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 dosage form which comprises a solid dispersion product comprising a pharmaceutically active ingredient, at least one pharmaceutically acceptable polymer, and at least one pharmaceutically acceptable solubilizer, said 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. 
     
     
         2 . The dosage form of  claim 1 , wherein the pharmaceutically acceptable solubilizer is selected from the group consisting of non-ionic solubilizers, anionic solubilizers and combinations thereof. 
     
     
         3 . The dosage form of  claim 2 , wherein the pharmaceutically acceptable non-ionic 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, and wherein the pharmaceutically acceptable anionic solubilizer is selected from the group consisting of alkyl sulfates, alkylcarboxylates, alkylbenzole sulfates and secondary alkane sulfonates. 
     
     
         4 . The dosage form 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. 
     
     
         5 . The dosage form of  claim 1 , wherein the pharmaceutically acceptable solubilizer comprises at least one of alpha tocopheryl polyethylene glycol succinate, sorbitan monolaurate and polyoxyethylene sorbitan monolaurate. 
     
     
         6 . The dosage form of  claim 2 , comprising at least one pharmaceutically acceptable non-ionic solubilizer and at least one pharmaceutically acceptable anionic solubilizer. 
     
     
         7 . The dosage form of  claim 6 , wherein the pharmaceutically acceptable non-ionic solubilizer is selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters and alpha tocopheryl polyethylene glycol succinate; and the pharmaceutically acceptable anionic solubilizer is sodium laurylsulfate. 
     
     
         8 . The dosage form of  claim 1 , containing a non-volatile solvent for the pharmaceutically active ingredient, said solvent being liquid at ambient temperature. 
     
     
         9 . The dosage form of  claim 8 , wherein said non-volatile solvent is propylene glycol. 
     
     
         10 . The dosage form of  claim 1 , wherein said pharmaceutically acceptable polymer is a homopolymer or copolymer of N-vinyl pyrrolidone. 
     
     
         11 . The dosage form of  claim 1 , wherein said pharmaceutically acceptable polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate. 
     
     
         12 . The dosage form 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. 
     
     
         13 . The dosage form of  claim 1 , containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants. 
     
     
         14 . The dosage form 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 said at least one pharmaceutically acceptable polymer, 2 to 20% by weight of said at least one solubilizer, and 0 to 15% by weight of additives. 
     
     
         15 . The dosage form of  claim 1 , wherein the solid dispersion comprises sulfoxide decomposition products, and further wherein the concentration of sulfoxide decomposition products is less than 1.5% by weight relative to the weight of the active ingredient. 
     
     
         16 . The dosage form of  claim 1 , wherein the solid dispersion comprises sulfoxide decomposition products, and further wherein the concentration of sulfoxide decomposition products is less than 1.2% by weight relative to the weight of the active ingredient. 
     
     
         17 . The dosage form of  claim 1 , wherein the solid dispersion comprises sulfoxide decomposition products, and further wherein the concentration of sulfoxide decomposition products is less than 0.9% by weight relative to the weight of the active ingredient. 
     
     
         18 . The dosage form of  claim 1 , wherein the solid dispersion product is a melt-processed, solidified mixture. 
     
     
         19 . A method for treating a proliferative disorder, comprising administering the dosage form of  claim 1  to a subject in need thereof. 
     
     
         20 . The method of  claim 19 , wherein the proliferative disorder is selected from tumors and cancers. 
     
     
         21 . The method of  claim 20 , wherein the proliferative disorder is selected from the group consisting of mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, cervical cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal and duodenal) cancer, chronic lymphocytic leukemia, acute lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular cancer (hepatic and biliary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, ovarian cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non-Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, and combinations thereof. 
     
     
         22 . A process for preparing a solid dosage form of  claim 1 , 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.   
     
     
         23 . The process of  claim 22 , further comprising grinding said solid dispersion product and compressing said solid dispersion product into a tablet. 
     
     
         24 . The process of  claim 22 , further comprising grinding said solid dispersion product and filling said solid dispersion product into a capsule shell.