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 )alkylesters 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 . The pharmaceutical composition according to  claim 1  in the form of a controlled release composition. 
     
     
         3 . A controlled release pharmaceutical composition for oral use 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 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester—when subjected to an in vitro dissolution test employing 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as dissolution medium—is as follows:
 within the first 3 hours after start of the test at the most about 70% w/w of the total amount of the fumaric acid ester contained in the composition is released. 
 
     
     
         4 . A controlled release pharmaceutical composition for oral use 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 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester—when subjected to an in vitro dissolution test employing 0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.5 as dissolution medium—is as follows:
 within the first 4 hours after start of the test at the most about 92% w/w of the total amount of the fumaric acid ester is released. 
 
     
     
         5 . The controlled release composition according to  claim 3 , wherein the release of the fumaric acid ester is as follows:
 within the first 4 hours after start of the test at the most about 92% w/w of the total amount of the fumaric acid ester is released.   
     
     
         6 . The controlled release composition according to any one of the  claims 3 - 5 , wherein the release of the fumaric acid ester is as follows:
 within the first 5 hours after start of the test at the most about 94% w/w of the total amount of the fumaric acid ester is released.   
     
     
         7 . The controlled release composition according to any one of the  claims 3 - 6 , wherein the release of the fumaric acid ester is as follows:
 within the first 6 hours after start of the test at the most about 95% w/w of the total amount of the fumaric acid ester contained in the composition is released.   
     
     
         8 . The controlled release composition according to any one of the  claims 3 - 7 , wherein the release of the fumaric acid ester is as follows:
 within the first 7 hours after start of the test at the most about 98% w/w of the total amount of the fumaric acid ester contained in the composition is released.   
     
     
         9 . The controlled release composition according to any one of the  claims 3 - 8 , wherein the release of the fumaric acid ester is as follows:
 within the first 9 hours after start of the test at the most about 99% w/w of the total amount of the fumaric acid ester contained in the composition is released.   
     
     
         10 . The controlled release composition according to any one of the  claims 3 - 9 , wherein the release of the fumaric acid ester is as follows:
 within the first 12 hours after start of the test at the most about 99% w/w of the total amount of the fumaric acid ester contained in the composition is released.   
     
     
         11 . The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the release has zero-order, first-order or square-root (Higuchi's equation) kinetics release profile. 
     
     
         12 . The controlled release pharmaceutical composition according to  claim 11 , wherein the release has a square-root (Higuchi's equation) kinetics release profile. 
     
     
         13 . The controlled release pharmaceutical composition according to any one of the  claims 3 - 12 , 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. 
     
     
         14 . A controlled release pharmaceutical composition comprising as an active substance from 10% to 90% by weight of one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, from 2% to 40% by weight pharmaceutically acceptable polymer(s), and from 1% to 40% by weight hydrophilic excipient(s), and optionally pharmaceutically acceptable excipients or additives. 
     
     
         15 . A controlled release pharmaceutical composition according to  claim 14  comprising as an active substance from 40% to 60% by weight of one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, from 15% to 25% by weight pharmaceutically acceptable polymer(s), and from 2% to 15% by weight hydrophilic excipient(s), and optionally pharmaceutically acceptable excipients or additives. 
     
     
         16 . A controlled release pharmaceutical composition according to  claim 14  comprising as an active substance from 65% to 80% by weight of one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, from 10% to 25% by weight pharmaceutically acceptable polymer(s), and from 2% to 15% by weight hydrophilic excipient(s), and optionally pharmaceutically acceptable excipients or additives. 
     
     
         17 . The controlled release pharmaceutical composition according to any one of the  claims 14 - 16 , wherein the pharmaceutically acceptable polymer is ethyl cellulose. 
     
     
         18 . The controlled release pharmaceutical composition according to any one of the  claims 14 - 17 , wherein the hydrophilic excipient is polyethylene glycol. 
     
     
         19 . The controlled release pharmaceutical composition according to any one of the  claims 14 - 17 , wherein the hydrophilic excipient is hydroxyl propyl cellulose. 
     
     
         20 . The controlled release pharmaceutical composition comprising as an active substance from 10% to 90% by weight of one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, and 2% to 40% by weight methacrylic acid copolymer A and B in a weight ratio between 1:9 and 9:1, and optionally pharmaceutically acceptable excipients or additives. 
     
     
         21 . The controlled release pharmaceutical composition according to any one of the  claims 14  and  16 - 20  comprising from 50% to 90% of one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The controlled release pharmaceutical composition according to any one of the  claims 14 - 21  having a dissolution profile according to any one of the  claims 3 - 13 . 
     
     
         23 . The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the fumaric acid ester is selected from the group consisting of dimethylfumarate, diethylfumarate, dipropylfumarate, dibutylfumarate, dipentylfumarate, methyl-ethyl-fumarate, methyl-propylfumarat, methyl-butylfumarat, methyl-pentylfumarate, monomethylfumarate, monoethylfumarate, monopropylfumarate, monobutylfumarate, and monopentylfumarate, including pharmaceutically acceptable salts thereof. 
     
     
         24 . The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the fumaric acid ester is a mono-(C 1 -C 5 )alkylester of fumaric acid that is present in the form of a pharmaceutically acceptable salt. 
     
     
         25 . The controlled release composition according to  claim 24 , wherein the salt is a metal salt such as a salt selected from alkali metal salts and alkaline earth metal salts. 
     
     
         26 . The controlled release composition according to any one of the  claim 24  or  25 , wherein the salt is a sodium, potassium, calcium, magnesium or zinc salt. 
     
     
         27 . The controlled release pharmaceutical composition according to any one of the preceding claims comprising dimethylfumarate as the active substance. 
     
     
         28 . The controlled release pharmaceutical composition according to any one of the preceding claims comprising monomethylfumarate as the active substance. 
     
     
         29 . The controlled release pharmaceutical composition according to  claim 28 , wherein monomethylfumarate is present in the form of its sodium, potassium, calcium, magnesium and/or zinc salt. 
     
     
         30 . The controlled release composition according to any one of the preceding claims for administration once, twice or three times daily. 
     
     
         31 . The controlled release composition according to  claim 30  for administration once daily. 
     
     
         32 . The controlled release composition according to  claim 30  for administration twice daily. 
     
     
         33 . The controlled release pharmaceutical composition according to any one of the preceding claims, wherein the amount of one or more fumaric acid esters selected from di-(C 1 -C 5 )alkylesters of fumaric acid and mono-(C 1 -C 5 )alkylesters of fumaric acid or a pharmaceutically acceptable salt thereof, in a dosage form is from 90 mg to 360 mg active substance. 
     
     
         34 . The controlled release pharmaceutical composition according to  claim 33 , wherein the amount in a dosage form is 90, 120, 180, 240 or 360 mg active substance. 
     
     
         35 . The controlled release pharmaceutical composition according to  claim 33 , wherein the amount in a dosage form is 120 mg active substance. 
     
     
         36 . The controlled release pharmaceutical composition according to  claim 33 , wherein the amount in a dosage form is 180 mg active substance. 
     
     
         37 . The controlled release pharmaceutical composition according to  claim 33 , wherein the amount in a dosage form is 240 mg active substance. 
     
     
         38 . The controlled release pharmaceutical composition according to  claim 33 , wherein the amount in a dosage form is 360 mg active substance. 
     
     
         39 . The controlled release pharmaceutical composition according to any one of the preceding claims in the form of a tablet. 
     
     
         40 . The controlled release pharmaceutical composition according to  claim 39 , wherein the tablet has a shape that makes it easy and convenient for a patient to swallow. 
     
     
         41 . The controlled release pharmaceutical composition according to any one of  claims 39 - 40 , wherein the tablet has a rounded or a rod-like shape without any sharp edges. 
     
     
         42 . The controlled release pharmaceutical composition according to any one of  claims 39 - 41 , wherein the tablet is designed to be divided into two or more parts. 
     
     
         43 . The controlled release pharmaceutical composition according to any one of  claims 1 - 38  in the form of a capsule. 
     
     
         44 . A method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, autoimmune diseases, such as polyarthritis, multiple sclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave's disease, SLE (systemic lupus erythematosus), Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoid arthritis (RA) and optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/sciatic pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or granuloma annulare, which method comprises administering orally to a patient in need thereof, an effective dosage of a pharmaceutical composition according to any one of  claims 1 - 43 . 
     
     
         45 . Use of a pharmaceutical composition according to any one of  claims 1 - 43  for the preparation of a medicament for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, autoimmune diseases, such as polyarthritis, multiple sclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave's disease, SLE (systemic lupus erythematosus), Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoid arthritis (RA) and optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/sciatic pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or granuloma annulare.