Pharmaceutical dosage form for oral administration of a bcl 2 family inhibitor

Abstract

The invention relates to a pharmaceutical dosage form which comprises a solid dispersion product comprising N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or a salt, hydrate or solvate thereof, at least one pharmaceutically acceptable polymer, and at least one pharmaceutically acceptable solubilizer. The invention is further directed to processes for preparing the pharmaceutical dosage form and to use of the dosage form for treating proliferative disorders

What is claimed is: 
     
         1 . A process for preparing a pharmaceutical dosage form, comprising:
 (a) preparing a homogeneous melt comprising a pharmaceutically active ingredient or a salt, hydrate, or solvate thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable solubilizer, wherein said pharmaceutically active ingredient is N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a salt, hydrate, or solvate thereof; and   (b) allowing the homogenous melt to solidify to obtain a solid dispersion product.   
     
     
         2 . The process of  claim 1 , wherein the homogeneous melt is prepared by melting the pharmaceutically active ingredient or the salt, hydrate, or solvate thereof, the pharmaceutically acceptable polymer, and the pharmaceutically acceptable solubilizer at a melt temperature between about 70° C. and about 250° C. 
     
     
         3 . The process of  claim 1 , wherein the homogeneous melt is prepared by melting the pharmaceutically active ingredient or the salt, hydrate, or solvate thereof, the pharmaceutically acceptable polymer, and the pharmaceutically acceptable solubilizer at a melt temperature between about 80° C. and about 180° C. 
     
     
         4 . The process of  claim 1 , wherein the homogeneous melt is prepared by melting the pharmaceutically active ingredient or the salt, hydrate, or solvate thereof, the pharmaceutically acceptable polymer, and the pharmaceutically acceptable solubilizer at a melt temperature between about 100° C. and about 140° C. 
     
     
         5 . The process of  claim 1 , wherein the pharmaceutically active ingredient or the salt, hydrate, or solvate thereof, the pharmaceutically acceptable polymer, and the pharmaceutically acceptable solubilizer are contacted with a solvent selected from the group consisting of alcohols, aliphatic hydrocarbons, esters, and liquid carbon dioxide before preparing the homogeneous melt. 
     
     
         6 . The process of  claim 1 , wherein the homogenous melt further comprises a non-volatile solvent for the pharmaceutically active ingredient, said solvent being liquid at ambient temperature. 
     
     
         7 . The process of  claim 6 , wherein said non-volatile solvent is propylene glycol. 
     
     
         8 . The process of  claim 1 , wherein the homogenous melt further comprises an additive selected from flow regulators, disintegrants, bulking agents, plasticizers, stabilizers, radical scavengers, and lubricants. 
     
     
         9 . The process of  claim 1 , further comprising extruding the homogenous melt. 
     
     
         10 . The process of  claim 9 , wherein the homogenous melt is extruded at a temperature between about 100° C. and about 140° C. 
     
     
         11 . The process of  claim 1 , further comprising:
 grinding said solid dispersion product; and   compressing said solid dispersion product into a tablet, to thereby prepare the pharmaceutical dosage form.   
     
     
         12 . The process of  claim 1 , further comprising:
 grinding said solid dispersion product; and   filling said solid dispersion product into a capsule shell, to thereby prepare the pharmaceutical dosage form.   
     
     
         13 . The process of  claim 1 , wherein said pharmaceutically active ingredient is selected from the group consisting of the free base, the sodium salt and the dihydrochloride salt of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, and combinations thereof. 
     
     
         14 . The process of  claim 1 , wherein the pharmaceutically acceptable solubilizer is selected from the group consisting of polyol fatty acid esters, polyalkoxylated polyol fatty acid esters, polyalkoxylated fatty alcohol ethers, tocopheryl compounds, and mixtures of two or more thereof. 
     
     
         15 . The process of  claim 1 , wherein the pharmaceutically acceptable solubilizer is selected from the group consisting of tocopheryl compounds having a polyalkylene glycol moiety, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. 
     
     
         16 . The process of  claim 1 , wherein the pharmaceutically acceptable solubilizer comprises at least one of alpha tocopheryl polyethylene glycol succinate, sorbitan monolaurate and polyoxyethylene sorbitan monolaurate. 
     
     
         17 . The process of  claim 1 , wherein the pharmaceutically acceptable solubilizer is selected from the group consisting of alkyl sulfates, alkylcarboxylates, alkylbenzole sulfates, and secondary alkane sulfonates. 
     
     
         18 . The process of  claim 1 , wherein the pharmaceutically acceptable solubilizer is sodium laurylsulfate. 
     
     
         19 . The process of  claim 1 , wherein said pharmaceutically acceptable polymer is a homopolymer or copolymer of N-vinyl pyrrolidone. 
     
     
         20 . The process of  claim 1 , wherein said pharmaceutically acceptable polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate. 
     
     
         21 . The process of  claim 1 , wherein the solid dispersion product comprises from about 0.5 to 40% by weight of the pharmaceutically active ingredient, 40 to 97.5% by weight of the pharmaceutically acceptable polymer, 2 to 20% by weight of the solubilizer, and optionally additives in a concentration up to 15% by weight of the solid dispersion product.