CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS COMPRISING A FUMARIC ACID ESTER
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 delayed release composition comprising an active ingredient consisting essentially of about 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients, wherein following oral administration of the composition to a human subject monomethylfumarate appears in the plasma of the subject with a Cmax between about 0.4 to about 2 mg/L.
47 . The composition of claim 46 , further comprising a methacrylic acid copolymer.
48 . The composition of claim 46 , wherein the pharmaceutically acceptable excipients comprise one or more 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.
49 . The composition of claim 48 , wherein the composition comprises from about 1 to about 60% micro crystalline cellulose.
50 . The composition of claim 48 , wherein the composition comprises from about 0.2 to about 3% magnesium stearate.
51 . The composition of claim 48 , wherein the composition comprises from about 0.2 to about 4% silica.
52 . The composition of claim 48 , wherein the composition comprises cross-linked sodium carboxymethylcellulose.
53 . The composition of claim 48 , wherein the composition comprises a surfactant having an HLB value above 8.
54 . The composition of claim 46 , wherein the composition is produced using dimethylfumarate micro crystals.
55 . The composition of claim 54 , wherein the composition is produced using dimethylfumarate micro crystals between 315 and 710 microns.
56 . The composition of claim 46 , wherein following oral administration of the composition to a human subject monomethylfumarate appears in the plasma of the subject with a Cmax of about 0.4 mg/L.
57 . The composition of claim 46 , wherein following oral administration of the composition to a human subject monomethylfumarate appears in the plasma of the subject with a Cmax of about 2 mg/L.
58 . The composition of claim 46 , wherein the plasma concentration of monomethylfumarate is 50% of the Cmax or more for a period of at least 2 hours.
59 . The composition of claim 46 , wherein the plasma concentration of monomethylfumarate is 50% of the Cmax or more for a period of from about 2 to about 15 hours.
60 . The composition of claim 46 , wherein the plasma concentration of monomethylfumarate is 50% of the Cmax or more for a period of from about 2.5 to about 10 hours.
61 . The composition of claim 46 , wherein the plasma concentration of monomethylfumarate is 50% of the Cmax or more for a period of from about 3 to about 8 hours.
62 . The composition of claim 46 , wherein the composition is a unit dosage form that is a capsule or a tablet.
63 . The composition of claim 62 , wherein the capsule is a hard gelatin capsule.
64 . The composition of claim 46 , wherein the composition is a unit dosage form comprising microtablets.
65 . The composition of claim 64 , wherein the microtablets are surrounded by an enteric coating.
66 . The composition of claim 46 , wherein the composition is a unit dosage form comprising beads.
67 . The composition of claim 46 , wherein the composition is produced using dimethylfumarate micro crystals.
68 . The composition of claim 67 , wherein the composition is a capsule containing enteric coated micro crystals that have one coating layer.
69 . The composition of claim 67 , wherein the composition is produced using dimethylfumarate micro crystals between 315 and 710 microns, which are subsequently coated with a layer containing an enteric coating polymer.
70 . The composition of claim 47 , wherein the methacrylic acid is in a layer.
71 . The composition of claim 70 , wherein the composition contains one layer.
72 . The composition of claim 46 , wherein the composition is a unit dosage form comprising pellets.
73 . The composition of claim 72 , wherein the methacrylic acid is in a layer on the pellets.
74 . The composition of claim 46 , comprising an active ingredient consisting essentially of 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients.
75 . A method of treating a subject by administering a delayed release composition of claim 46 , wherein about 240 mg of said composition is administered twice daily.
76 . The method of claim 75 , wherein about 240 mg is administered in the morning and the remainder is administered later in the day.
77 . The method of claim 75 , wherein 240 mg of said composition is administered twice daily.
78 . The method of claim 76 , wherein 240 mg is administered in the morning and the remainder is administered later in the day.