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 . A pharmaceutical composition comprising as an active substance one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylester of fumaric acid, or a pharmaceutically acceptable salt thereof, which—upon oral administration and in comparison to that obtained after oral administration of Fumaderm® tablets in an equivalent dosage—gives a reduction in GI related side effects. 
     
     
         2 - 45 . (canceled) 
     
     
         46 . A method of treating a subject in need of treatment for multiple sclerosis comprising orally administering to the subject in need thereof a pharmaceutical composition in unit dosage form consisting essentially of (a) from about 120 mg to about 240 mg of dimethylfumarate formulated for delayed release, and (b) one or more pharmaceutically acceptable excipients, wherein following the orally administering of the unit dosage form monomethylfumarate appears in the plasma of the subject and the C max  of the monomethylfumarate in the plasma of the subject is between about 0.4 and about 2 mg/L, and wherein about 480 mg of dimethylfumarate per day is orally administered to the subject. 
     
     
         47 . The method of  claim 46 , wherein the unit dosage form is administered in separate administrations of 1, 2, or 3 doses per day. 
     
     
         48 . The method of  claim 46 , comprising orally administering twice daily to the subject in need thereof a pharmaceutical composition in unit dosage form consisting essentially of (a) about 240 mg of dimethylfumarate formulated for controlled release, and (b) one or more pharmaceutically acceptable excipients, wherein following the orally administering of the unit dosage form the C max  of the monomethylfumarate in the plasma of the subject is about 2 mg/L. 
     
     
         49 . The method of  claim 46 , wherein the pharmaceutical composition is administered with a meal. 
     
     
         50 . The method of  claim 46 , wherein the pharmaceutical composition is in the form of a tablet or a capsule. 
     
     
         51 . The method of  claim 50 , wherein the pharmaceutical composition comprises microtablets. 
     
     
         52 . The method of  claim 51 , wherein the microtablets have an enteric coating. 
     
     
         53 . The method of  claim 46 , wherein the pharmaceutical composition comprises pellets. 
     
     
         54 . The method of  claim 46 , wherein the pharmaceutically acceptable excipients comprise one or more of the following: micro crystalline cellulose, cross-linked sodium carboxymethylcellulose, talc, silica, colloidal silicon dioxide, magnesium stearate, or a surfactant having an HLB value above 8. 
     
     
         55 . The method of  claim 54 , wherein the pharmaceutical composition comprises from about 1 to about 60% micro crystalline cellulose. 
     
     
         56 . The method of  claim 54 , wherein the pharmaceutical composition comprises from about 0.2 to about 3% magnesium stearate. 
     
     
         57 . The method of  claim 54 , wherein the pharmaceutical composition comprises from about 0.2 to about 4% silica. 
     
     
         58 . The method of  claim 54 , wherein the pharmaceutical composition comprises cross-linked sodium carboxymethylcellulose. 
     
     
         59 . The method of  claim 54 , wherein the pharmaceutical composition comprises a surfactant having an HLB value above 8. 
     
     
         60 . The method of  claim 46 , wherein the pharmaceutical composition is produced using dimethylfumarate micro crystals. 
     
     
         61 . The method of  claim 60 , wherein the pharmaceutical composition is a capsule containing dimethylfumarate produced using micro crystals which are subsequently coated with a layer containing an enteric coating polymer. 
     
     
         62 . The method of  claim 60 , wherein the pharmaceutical composition is produced using dimethylfumarate micro crystals between 315 and 710 microns. 
     
     
         63 . The method of  claim 46 , wherein said about 480 mg of dimethylfumarate per day is administered in two equal doses. 
     
     
         64 . The method of  claim 46 , wherein said pharmaceutical composition is administered at least 30 minutes before a meal to about two hours after a meal. 
     
     
         65 . The method of  claim 46 , wherein about 240 mg dimethylfumarate is administered in the morning and the remainder is administered later in the day. 
     
     
         66 . The method of  claim 46 , wherein said about 480 mg of dimethylfumarate per day is administered in two equal doses at different times of the day. 
     
     
         67 . The method of  claim 46 , wherein the pharmaceutical composition comprises beads. 
     
     
         68 . The method of  claim 67 , wherein the pharmaceutical composition comprises beads in a capsule. 
     
     
         69 . The method of  claim 51 , wherein each of the microtablets has an enteric coating. 
     
     
         70 . The method of  claim 51 , wherein the microtablets are surrounded by an enteric coating.