylalkoxy of 7 to 12 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms or alkanesulfonamido of 1 to 6 carbon atoms;  
 R 4  is hydrogen or alkyl of 1 to 6 carbon atoms;  
 n is one of the integers 0, 1, 2, 3, 4, 5, or 6;  
 Z is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, polycyclic alkyl of 7 to 15 carbon atoms, phenyl optionally substituted with R 3  as defined above, phenoxy optionally substituted with R 3  as defined above, naphthyl optionally substituted with R 3  as defined above or naphthyloxy optionally substituted with R 3  as defined above, heteroaryl or heteroaryloxy, in which the heterocyclic ring of the heteroaryl or heteroaryloxy group is selected from thiophene, furan, pyridine, pyrazine, pyrimidine, indole, indazole, imidazole, chroman, coumarin, carbostyril, quinoline, benzisoxazole, benzoxazole, pyrazole, pyrrole, thiazole, oxazole, or isoxazole and the heterocyclic ring is optionally substituted by R 3  as defined above;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The controlled release formulation of  claim 1  wherein said compound is 2-[(Benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one, or a pharmaceutically acceptable salt thereof.  
     
     
         3 . The controlled release formulation of  claim 1  wherein said compound has the formula S-2-[(Benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one,  
       or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The controlled release dosage formulation of  claim 3  wherein said formulation is an oral dosage formulation.  
     
     
         5 . The oral controlled release dosage formulation of  claim 4  further comprising one or more release rate controlling polymers.  
     
     
         6 . The oral controlled release dosage formulation of  claim 5  wherein said release rate controlling polymer comprises polymethacrylates, methacrylic acid-methacrylic acid ester copolymers, cellulose acetate phthalate, ethyl cellulose, polyvinyl acetate-phthalate, hydroxypropyl methyl cellulose phthalate, or combinations of two or more thereof.  
     
     
         7 . The oral controlled release dosage formulation of  claim 6  wherein said release rate controlling polymer is high viscosity matrix forming hydroxypropyl methyl celluloses, low viscosity matrix forming hydroxypropyl methyl celluloses or combinations thereof.  
     
     
         8 . The oral controlled release dosage formulation of  claim 7  wherein said high viscosity matrix forming hydroxypropyl methyl celluloses is Methocel K4M, Methocel K15M, Methocel K100M, Methocel E4M or combinations thereof.  
     
     
         9 . The oral controlled release dosage formulation of  claim 8  wherein said high viscosity matrix forming hydroxypropyl methylcellulose is Methocel K4M.  
     
     
         10 . The oral controlled release dosage formulation of  claim 9  wherein said high viscosity matrix forming hydroxypropyl methylcellulose comprises Methocel K4M in an amount by weight of about 15% to about 80%.  
     
     
         11 . The oral controlled release dosage formulation of  claim 9  wherein said high viscosity hydroxypropyl methyl cellulose comprises Methocel K4M in an amount by weight of about 25% to about 50%.  
     
     
         12 . The oral controlled release dosage formulation of  claim 7  wherein said low viscosity matrix forming polymer is a hydroxypropyl methylcellulose selected from Methocel K100LV, Methocel E50LV, Methocel E5, Methocel E15LV or a combination of two or more thereof.  
     
     
         13 . The oral controlled release dosage formulation of  claim 12  wherein said low viscosity matrix forming hydroxypropyl methyl cellulose is Methocel K100LV.  
     
     
         14 . The oral controlled release dosage formulation of  claim 13  wherein said low viscosity matrix forming hydroxypropyl methyl cellulose is present in an amount by weight of about 15% to about 80%.  
     
     
         15 . The oral controlled release dosage formulation of  claim 13  wherein said low viscosity matrix forming hydroxypropyl methyl cellulose is present in an amount by weight of from about 20% to about 50%.  
     
     
         16 . The oral controlled release dosage formulation of  claim 5  further comprising: 
 a high viscosity matrix forming hydroxypropyl methyl cellulose in an amount of about 20% to about 60% by weight; and  
 a low viscosity matrix forming hydroxypropyl methyl cellulose in an amount of about 20% to about 60% by weight.  
 
     
     
         17 . The oral controlled release dosage formulation of  claim 4  comprising: 
 a pharmaceutically effective amount of said aplindore or a pharmaceutically acceptable salt thereof;  
 a water soluble compensating excipient in an amount of from about 0.5% to about 5% by weight;  
 a water dispersible excipient in an amount of from about 5% to about 30% by weight;  
 a matrix forming hydroxypropyl methyl cellulose in an amount of from about 20% to about 80% by weight; and  
 a lubricant in an amount of from about 0.1% to about 1% by weight.  
 
     
     
         18 . The oral controlled release dosage formulation of  claim 4  comprising: 
 a pharmaceutically effective amount of said aplindore or a pharmaceutically acceptable salt thereof;  
 a water soluble compensating excipient in an amount of from about 0.5% to about 5% by weight;  
 a water dispersible excipient in an amount of from about 5% to about 30% by weight;  
 a matrix forming hydroxypropyl methyl cellulose in an amount of from about 25% to about 50% by weight; and  
 a lubricant in an amount of from about 0.1% to about 1% by weight.  
 
     
     
         19 . The oral controlled release dosage formulation according to  claim 17  in which the matrix forming hydroxypropyl methyl cellulose is a high viscosity hydroxypropyl methyl cellulose, low viscosity hydroxypropyl methyl cellulose or combination thereof.  
     
     
         20 . The oral controlled release dosage formulation of  claim 6  wherein said compound is present in an amount of from about 0.02% to about 16% by weight of said formulation.  
     
     
         21 . The oral controlled release dosage formulation of  claim 6  wherein said compound is present in an amount of from about 0.02% to about 4% by weight of said formulation.  
     
     
         22 . A method of treating a disorder of the dopaminergic system comprising administering to a patient in need of such treatment a controlled release dosage formulation according to  claim 1 .  
     
     
         23 . A method of treating a disorder of the dopaminergic system comprising administering to a patient in need of such treatment a controlled release dosage formulation according to  claim 20 .  
     
     
         24 . The oral controlled release dosage formulation of  claim 5  wherein said compound is released from said dosage form at a rate to provide a T max  that is at least about 1.5 times greater than a T max  of an instant release formulation containing said compound.  
     
     
         25 . The oral controlled release dosage formulation of  claim 5  wherein said compound is released from said dosage form at a rate to provide a T max  that is at least about 2 times greater than a T max  of an instant release formulation containing said compound.  
     
     
         26 . The oral controlled release dosage formulation of  claim 5  wherein said compound is released from said dosage form at a rate to provide a C max  that is less than a C max  of an instant release formulation containing said compound.  
     
     
         27 . The oral controlled release dosage formulation of  claim 5  wherein said compound is released from said dosage form at a rate to provide a C max  that is less than about 0.75 times a C max  of an instant release formulation containing said compound.  
     
     
         28 . The oral controlled release dosage formulation of  claim 5  wherein said compound is released from said dosage form at a rate effective to provide an AUC 0-12  that is at least about 1.05 times an AUC 0-12  of an instant release formulation containing said compound.  
     
     
         29 . The oral controlled release dosage formulation of  claim 5  wherein said compound is released from said dosage form at a rate effective to provide an AUC 0-12  that is at least about 1.10 times an AUC 0-12  of an instant release formulation containing said compound.  
     
     
         30 . The controlled release dosage formulation of  claim 1  containing about 0.1 mg of said compound which provides an AUC 0-12  from about 260 pg*h/mL to about 2400 pg*h/mL.  
     
     
         31 . The controlled release dosage formulation of  claim 30  wherein said AUC 0-12  is from about 290 pg*h/mL to about 1300 pg*h/mL.  
     
     
         32 . The controlled release dosage formulation of  claim 1  containing about 0.1 mg of said compound which provides a C max  from about 40 pg/mL to about 190 pg/mL.  
     
     
         33 . The controlled release dosage formulation of  claim 32  wherein said C max  is from about 40 pg/mL to about 180 pg/mL.  
     
     
         34 . The controlled release dosage formulation of  claim 1  containing about 5 mg of said compound which provides an AUC 0-12  from about 36000 pg*h/mL to about 109000 pg*h/mL.  
     
     
         35 . The controlled release dosage formulation of  claim 34  wherein said AUC 0-12  is from about 36000 pg*h/mL to about 75000 pg*h/mL.  
     
     
         36 . The controlled release dosage formulation of  claim 1  containing about 5 mg of said compound which provides a C max  from about 4000 pg/mL to about 14000 pg/mL.  
     
     
         37 . The controlled release dosage formulation of  claim 36  wherein said C max  is from about 6000 pg/mL to about 12000 pg/mL.  
     
     
         38 . The controlled release dosage formulation of  claim 1  containing about 30 mg of said compound which provides an AUC 0-12  from about 121000 pg*h/mL to about 890000 pg*h/mL.  
     
     
         39 . The controlled release dosage formulation of  claim 38  wherein said AUC 0-12  is from about 170000 pg*h/mL to about 760000 pg*h/mL.  
     
     
         40 . The controlled release dosage formulation of  claim 1  containing about 30 mg of said compound which provides a C max  from about 18000 pg/mL to about 110000 pg/mL.  
     
     
         41 . A controlled release dosage formulation of  claim 40  wherein said C max  is from about 20000 pg/mL to about 92000 pg/mL.  
     
     
         42 . A set of controlled release dosage forms, comprising a plurality of individual controlled release dosage forms, wherein two or more of said individual dosage forms comprise different amounts of said compound of  claim 1 .  
     
     
         43 . The set of controlled release dosage forms of  claim 42  wherein at least one of said individual controlled release dosage forms comprises from about 0.05 to about 0.4 mg of said compound of  claim 1 .  
     
     
         44 . The set of controlled release dosage forms of  claim 42  wherein two or more of said individual controlled release dosage forms are selected from 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8, mg, 10 mg, 11 mg, 12 mg, 13mg, 14 mg, 15 mg, 16 mg, 17 mg, 20 mg, 23 mg, 24 mg, 25 mg 26 mg, or 30 mg of said compound.  
     
     
         45 . The set of  claim 42  wherein the two or more different individual controlled release dosage forms contain different amounts of said compound in amounts differing by at least ten percent, and wherein the amount of said compound in the two or more different individual controlled release dosage forms ranges from about 0.05 mg to about 30 mg.  
     
     
         46 . The set of  claim 45  wherein the two or more different individual dosage forms provides an AUC 0-12  ranging from about 260 pg*h/mL to about 890000 pg*h/m L.  
     
     
         47 . A method of administering 2-[(benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one or a pharmaceutically acceptable salt thereof comprising: 
 a) administering to a mammal in need thereof a starting controlled release dosage formulation comprising 2-[(benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one or a pharmaceutically acceptable salt thereof; and thereafter    b) administering to the mammal at least one other controlled release dosage formulation comprising 2-[(benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one or a pharmaceutically acceptable salt thereof, wherein the starting controlled release dosage formulation contains a lesser amount of 2-[(benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one relative to the other controlled release dosage formulation.    
     
     
         48 . A controlled release dosage formulation comprising 2-[(benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one or a pharmaceutically acceptable salt thereof wherein the 2-[(benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one is present in the formulation in an amount to provide an AUC 0-12  ranging from about 260 pg*h/mL to about 890000 pg*h/mL upon administration to a mammal.  
     
     
         49 . The controlled release dosage formulation of  claim 48  wherein the formulation comprises a single unit dosage form or multiple unit dosage forms.