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 delayed release pharmaceutical composition using an increasing dose regimen, wherein an initial daily amount of drug administered is increased later to a higher daily amount and the pharmaceutical composition consists essentially of (a) dimethylfumarate and (b) one or more pharmaceutically acceptable excipients, and wherein the higher daily amount is about 480 mg of dimethylfumarate. 
     
     
         47 . The method of  claim 46 , wherein the delayed release pharmaceutical composition is contained in a capsule. 
     
     
         48 . The method of  claim 46 , wherein the delayed release pharmaceutical composition is in the form of a tablet. 
     
     
         49 . The method of  claim 46 , wherein the delayed release pharmaceutical composition is taken with a meal. 
     
     
         50 . The method of  claim 46 , wherein the increasing dose regimen comprises (i) orally administering to the subject in need thereof the delayed release pharmaceutical composition an initial daily dose for a period of time and (ii) following step (i), orally administering to the subject in need thereof the delayed release pharmaceutical composition at a higher daily dose, wherein the higher daily dose is about twice the initial daily dose. 
     
     
         51 . The method of  claim 50 , wherein the initial daily dose is about 240 mg per day. 
     
     
         52 . The method of  claim 50 , wherein the delayed release pharmaceutical composition is taken with a meal. 
     
     
         53 . The method of  claim 50 , wherein the delayed release pharmaceutical composition is contained in a capsule. 
     
     
         54 . The method of  claim 50 , wherein the delayed release pharmaceutical composition is in the form of a tablet. 
     
     
         55 . The method of  claim 50 , wherein the delayed release pharmaceutical composition comprises microtablets. 
     
     
         56 . The method of  claim 55 , wherein the microtablets are surrounded by an enteric coating. 
     
     
         57 . The method of  claim 50 , wherein the delayed release pharmaceutical composition comprises pellets. 
     
     
         58 . The method of  claim 46 , wherein the pharmaceutically acceptable excipients comprise one or more of any one 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. 
     
     
         59 . The method of  claim 58 , wherein the delayed release pharmaceutical composition comprises from about 1 to about 60% micro crystalline cellulose. 
     
     
         60 . The method of  claim 58 , wherein the delayed release pharmaceutical composition comprises from about 0.2 to about 3% magnesium stearate. 
     
     
         61 . The method of  claim 58 , wherein the delayed release pharmaceutical composition comprises from about 0.2 to about 4% silica. 
     
     
         62 . The method of  claim 58 , wherein the delayed release pharmaceutical composition comprises cross-linked sodium carboxymethylcellulose. 
     
     
         63 . The method of  claim 58 , wherein the delayed release pharmaceutical composition comprises a surfactant having an HLB value above 8. 
     
     
         64 . The method of  claim 46 , wherein the delayed release pharmaceutical composition is produced using dimethylfumarate micro crystals. 
     
     
         65 . The method of  claim 64 , wherein the delayed release pharmaceutical composition containing the dimethylfumarate is a capsule produced using enteric coated micro crystals that have one coating layer. 
     
     
         66 . The method of  claim 64 , wherein the micro crystals are between 315 and 710 microns, which are subsequently coated with a layer containing an enteric coating polymer. 
     
     
         67 . The method of  claim 46 , wherein about 240 mg dimethylfumarate is administered in the morning and the remainder is administered later in the day. 
     
     
         68 . The method of  claim 46 , wherein said about 480 mg in a day is administered in two equal doses at different times of the day. 
     
     
         69 . The method of  claim 46 , wherein said delayed release pharmaceutical composition is administered at least 30 minutes before a meal to about two hours after a meal. 
     
     
         70 . The method of  claim 50 , wherein the delayed release pharmaceutical composition comprises beads. 
     
     
         71 . The method of  claim 70 , wherein the delayed release pharmaceutical composition comprises beads in a capsule. 
     
     
         72 . The method of  claim 55 , wherein each of the microtablets has an enteric coating. 
     
     
         73 . The method of  claim 55 , wherein the microtablets are surrounded by an enteric coating.