Controlled release pharmaceutical compositions comprising a fumaric acid ester

Abstract

The invention features a kit. The kit includes: (i) a first unit dosage form consisting essentially of about 120 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients, wherein the dimethylfumarate is formulated for delayed release; and (ii) a second unit dosage form consisting essentially of about 240 mg of dimethylfumarate and one or more pharmaceutically acceptable excipients, wherein the dimethylfumarate is formulated for delayed release.

Description

FIELD OF THE INVENTION[0001]The present invention relates to controlled release pharmaceutical compositions comprising a fumaric acid ester as an active substance. The compositions are suitable for use in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designed 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.BACKGROUND OF THE INVENTION[0002]Fumaric acid esters, i.e. dimethylfumarate in combination with ethylhydrogenfumarat have been used in the treatment of psoriasis for many years. The combination is marketed under the tradename Fumaderm®. It is in the form of tablets intended for oral use and it is available in two different dosage strengths (Fumaderm® initial and Fumaderm®):Fumaderm ® InitialFumaderm ®Dimethy...

AI Technical Summary

Benefits of technology

[0041]Another interesting technology for use in formulating compositions according to the present invention is the so-called MeltDose® technology as described in WO 03 / 004001 (see http: / / www.lifecyclepharma.com. MeltDose® involves formulating solubilized, individual molecules into tablets. By formulating individual molecules, the primary limitation of oral absorption of drugs with low water-solubility is removed, and a superior bioavailability can be attained). By employing this technology it is possible to obtain a particulate material that is suitable for processing into various pharmaceutical dosage forms e.g. in the form of pellets or tablets. Furthermore, the technology is suitable for use as it is possible to obtain a suitable release profile of the active substance, e.g. such as those release profiles described herein. In one embodiment, pellets suitable for use may have a mean particle size larger than 2000 μm. In another embodiment, pellets suitable for use may have a mean particle size of from about 0.01 μm to about 250 μm.

[0097]Typically, as described above, the compositions according to the invention are designed to deliver the active substance (i.e. the monoalkylester of fumaric acid, which in turn is metabolised to fumaric acid and, which subsequently is subjected to a rapid elimination process) in a prolonged manner. Apart from the characteristic in vitro release patterns described herein, such a prolonged release is reflected in the pharmacokinetic parameters obtained after a clinical study as well. Accordingly, it is contemplated that the Cmax of the monoalkylester of fumaric acid (which appears in the plasma upon hydrolysis or metabolism of the dialkylester ad ministered) is of the same order of magnitude as previously described in the literature provided that a similar or equivalent dose is administered (i.e. Cmax of monomethylfumarate in a range of from about 0.4 to about 2.0 mg / l corresponding to an oral dose of 120 to 240 mg dimethylfumarate). However, in order to avoid many frequent daily administrations (2-4 tablets 1-3 times daily) it is an aim to prolong the time period where the concentration is within the therapeutic window. Accordingly, it is contemplated that W50 (i.e. the time period in which the plasma concentration is 50% of Cmax or more) is prolonged compared to the marketed treatment with at least 10% such as, e.g. at least 20%, at least 30%, at least 40% or at least 50%. A suitable W50 is believed to be at least 2 hours such as in a range of from about 2 to about 15 hours or from about 2.5 to about 10 hours or from about 3 to about 8 hours.

[0098]Furthermore, it is contemplated that a controlled release composition according to the invention may lead to a reduced interindividual and / or intraindividual variation in the plasma profile and to a reduced dependency on whether the composition is taken together with or without food (a reduced variation of the plasma concentration profile of monomethylfumarate when the pharmaceutical composition is administered with or without concomitant food intake). Therefore, the controlled release composition according to the invention may lead to a reduced frequency of dosing and / or a reduced average total daily dose, and / or an increased efficacy at the same total daily dose of the active substance compared to Fumaderm®.

[0164]It is contemplated that such combination therapy leads to an improved therapeutic response and / or an increased convenience for the individual, compared to said individual being treated without the composition or kit according to the invention.

[0165]In a further aspect, the invention relates to a method of reducing side effects associated with oral treatment of any of the conditions a-e and 1-5 listed above, in which method the active pharmaceutical ingredient for treating said condition is used in combination with one or more of the following agents:a) an antacid such as 1) magnesium hydroxide, 2) magnesium trisilicate, 3) aluminium hydroxyde gel, 3) sodium hydrogencarbonate, 4) magaldrat or any combination of 1-5 and / orb) a histamine H-2 antagonist such as 1) cimetidine, 2) ranitidine, 3) nizatidine, 4) famotidine, 5) roxatidine, 6) lafutadine or any combination of 1-6 and / orc) a cytoprotective agent such as 1) sucralfate, 2) tripotassium dictitratobismuthate, 3) carbenoxolone, 4) prostaglandin E-2 analogues such as misoprostol, 5) ecabet, 6) cetraxate HCl, 7) teprenone, 8) troxipide, 9) dicyclomine hydrochloride, 10) sofalcon or any combination of 1-10 and / ord) a proton pump inhibitor (PPI) such as 1) omeprazole, 2) esomeprazole, 3) lansoproazole, 4) pantoprazole, 5) rabeprazole, 6) CS-526 / R-105266, 7) AZD 0865, 8) soraprazan or any combination of 1-8, and / ore) an NSAID or a COX or a LOX inhibitor such as e.g. a COX-2 inhibitor or a COX / 5-LOX inhibitor, and / orf) pentoxifylline, e.g. at a dose range of from 400 to 800 mg / day.

Problems solved by technology

However, therapy with fumarates like e.g. Fumaderm® frequently gives rise to gastro-intestinal side effects such as e.g. fullness, diarrhea, upper abdominal cramps, flatulence and nausea.

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