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 kit comprising:
 (a) a first unit dosage form consisting essentially of 120 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients, wherein the dimethylfumarate is formulated for delayed release; and   (b) a second unit dosage form consisting essentially of 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients, wherein the dimethylfumarate is formulated for delayed release.   
     
     
         47 . The kit of  claim 46 , wherein the first unit dosage form is in the form of a capsule or a tablet. 
     
     
         48 . The kit of  claim 47 , wherein the capsule is a hard gelatin capsule. 
     
     
         49 . The kit of  claim 47 , wherein the first unit dosage form comprises microtablets. 
     
     
         50 . The kit of  claim 49 , wherein the microtablets are surrounded by an enteric coating. 
     
     
         51 . The kit of  claim 47 , wherein the first unit dosage form comprises pellets. 
     
     
         52 . The kit of  claim 47 , wherein the kit comprises fourteen capsules of the first unit dosage form. 
     
     
         53 . The kit of  claim 50 , wherein the kit consists of fourteen capsules of the first unit dosage form. 
     
     
         54 . The kit of  claim 46 , wherein the pharmaceutically acceptable excipients in the first unit dosage 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 kit of  claim 54 , wherein the first unit dosage form comprises from about 1 to about 60% micro crystalline cellulose. 
     
     
         56 . The kit of  claim 54 , wherein the first unit dosage form comprises from about 0.2 to about 3% magnesium stearate. 
     
     
         57 . The kit of  claim 54 , wherein the first unit dosage form comprises from about 0.2 to about 4% silica. 
     
     
         58 . The kit of  claim 54 , wherein the first unit dosage form comprises cross-linked sodium carboxymethylcellulose. 
     
     
         59 . The kit of  claim 54 , wherein the first unit dosage form comprises a surfactant having an HLB value above 8. 
     
     
         60 . The kit of  claim 46 , wherein the second unit dosage form is in the form of a capsule or a tablet. 
     
     
         61 . The kit of  claim 60 , wherein the capsule is a hard gelatin capsule. 
     
     
         62 . The kit of  claim 60 , wherein the second unit dosage form comprises microtablets. 
     
     
         63 . The kit of  claim 62 , wherein the microtablets are surrounded by an enteric coating. 
     
     
         64 . The kit of  claim 60 , wherein the second unit dosage form comprises pellets. 
     
     
         65 . The kit of  claim 60 , wherein the kit comprises fourteen capsules of the second unit dosage form. 
     
     
         66 . The kit of  claim 46 , wherein the pharmaceutically acceptable excipients in the second unit dosage form comprise at least one of the following excipients micro crystalline cellulose, cross-linked sodium carboxymethylcellulose, talc, silica colloidal silicon dioxide, magnesium stearate, or a surfactant having an HLB value above 8. 
     
     
         67 . The kit of  claim 66 , wherein the second dosage unit comprises from about 1 to about 60% micro crystalline cellulose. 
     
     
         68 . The kit of  claim 66 , wherein the second dosage unit comprises from about 0.2 to about 3% magnesium stearate. 
     
     
         69 . The kit of  claim 66 , wherein the second dosage unit comprises from about 0.2 to about 4% silica. 
     
     
         70 . The kit of  claim 66 , wherein the second unit dosage comprises cross-linked sodium carboxymethylcellulose. 
     
     
         71 . The kit of  claim 66 , wherein the second dosage unit comprises a surfactant having an HLB value above 8. 
     
     
         72 . The kit of  claim 46 , wherein said first dosage unit and said second dosage unit are produced using dimethylfumarate micro crystals. 
     
     
         73 . The kit of  claim 72 , wherein said micro crystals are surrounded by an enteric coating. 
     
     
         74 . The kit of  claim 72 , wherein said first unit dosage form and said second unit dosage form are produced using dimethylfumarate micro crystals between 315 and 710 microns, which are subsequently coated with a layer containing an enteric coating polymer. 
     
     
         75 . The kit of  claim 46 , further comprising a label containing instructions for an oral dosage regimen of (i) and (ii).