Controlled Release Dosage Form for Once Daily Administration of Dimethyl Fumarate

Abstract

A controlled release dosage form containing monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof wherein the monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof is delivered to the subject. Also provided is a method of treating a disease or disorder (e.g., multiple sclerosis) by orally administering a controlled release dosage form containing monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof, wherein the monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof.

What is claimed is: 
     
         1 . A controlled release dosage form comprising an active agent selected from the group consisting of monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof and combinations thereof, wherein the active agent is retained in the stomach and/or small intestine of a subject treated for at least 3 hours. 
     
     
         2 . The controlled release dosage form of  claim 1 , wherein the dosage form swells when exposed to gastric fluid, thereby retaining the active agent in the stomach. 
     
     
         3 . The controlled release dosage form of  claim 1 , wherein the dosage form floats when exposed to gastric fluid, thereby retaining the active agent in the stomach. 
     
     
         4 . The controlled release dosage form of  claim 1 , wherein the dosage form is a mucoadhesive dosage form, wherein the active agent is retained in the small intestine. 
     
     
         5 . The controlled release dosage form of  claim 1 , wherein the active agent has a particle size of about 50 um to about 500 um, wherein the active agent is retained in the small intestine. 
     
     
         6 . The controlled release dosage form of  claim 1 , wherein the dosage form is in the form of a matrix. 
     
     
         7 . The controlled release dosage form of  claim 1 , wherein the dosage form is an osmotic dosage form. 
     
     
         8 . The controlled release dosage form of any one of  claims 1 - 7 , wherein subjects administered the controlled release dosage exhibit one or more of the pharmacokinetic parameters consisting of (a) a mean plasma MMF AUC overall  m ranging from about 4.81 h·mg/L to about 11.2 h·mg/L; (b) a mean plasma MMF AUC 0-12  ranging from about 2.4 h·mg/L to about 5.5 h·mg/L; and (c) a mean AUC 0-infinity  ranging from about 2.4 h·mg/L to about 5.6 h·mg/L. 
     
     
         9 . A unit dosage form comprising
 (a) a first dosage component comprising a first dose of monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof; and   (b) a second dosage component comprising a second dose of monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof;   wherein when the unit dosage form is administered to a subject orally, the first and second doses of monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof are delivered in a sustained or pulsatile manner, and wherein the second dose is retained in the stomach and/or small intestine of a subject treated for at least 3 hours.   
     
     
         10 . The unit dosage form of  claim 9 , wherein first and the second doses are delivered in a pulsatile manner and the pulsatile manner is characterized by a lag time of about 2 hours to about 14 hours between delivery of the first and second doses of monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof. 
     
     
         11 . The unit dosage form of  claim 10 , wherein the lag time is about 8 hours to about 12 hours. 
     
     
         12 . The unit dosage form of any of  claims 9 - 11 , wherein the second dosage component is a controlled release dosage form selected from the group consisting of a swellable dosage form, a floating dosage form, a mucoadhesive dosage form, a matrix, an osmotic dosage form, and a combination thereof. 
     
     
         13 . The unit dosage form of  claim 12 , wherein the controlled release dosage form has a gastric residence time of about 4 hours to about 18 hours. 
     
     
         14 . The unit dosage form of  claim 13 , wherein the second dosage component has a gastric residence time of about 8 hours to about 14 hours. 
     
     
         15 . The unit dosage form of any of  claims 9 - 14 , wherein the first dosage component is in a form of micro-pellets, micro-tablets, capsules, granulates, or tablets. 
     
     
         16 . The unit dosage form of  claim 9  or  10 , wherein the first dosage component is an enterically coated immediate release dosage form. 
     
     
         17 . The unit dosage form of any of  claims 9  or  10 , wherein the first dosage component is in the form of microtablets, wherein the microtablets are enteric-coated. 
     
     
         18 . The unit dosage form of any of  claims 9  or  10 , wherein the first dosage component is in the form enteric-coated crystals or particles. 
     
     
         19 . The controlled release dosage form of any of  claims 1 - 7 , wherein the controlled release dosage form contains about 80 mg to about 1000 mg monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof. 
     
     
         20 . The unit dosage form of any of  claims 9 - 18 , wherein the first dose of monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof in the first dosage component is about 80 mg to about 1000 mg monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof. 
     
     
         21 . The unit dosage form of any of  claims 9 - 18 , wherein the second dose of monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof in the second dosage component is about 80 mg to about 1000 mg monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof. 
     
     
         22 . The unit dosage form of any one of  claims 9 - 18 ,  20 , and  21 , wherein subjects administered the unit dosage form exhibit one or more of the pharmacokinetic parameters consisting of (a) a mean plasma MMF AUC overall  ranging from about 4.81 h·mg/L to about 11.2 h·mg/L; (b) a mean plasma MMF AUC 0-12  ranging from about 2.4 h·mg/L to about 5.5 h·mg/L; and (c) a mean AUC 0-infinity  ranging from about 2.4 h·mg/L to about 5.6 h·mg/L. 
     
     
         23 . The unit dosage form of any of  claims 9 - 18  and  20 - 22 , wherein the first dosage component consists essentially of a plurality of enteric-coated monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof microtablets or micropellets. 
     
     
         24 . The unit dosage form of  claim 23 , wherein the enteric-coated monomethyl fumarate, a compound that can be metabolized into monomethyl fumarate in vivo, or a pharmaceutically acceptable salt thereof or combinations thereof microtablets or micropellets in the first dosage component have a mean diameter of 5,000 microns or less. 
     
     
         25 . A method for the treatment or prophylactic treatment of a disease or disorder in a subject in need thereof, the method comprising administering to the subject a controlled release dosage form or unit dosage form of any of  claims 1 - 24  once per day, wherein the disease or disorder is
 (1) an autoimmune disease selected from the group consisting of polyarthritis, especially rheumatoid arthritis, multiple sclerosis, graft-versus-host reactions, juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome, pernicious anaemia and chronic active (=lupoid) hepatitis, psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn; 
 (2) a mitochondrial disease selected from the group consisting of Parkinson syndrome, Alzheimer's disease, Chorea Huntington disease, retinopathia pigmentosa or forms of mitochondrial encephalomyopathy; 
 (3) a NF-kappaB mediated diseases selected from the group consisting of progressive systemic sclerodermia, osteochondritis syphilitica (Wegener's disease), cutis marmorata (livedo reticularis), Behcet disease, panarteriitis, colitis ulcerosa, vasculitis, osteoarthritis, gout, artenosclerosis, Reiter's disease, pulmonary granulomatosis, types of encephalitis, endotoxic shock (septic-toxic shock), sepsis, pneumonia, encephalomyclitis, anorexia nervosa, hepatitis (acute hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced hepatitis, viral hepatitis, jaundice, liver insufficiency and cytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangial nephritis, post-angioplastic restenosis, reperfusion syndrome, cytomegaloviral retinopathy, adenoviral diseases such as adenoviral colds, adenoviral pharyngoconjunctival fever and adenoviral ophthalmia, AIDS, Guillain-Barré syndrome, post-herpetic or post-zoster neuralgia, inflammatory demyelinising polyneuropathy, mononcuropathia multiplex, mucoviscidosis, Bcchterew's disease, Barett ocsophagus, EBV (Epstein-Barr virus) infection, cardiac remodeling, interstitial cystitis, diabetes mellitus type II, human tumour radiosensitisation, multi-resistance of malignant cells to chemotherapeutic agents (multidrug resistance in chemotherapy), granuloma annulare and cancers such as mamma carcinoma, colon carcinoma, melanoma, primary liver cell carcinoma, adenocarcinoma, kaposi's sarcoma, prostate carcinoma, leukaemia such as acute myeloid leukaemia, multiple myeloma (plasmocytoma), Burkitt lymphoma and Castleman tumour; 
 (4) a cardiovascular disease selected from the group consisting of cardiac insufficiency, myocardial infarct, angina pectoris and combinations thereof; 
 (5) a respiratory disease selected from the group consisting of asthma, chronic obstructive pulmonary diseases, PDGF induced thymidine uptake of bronchial smooth muscle cells, bronchial smooth muscle cell proliferation, and combinations thereof; 
 (6) a neurodegeneration or neuroinflammation selected from the group consisting of Adrenal Leukodystrophy (ALD), Alcoholism, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's Disease), Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cerebral palsy, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Familial Fatal Insomnia, Frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy body dementia, Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Progressive Supranuclear Palsy, Refsum's disease, Sandhoff disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjögren-Batten disease (also known as Batten disease), Spinocerebellar ataxia, Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, Toxic encephalopathy, LHON (Leber's Hereditary optic neuropathy), MELAS (Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke), MERRF (Myoclonic Epilepsy; Ragged Red Fibers), PEO (Progressive External Opthalmoplegia), Leigh's Syndrome, MNGIE (Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy), Kearns-Sayre Syndrome (KSS), NARP, Hereditary Spastic Paraparesis, Mitochondrial myopathy, and Friedreich Ataxia; or 
 (7) a demyelinating neurological disorder selected from the group consisting of optic neuritis, acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), acute transverse myelitis, progressive multifocal leukoencephalopathy (PML), acute disseminated encephalomyelitis (ADEM) or other hereditary disorders (e.g., leukodystrophies, Leber's optic atrophy, and Charcot-Marie-Tooth disease). 
 
     
     
         26 . A method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a controlled release dosage form or a unit dosage form of any of  claims 1 - 24  once per day.