Pharmaceutical composition

Abstract

The invention concerns pharmaceutical compositions containing a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide and solvates, crystalline forms and amorphous forms thereof, to the use of said compositions as a medicament; and to processes for the preparation of said compositions.

1 - 38 . (canceled) 
     
     
         39 . A pharmaceutical composition comprising a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide, and a carrier matrix, wherein the carrier matrix consists essentially of one or more pharmaceutically acceptable carriers selected from the following groups:
 (a) d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS);   (b) polyglycolised glycerides; and   (c) polyethylene glycols;   
       and wherein the hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is dispersed within the carrier matrix. 
     
     
         40 . The pharmaceutical composition according to  claim 39 , wherein the carrier matrix consists essentially of one or both of the following:
 (a) d-alpha-tocopher polyethylene glycol 1000 succinate; and   (b) polyglycolised glycerides.   
     
     
         41 . The pharmaceutical composition according to  claim 39 , wherein the carrier matrix is d-alpha-tocopheryl polyethylene glycol 1000 succinate or Lauroyl Macrogol-32 Glycerides. 
     
     
         42 . The pharmaceutical composition according to  claim 39 , wherein the carrier matrix is a mixture of d-alpha-tocopheryl polyethylene glycol 1000 succinate and Lauroyl Macrogol-32 Glycerides and wherein the Lauroyl Macrogol-32 Glycerides are present in an amount to make up approximately 30-55% by weight of the carrier matrix component of the composition. 
     
     
         43 . The pharmaceutical composition according to  claim 39 , wherein the carrier matrix is d-alpha-tocopheryl polyethylene glycol 1000 succinate. 
     
     
         44 . The pharmaceutical composition according to  claim 43 , wherein the d-alpha-tocopheryl polyethylene glycol 1000 succinate is present in an amount to make up approximately 65 to 95% by weight of the composition. 
     
     
         45 . The pharmaceutical composition according to  claim 39 , wherein greater than 90% by weight of the total amount of the hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide present in the composition is dispersed within the carrier matrix. 
     
     
         46 . The pharmaceutical composition according to  claim 39 , wherein the composition contains between 5 to 30% by weight of the hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide. 
     
     
         47 . The pharmaceutical composition according to  claim 39 , wherein the composition is semi-solid or solid at ambient temperature. 
     
     
         48 . The pharmaceutical composition according to  claim 39 , wherein the hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is dispersed in the form of finely divided particles that are distributed throughout the phase comprising the carrier matrix. 
     
     
         49 . The pharmaceutical composition according to  claim 39 , comprising:
 (i) from 15 to 25 parts of a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; and   (ii) from 75 to 85 parts of d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS);   
       wherein both parts are by weight and the sum of the parts (i)+(ii)=100; 
       and wherein the hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is dispersed within the Vitamin E TPGS and the composition is semi-solid or solid at ambient temperature. 
     
     
         50 . The pharmaceutical composition according to  claim 39 , comprising:
 (i) from 18 to 22 parts of a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; and   (ii) from 78 to 82 parts of d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS);   
       wherein both parts are by weight and the sum of the parts (i)+(ii)=100; 
       and wherein the hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is dispersed within the Vitamin E TPGS and the composition is semi-solid or solid at ambient temperature. 
     
     
         51 . The pharmaceutical composition according to  claim 39 , comprising:
 (i) 19-21 parts of hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; and   (ii) 79-81 parts of d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS);   
       wherein both parts are by weight and the sum of the parts (i)+(ii)=100; 
       and wherein the hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is dispersed within the Vitamin E TPGS and the composition is semi-solid or solid at ambient temperature. 
     
     
         52 . The pharmaceutical composition according to  claim 39 , wherein the composition contains 30.25+/−2 mg of a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide. 
     
     
         53 . The pharmaceutical composition according to  claim 39 , wherein the composition contains 12.1+/−2 mg of a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide. 
     
     
         54 . The pharmaceutical composition according to  claim 39 , wherein the composition is an oral capsule composition. 
     
     
         55 . A process for the preparation of a pharmaceutical composition according to  claim 39  comprising the steps of:
 (a) Mixing and melting the components of the carrier matrix; 
 (b) Mixing a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide into the carrier matrix in order to obtain a homogenous mixture; and 
 (c) Filling the product of step (b) into a capsule and allowing the mixture to cool to form a viscous liquid, semi-solid or solid mass within the capsule. 
 
     
     
         56 . A method of treating a condition treatable with a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide comprising administering a pharmaceutical composition according to  claim 39  to a subject in need thereof. 
     
     
         57 . The method of  claim 56 , wherein the condition is cancer. 
     
     
         58 . The method of  claim 57 , wherein the cancer is malignant melanoma, brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological or thyroid cancer. 
     
     
         59 . The method of  claim 57 , wherein the cancer is lung cancer. 
     
     
         60 . The method of  claim 57 , wherein the cancer thyroid cancer. 
     
     
         61 . The method of  claim 57 , wherein the cancer malignant melanoma. 
     
     
         62 . The method of  claim 57 , further comprising administering the composition in combination with taxotere. 
     
     
         63 . The method of  claim 57 , further comprising administering the composition in combination with an alkylating agent.