Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix

Abstract

A pharmaceutical formulation comprising an erosion matrix comprising one or more fumaric acid esters as well as one or more rate-controlling agents, wherein erosion of said erosion matrix permits controlled release of said fumaric acid ester(s).

1 . A pharmaceutical formulation in the form of an erosion matrix tablet comprising:
 i) 10% 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, as an active substance; and   ii) 1-50% by weight of one or more rate-controlling agents;   
       wherein erosion of said erosion matrix permits controlled or sustained release of said active substance. 
     
     
         2 . A pharmaceutical formulation in the form of an erosion matrix tablet comprising:
 i) 30% 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, as an active substance; and   ii) 3-40% by weight of one or more rate-controlling agents;   
       wherein erosion of said erosion matrix permits controlled or sustained release of said active substance. 
     
     
         3 . A pharmaceutical formulation in the form of a monolithic erosion matrix tablet comprising:
 i) 10% 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, as an active substance; and   ii) 1-50% by weight of one or more rate-controlling agents;   
       wherein erosion of said erosion matrix permits controlled or sustained release of said active substance. 
     
     
         4 . A pharmaceutical formulation in the form of a monolithic erosion matrix tablet comprising:
 i) 30% 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, as an active substance; and   ii) 3-40% by weight of one or more rate-controlling agents;   
       wherein erosion of said erosion matrix permits controlled or sustained release of said active substance. 
     
     
         5 . The formulation according to any of the preceding claims, wherein the rate-controlling agent is a water-soluble polymer. 
     
     
         6 . The formulation according to any of the preceding claims, wherein the rate-controlling agent is a cellulose polymer or a cellulose derivative or a mixture thereof. 
     
     
         7 . The formulation according to  claim 6 , wherein the rate-controlling agent is selected from the group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose and mixtures thereof. 
     
     
         8 . The formulation according to  claim 7 , wherein the rate-controlling agent is hydroxypropyl cellulose. 
     
     
         9 . The formulation according to any of the preceding claims, wherein the rate-controlling agent is present in an amount of 1-40% by weight, such as 3-35% by weight, such as 4-15% by weight, such as 4-10% by weight, such as 3-15% by weight, such as 3-10% by weight, such as 4-6% by weight, such as 3-6% by weight, such as 3-5.5% by weight, 
     
     
         10 . The formulation according to any of the preceding claims, further comprising a binder. 
     
     
         11 . The formulation according to  claim 10 , wherein said binder is lactose. 
     
     
         12 . The formulation according to any of the preceding claims comprising:
 i) 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, as an active substance;   ii) 4-6% by weight of a rate-controlling agent;   iii) 35-55% by weight of a binder.   
     
     
         13 . The formulation according to any of  claims 1 - 11  comprising:
 i) 30% 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, as an active substance; 
 ii) 3-6% by weight of a rate-controlling agent; 
 iii) 35-65% by weight of a binder. 
 
     
     
         14 . The formulation according to any of the preceding claims, further comprising one or more pharmaceutically acceptable excipients and additives selected from the group comprising lubricants, glidants, disintegrants, flow control agents, solubilizers, pH control agents, surfactants and emulsifiers. 
     
     
         15 . The formulation according to any of the preceding claims, further comprising one or more coatings. 
     
     
         16 . The formulation according to  claim 15 , wherein said coatings are film coatings and/or enteric coatings. 
     
     
         17 . The formulation according to  claim 16 , wherein said coating is an enteric coating. 
     
     
         18 . The formulation according to  claim 17 , wherein said enteric coating is applied at a level of about 1.0-5.0% by weight of the core. 
     
     
         19 . The formulation according to  claim 18 , wherein said enteric coating is applied at a level of about 1.5-3.5% by weight of the core. 
     
     
         20 . The formulation according to any of the preceding claims, 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 6.8 as dissolution medium—is as follows: 
       within the first 2 hours after start of the test from about 0% w/w to about 50% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 3 hours after start of the test from about 20% w/w to about 75% w/w of the total amount of the fumaric acid ester contained in the formulation is released. 
     
     
         21 . The formulation according to any of the preceding claims, 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 6.8 as dissolution medium—is as follows: 
       within the first 3.5 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 formulation is released. 
     
     
         22 . The formulation according to any of the preceding claims, 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 6.8 as dissolution medium—is as follows: 
       within the first 4 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 formulation is released. 
     
     
         23 . The formulation according to any 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-propylfumarate, methyl-butylfumarate, methyl-pentylfumarate, monomethylfumarate, monoethylfumarate, monopropylfumarate, monobutylfumarate, and monopentylfumarate, including pharmaceutically acceptable salts thereof. 
     
     
         24 . The formulation 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 formulation according to any one of the preceding claims comprising dimethylfumarate as the active substance. 
     
     
         26 . The formulation according to any one of  claims 1 - 25  comprising monomethylfumarate or a pharmaceutically acceptable salt thereof as the active substance. 
     
     
         27 . The formulation according to any of the preceding claims comprising:
 i) 40% to 55% by weight of dimethyl fumarate;   ii) 4-6% by weight of hydroxypropyl cellulose;   iii) 35-55% by weight of lactose.   
     
     
         28 . The formulation according to any of  claims 1 - 26  comprising:
 i) 30% to 60% by weight of dimethyl fumarate; 
 ii) 3-6% by weight of hydroxypropyl cellulose; 
 iii) 35-65% by weight of lactose. 
 
     
     
         29 . The formulation according to any of the preceding claims wherein the rate-controlling agent is hydroxypropyl cellulose having a viscosity (mPa·s) of 3.0-5.9 as measured in an aqueous solution containing 2% by weight of dry HPC at 20° C. 
     
     
         30 . The formulation according to any one of the preceding claims for administration once, twice or three times daily. 
     
     
         31 . A pharmaceutical formulation in the form of an erosion matrix tablet comprising:
 A) A tablet core comprising:
 i) 30-60% 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, as an active substance, 
 ii) 3-6% by weight of a rate-controlling agent; 
 iii) 35-65% by weight of a binder; 
   B) an enteric coating in an amount of about 1.5-3.5% by weight of the core;   
       wherein erosion of said erosion matrix results in 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 6.8 as dissolution medium—as follows: 
       within the first 2 hours after start of the test from about 0% w/w to about 10% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 3 hours after start of the test from about 20% w/w to about 75% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 4 hours after start of the test from about 50% w/w to about 98% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 5 hours after start of the test from about 70% w/w to about 100% w/w of the total amount of the fumaric acid ester contained in the formulation is released. 
     
     
         32 . A pharmaceutical formulation in the form of a monolithic erosion matrix tablet comprising:
 A) A tablet core comprising:
 i) 30-60% 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, as an active substance, 
 ii) 3-6% by weight of a rate-controlling agent; 
 iii) 35-65% by weight of a binder; 
   B) an enteric coating in an amount of about 1.5-3.5% by weight of the core;   
       wherein erosion of said erosion matrix results in 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 6.8 as dissolution medium—as follows: 
       within the first 2 hours after start of the test from about 0% w/w to about 10% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 3 hours after start of the test from about 20% w/w to about 75% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 4 hours after start of the test from about 50% w/w to about 98% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 5 hours after start of the test from about 70% w/w to about 100% w/w of the total amount of the fumaric acid ester contained in the formulation is released. 
     
     
         33 . The formulation according to any of  claims 31 - 32  wherein the rate-controlling agent is hydroxypropyl cellulose having a viscosity (mPa·s) of 3.0-5.9 as measured in an aqueous solution containing 2% by weight of dry HPC at 20° C. 
     
     
         34 . A pharmaceutical formulation in the form of an erosion matrix tablet comprising:
 A) A tablet core comprising:
 i) 30-60% by weight of dimethyl fumarate, 
 ii) 3-6% by weight of hydroxypropyl cellulose; 
 iii) 35-65% by weight of lactose; 
   B) an enteric coating in an amount of about 1.5-3.5% by weight of the core;   
       wherein erosion of said erosion matrix results in release of the dimethyl fumarate—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 6.8 as dissolution medium—as follows: 
       within the first 2 hours after start of the test from about 0% w/w to about 10% w/w of the dimethyl fumarate contained in the formulation is released, and/or 
       within the first 3 hours after start of the test from about 20% w/w to about 75% w/w of the dimethyl fumarate contained in the formulation is released, and/or 
       within the first 4 hours after start of the test from about 50% w/w to about 98% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 5 hours after start of the test from about 70% w/w to about 100% w/w of the total amount of the dimethyl fumarate contained in the formulation is released. 
     
     
         35 . A pharmaceutical formulation in the form of a monolithic erosion matrix tablet comprising:
 A) A tablet core comprising:
 i) 30-60% by weight of dimethyl fumarate, 
 ii) 3-6% by weight of hydroxypropyl cellulose; 
 iii) 35-65% by weight of lactose; 
   B) an enteric coating in an amount of about 1.5-3.5% by weight of the core;   
       wherein erosion of said erosion matrix results in release of the dimethyl fumarate—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 6.8 as dissolution medium—as follows: 
       within the first 2 hours after start of the test from about 0% w/w to about 10% w/w of the dimethyl fumarate contained in the formulation is released, and/or 
       within the first 3 hours after start of the test from about 20% w/w to about 75% w/w of the dimethyl fumarate contained in the formulation is released, and/or 
       within the first 4 hours after start of the test from about 50% w/w to about 98% w/w of the fumaric ester contained in the formulation is released, and/or 
       within the first 5 hours after start of the test from about 70% w/w to about 100% w/w of the total amount of the dimethyl fumarate contained in the formulation is released. 
     
     
         36 . The formulation according to any of  claims 34 - 35  wherein the hydroxypropyl cellulose is hydroxypropyl cellulose having a viscosity (mPa·s) of 3.0-5.9 as measured in an aqueous solution containing 2% by weight of dry HPC at 20° C. 
     
     
         37 . A method for preparing the formulation according to any of the preceding claims, comprising the steps of:
 a) Dissolving or suspending either one or both of a fumaric acid ester and a rate-controlling agent in the form of a polymeric matrix material in water to obtain an aqueous suspension thereof;   b) Spraying said aqueous suspension on granules of a fumaric acid ester and/or a binder for a period of time sufficient to obtain a uniform coating thereon;   c) Drying the granules obtained;   d) Optionally sieving or milling said granules;   e) Blending of any pharmaceutically acceptable excipients and additives in a manner known per se to obtain a tablet formulation;   f) Optionally film and/or enteric coating of said tablet formulation in a manner known per se;   
       wherein the above steps are performed at a temperature to allow a product temperature not exceeding 45° C. 
     
     
         38 . A method for preparing the formulation according to any of  claims 1 - 36 , comprising the steps of:
 a) Dissolving or suspending a rate-controlling agent in the form of a polymeric matrix material in water to obtain an aqueous suspension thereof;   b) Spraying said aqueous suspension on granules of a fumaric acid ester for a period of time sufficient to obtain a uniform coating thereon;   c) Drying the granules obtained;   d) Optionally sieving or milling said granules;   e) Blending of any pharmaceutically acceptable excipients and additives in a manner known per se to obtain a tablet formulation;   f) Optionally film and/or enteric coating of said tablet formulation in a manner known per se;   
       wherein the above steps are performed at a temperature to allow a product temperature not exceeding 45° C. 
     
     
         39 . A method for preparing the formulation according to any of  claims 1 - 36 , comprising the steps of:
 a) Optionally sieving or milling crystals of fumaric acid ester;   b) Blending of said crystals of fumaric acid ester, a rate-controlling agent in the form of a polymeric matrix material, and any pharmaceutically acceptable excipients and additives by direct compression to obtain a tablet formulation;   c) Optionally film and/or enteric coating of said tablet formulation in a manner known per se;   
       wherein the above steps are performed at a temperature to allow a product temperature not exceeding 45° C. 
     
     
         40 . The method according to  claim 39 , wherein the crystals of fumaric acid ester are sieved or milled such that 90% of the particles have a particle size in the range of 5-1000 μm, such as in the range of 10-900 μm, such as in the range of 20-800 μm, such as in the range of 30-750 μm, such as in the range of 40-600 μm, or such as in the range of 50-500 μm. 
     
     
         41 . A pharmaceutical formulation according to any of the  claims 1 - 36  for use for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, 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), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, 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. 
     
     
         42 . A use of a pharmaceutical formulation according to any one of  claims 1 - 36  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, 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), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, 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. 
     
     
         43 . The use according to  claim 42  for the treatment of psoriasis. 
     
     
         44 . The use according to  claim 42  for the treatment of psoriatic arthritis. 
     
     
         45 . The use according to  claim 42  for the treatment of multiple sclerosis. 
     
     
         46 . The use according to  claim 42  for the treatment of rheumatoid arthritis. 
     
     
         47 . A method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, 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), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, 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 formulation according to any one of  claims 1 - 36 . 
     
     
         48 . The method according to  claim 47  for the treatment of psoriasis. 
     
     
         49 . The method according to  claim 47  for the treatment of psoriatic arthritis. 
     
     
         50 . The method according to  claim 47  for the treatment of multiple sclerosis. 
     
     
         51 . The method according to  claim 47  for the treatment of rheumatoid arthritis.