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 pharmaceutical composition comprising (a) 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 pharmaceutically acceptable salt, hydrate, or solvate thereof and (b) a JAK2 inhibitor, a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         2 . The pharmaceutical composition of  claim 1  further comprising a pharmaceutically acceptable excipient. 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein the JAK2 inhibitor is selected from the group consistent of CEP-701 (lesaurtinib), XL019, INCB-018424, and any combination thereof. 
     
     
         4 . A pharmaceutical dosage form 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, a salt, a hydrate, or a solvate thereof;   at least one pharmaceutically acceptable polymer comprising a copolymer of N-vinyl pyrrolidone;   a single pharmaceutically acceptable solubilizer, said single pharmaceutically acceptable solubilizer being a tocopheryl compound having a polyalkylene glycol moiety;   wherein the 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, a hydrate, or a solvate thereof is dispersed within a solid dispersion product in a concentration from 0.5 to 40% by weight, the solid dispersion product further comprising from 40 to 97.5% by weight of the at least one pharmaceutically acceptable polymer and from 2 to 20% by weight of the single pharmaceutically acceptable solubilizer.   
     
     
         5 . A method for treating a proliferative disorder, comprising administering the dosage form of  claim 4  to a subject in need thereof. 
     
     
         6 . A process for preparing a solid dosage form of  claim 4 , comprising: (a) preparing a homogeneous melt of the pharmaceutically active ingredient or a salt, hydrate or solvate thereof, the at least one pharmaceutically acceptable polymer and the at least one solubilizer, and (b) allowing the melt to solidify to obtain a solid dispersion product. 
     
     
         7 . A pharmaceutical product comprising (a) a first pharmaceutical composition 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof, and (b) a second pharmaceutical composition comprising a JAK2 inhibitor, a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         8 . The pharmaceutical product of  claim 7  wherein the first pharmaceutical composition further comprises a pharmaceutically acceptable excipient. 
     
     
         9 . The pharmaceutical product of  claim 7  wherein the second pharmaceutical composition further comprises a pharmaceutically acceptable excipient. 
     
     
         10 . The pharmaceutical product of  claim 7  wherein the first pharmaceutical composition and the second pharmaceutical composition are the same. 
     
     
         11 . The pharmaceutical product of  claim 7  wherein the JAK2 inhibitor is selected from the group consistent of CEP-701 (lesaurtinib), XL019, INCB-018424, and any combination thereof. 
     
     
         12 . A combination of therapeutic agents for use in treating a patient having a proliferative disorder, wherein said combination comprises (a) a therapeutically effective amount 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof and (b) a therapeutically effective amount of a JAK2 inhibitor, a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         13 . A solid dispersion product consisting of:
 from 0.5 to 40% by weight of a pharmaceutically active ingredient being 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;   from 40 to 97.5% by weight of at least one pharmaceutically acceptable polymer being a copolymer of N-vinyl pyrrolidone;   from 2 to 20% by weight of a single pharmaceutically acceptable solubilizer being a tocopheryl compound having a polyalkylene glycol moiety;   from 2% to 10% by weight of a non-volatile solvent for the pharmaceutically active ingredient, said solvent being a liquid at ambient temperature and ambient pressure; and   colloidal silicon dioxide.   
     
     
         14 . A method of treating a proliferative disorder comprising administering to a patient in need of treatment a combination of (a) a therapeutically effective amount 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof and (b) a therapeutically effective amount of a JAK2 inhibitor, a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         15 . The method of  claim 14  comprising administering a pharmaceutical dosage form comprising from about 0.5 to 40% by weight 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         16 . The method of  claim 15  wherein the pharmaceutical dosage form further comprises:
 from about 40 to 97.5% by weight of at at least one pharmaceutically acceptable polymer; and 
 from about 2 to 20% by weight of at least one solubilizer. 
 
     
     
         17 . The method of  claim 14  wherein the therapeutically effective amount 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof is between about 50 mg to about 1000 mg. 
     
     
         18 . The method of  claim 14  wherein the therapeutically effective amount 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof is between about 100 mg to about 500 mg. 
     
     
         19 . The method of  claim 14  wherein the therapeutically effective amount 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof is about 200 mg, administered to a mammalian subject. 
     
     
         20 . A pharmaceutical dosage form consisting of:
 a solid dispersion product consisting of from 0.5 to 40% by weight of a pharmaceutically active ingredient being 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; from 40 to 97.5% by weight of at least one pharmaceutically acceptable polymer being a copolymer of N-vinyl pyrrolidone; from 2 to 20% by weight of a single pharmaceutically acceptable solubilizer being a tocopheryl compound having a polyalkylene glycol moiety; from 2% to 10% by weight of a non-volatile solvent for the pharmaceutically active ingredient, said solvent being a liquid at ambient temperature and ambient pressure; and colloidal silicon dioxide;   a disintegrant;   a bulking agent;   a flow regulator; and   a lubricant.   
     
     
         21 . A kit for use in the treatment of a patient having a proliferative disorder, the kit comprising (a) a therapeutically effective amount 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, a pharmaceutically acceptable salt, hydrate, or solvate thereof and (b) a therapeutically effective amount of a JAK2 inhibitor, a pharmaceutically acceptable salt, hydrate, or solvate thereof.