Controlled release pharmaceutical compositions comprising a fumaric acid ester

Abstract

The present invention relates to controlled release pharmaceutical compositions comprising fumaric acid ester(s) as active substance(s). The compositions are suitable for use in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designated to release the fumaric acid ester in a controlled manner so that local high concentrations of the active substance within the gastrointestinal tract upon oral administration can be avoided and, thereby, enabling a reduction in gastro-intestinal related side-effects.

1 .- 45 . (canceled) 
     
     
         46 . A pharmaceutical dosage form which comprises an active ingredient selected from the group consisting of dimethyl fumarate (DMF), monomethyl fumarate (MMF), a pharmaceutically acceptable salt of MMF, or a combination thereof, wherein the release of the active ingredient is prolonged, slow and/or delayed compared to Fumaderm®. 
     
     
         47 . The pharmaceutical dosage form of  claim 46 , wherein the active ingredient is embedded in a matrix comprising povidone. 
     
     
         48 . The pharmaceutical dosage form of  claim 47  wherein the matrix further comprises polyoxyl 40 hydrogenated castor oil NF. 
     
     
         49 . The pharmaceutical dosage form of  claim 48  wherein the matrix further comprises corn oil-mono-di-triglycerides. 
     
     
         50 . The pharmaceutical dosage form of  claim 47 , that is a capsule. 
     
     
         51 . The pharmaceutical dosage form of  claim 50 , that is coated with a controlled release coating. 
     
     
         52 . The pharmaceutical dosage form of  claim 50 , wherein the capsule is a soft gelatin capsule. 
     
     
         53 . The pharmaceutical dosage form of  claim 50 , wherein the capsule is a hard gelatin capsule. 
     
     
         54 . The pharmaceutical dosage form of  claim 50 , wherein the capsule contains a semi-solid formulation 
     
     
         55 . The pharmaceutical dosage form of  claim 47 , which has an enteric coating. 
     
     
         56 . The dosage form of  claim 47 , wherein the active ingredient is DMF. 
     
     
         57 . The dosage form of  claim 47 , wherein the active ingredient is MMF. 
     
     
         58 . The dosage form of  claim 47 , wherein the active ingredient is DMF and MMF in a weight ratio between about 1:10 and about 10:1. 
     
     
         59 . The dosage form of  claim 47 , wherein the active ingredient is a salt of MMF. 
     
     
         60 . The pharmaceutical dosage form of  claim 47 , wherein the active ingredient comprises micronized particles of DMF, MMF, a pharmaceutically acceptable salt of MMF, or a combination thereof. 
     
     
         61 . The pharmaceutical dosage form of  claim 60 , wherein the active ingredient particles have an average particle size of 100 μm to 10 nm. 
     
     
         62 . The pharmaceutical dosage form of  claim 60 , wherein the active ingredient is in a suspension. 
     
     
         63 . The pharmaceutical dosage form of  claim 56 , wherein the release of DMF, when subjected to an in vitro dissolution test employing 0.1 N HCl as the dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as the dissolution medium, wherein the dissolution profile is determined as described in the US Pharmacopoeia at 37° C. and a rotation speed of 100 rpm, is as follows: within the first 3 hours after the start of the test at most about 70% of DMF is released. 
     
     
         64 . The pharmaceutical dosage form of  claim 57 , wherein the release of MMF, when subjected to an in vitro dissolution test employing 0.1 N HCl as the dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as the dissolution medium, wherein the dissolution profile is determined as described in the US Pharmacopoeia at 37° C. and a rotation speed of 100 rpm, is as follows: within the first 3 hours after the start of the test at most about 70% of MMF is released. 
     
     
         65 . The pharmaceutical dosage form of  claim 58 , wherein the release of DMF and MMF, when subjected to an in vitro dissolution test employing 0.1 N HCl as the dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as the dissolution medium, wherein the dissolution profile is determined as described in the US Pharmacopoeia at 37° C. and a rotation speed of 100 rpm, is as follows: within the first 3 hours after the start of the test at most about 70% of DMF and MMF combined is released. 
     
     
         66 . The pharmaceutical dosage form of  claim 59 , wherein the release of the salt of MMF, when subjected to an in vitro dissolution test employing 0.1 N HCl as the dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as the dissolution medium, wherein the dissolution profile is determined as described in the US Pharmacopoeia at 37° C. and a rotation speed of 100 rpm, is as follows: within the first 3 hours after the start of the test at most about 70% of the salt of MMF is released.