US20140099364A2 - Controlled release pharmaceutical compositions comprising a fumaric acid ester - Google Patents

Controlled release pharmaceutical compositions comprising a fumaric acid ester Download PDF

Info

Publication number
US20140099364A2
US20140099364A2 US11/576,871 US57687105A US2014099364A2 US 20140099364 A2 US20140099364 A2 US 20140099364A2 US 57687105 A US57687105 A US 57687105A US 2014099364 A2 US2014099364 A2 US 2014099364A2
Authority
US
United States
Prior art keywords
fumaric acid
acid ester
composition
hours
test
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/576,871
Other languages
English (en)
Other versions
US20090304790A1 (en
Inventor
Henrik Nilsson
Florian Schoenharting
Bernd W. Mueller
Joseph R. Robinson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forward Pharma Operations Aps
Biogen Swiss Manufacturing GmbH
Original Assignee
Forward Pharma AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=50726313&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20140099364(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Forward Pharma AS filed Critical Forward Pharma AS
Priority to US11/576,871 priority Critical patent/US20140099364A2/en
Assigned to ADITECH PHARMA AB reassignment ADITECH PHARMA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEGAL HEIR TO JOSEPH R. ROBINSON (DECEASED), BONNA ROBINSON, MUELLER, BERND W., NILSSON, HENRIK, SCHOENHARTING, FLORIAN
Assigned to ADITECH PHARMA AG reassignment ADITECH PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADITECH PHARMA AB
Publication of US20090304790A1 publication Critical patent/US20090304790A1/en
Assigned to FORWARD PHARMA A/S reassignment FORWARD PHARMA A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADITECH PHARMA AG
Priority to US13/957,147 priority patent/US20130315993A1/en
Priority to US13/957,220 priority patent/US20130316003A1/en
Priority to US13/957,250 priority patent/US20140037740A1/en
Priority to US13/957,117 priority patent/US20140037720A1/en
Priority to US14/209,712 priority patent/US20140199386A1/en
Priority to US14/209,756 priority patent/US20140199393A1/en
Priority to US14/209,823 priority patent/US20150024049A1/en
Priority to US14/209,480 priority patent/US20170112793A2/en
Priority to US14/209,584 priority patent/US20140200272A1/en
Priority to US14/209,651 priority patent/US20140200273A1/en
Priority to US14/213,321 priority patent/US20140199387A1/en
Priority to US14/212,685 priority patent/US20140199392A1/en
Priority to US14/212,503 priority patent/US20140199390A1/en
Priority to US14/213,673 priority patent/US20140199388A1/en
Priority to US14/213,399 priority patent/US20140205659A1/en
Publication of US20140099364A2 publication Critical patent/US20140099364A2/en
Priority to US15/581,966 priority patent/US20170231941A1/en
Assigned to FORWARD PHARMA OPERATIONS APS reassignment FORWARD PHARMA OPERATIONS APS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FORWARD PHARMA A/S
Assigned to FWP IP APS reassignment FWP IP APS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FORWARD PHARMA OPERATIONS APS
Priority to US15/728,872 priority patent/US20180028483A1/en
Priority to US15/834,870 priority patent/US20180098957A1/en
Priority to US15/988,628 priority patent/US20180263947A1/en
Priority to US16/046,509 priority patent/US20180325855A1/en
Priority to US16/204,403 priority patent/US20190091191A1/en
Priority to US16/204,503 priority patent/US20190091192A1/en
Priority to US16/204,559 priority patent/US20190091193A1/en
Priority to US16/294,038 priority patent/US20190201368A1/en
Assigned to BIOGEN SWISS MANUFACTURING GMBH reassignment BIOGEN SWISS MANUFACTURING GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FWP IP APS
Priority to US16/525,392 priority patent/US11052062B2/en
Priority to US17/185,600 priority patent/US20210220318A1/en
Priority to US17/553,367 priority patent/US20220105064A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • 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.
  • 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®):
  • the two strengths are intended to be applied in an individually based dose regimen starting with Fumaderm® initial in an escalating dose, and then after e.g. three weeks of treatment switching to Fumaderm®.
  • Both Fumaderm® initial and Fumaderm® are enteric coated tablets.
  • Fumaraat 120® Another marketed composition is Fumaraat 120® containing 120 mg of dimethylfumarate and 95 mg of calcium monoethylfumarate (TioFarma, Oud-Beijerland, Netherlands).
  • Fumaraat 120® containing 120 mg of dimethylfumarate and 95 mg of calcium monoethylfumarate (TioFarma, Oud-Beijerland, Netherlands).
  • the pharmacokinetic profile of Fumaraat 120® is described in healthy subjects. The results show that a single oral dose of Fumaraat 120® is followed by a rise in serum monomethylfumarate concentration and only negligible concentrations of dimethylfumarate and fumaric acid is observed.
  • t max is prolonged (mean for fasted conditions is 182 min, whereas for fed conditions mean is 361 min) [lag time is 90 min for fasted and 300 min for fed] and C max is decreased (fasted: 0.84 mg/l, fed: 0.48 mg/l) by concomitant food-intake.
  • Another study (Reddingius W. G. Bioanalysis and Pharmacokinetics of Fumarates in Humans. Dissertation ETH Zurich No. 12199 (1997)) in healthy subjects with two tablets of Fumaderm® P forte revealed C max values (determined as monoethyl- or monomethylfumarate) in a range from 1.0 to 2.4 ⁇ g/ml and a t max in a range of from 4.8 to 6.0 hours.
  • U.S. Pat. No. 6,277,882 and U.S. Pat. No. 6,355,676 disclose respectively the use of alkyl hydrogen fumarates and the use of certain fumaric acid mono alkyl ester salts for preparing micro tablets for treating psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn.
  • U.S. Pat. No. 6,509,376 discloses the use of certain dialkyl fumarates for the preparation of pharmaceutical preparations for use in transplantation medicine or the therapy of autoimmune diseases in the form of micro tablets or pellets.
  • compositions containing different salts of fumaric acid monoalkyl ester alone or in combination with dialkyl fumarate disclose compositions containing different salts of fumaric acid monoalkyl ester alone or in combination with dialkyl fumarate.
  • GB 1,153,927 relates to medical compositions comprising dimethylmaleic anhydride and/or dimethylmaleic acid and/or a dimethylfumaric acid compounds.
  • compositions comprising one or more therapeutically or prophylactically active fumaric acid esters that provide an improved treatment with a reduction in gastro-intestinal related side effects upon oral administration.
  • an improved treatment regimen may be obtained by administration of a pharmaceutical composition that is designed to deliver the active substance in a controlled manner, i.e. in a manner that is prolonged, slow and/or delayed compared with the commercially available product.
  • a suitable therapeutic response may be achieved by use of a single fumaric acid ester alone such as dimethylfumaric acid.
  • the present invention relates to a pharmaceutical composition
  • 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 (gastro-intestinal) related side-effects.
  • GI gastro-intestinal
  • the present inventors contemplate that a suitable way of reducing the gastro-intestinal related side-effects is by administration of the active substance in the form of a controlled release composition.
  • the present invention relates in a further aspect to a controlled release pharmaceutical composition for oral use comprising as an active substance one or more fumaric acid esters selected from di-(C 3 -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:
  • FIG. 1 shows an example of an in vitro dissolution profile of a capsule prepared as described in example 5.
  • FIG. 2 shows an example of an in vitro dissolution profile of a sample of a tablet (before the enteric coating is applied) prepared as described in example 16.
  • FIG. 3 shows an example of an in vitro dissolution profile of a sample of a tablet (before the enteric coating is applied) prepared as described in example 17.
  • a controlled release composition is a composition that is designed to release the fumaric acid ester in a prolonged, slow and/or delayed manner compared to the release of the commercially available product Fumaderm®, when tested under comparable conditions (e.g. for in vivo studies: dose equivalents, with or without standardized meal etc., or for in vitro studies: dose equivalents, dissolution test apparatus and working conditions including e.g. composition, volume and temperature of dissolution medium employed, rotation speed etc.).
  • the release in vivo may be tested by measuring the plasma concentration at predetermined time periods and thereby obtaining a plasma concentration versus time profile for the fumaric acid ester in question or, if relevant, a metabolite thereof.
  • the active substance is envisaged to be methylhydrogenfumarate, i.e. the monomethyl ester of fumaric acid.
  • metabolism already takes place within the gastro-intestinal tract or during passage of the gastro-intestinal mucosa, or upon first passage through the hepatic circulation. Accordingly, when dimethylfumarate is administered, the relevant component to search for in the plasma may be the monomethyl ester and not the dimethylester of fumaric acid.
  • mice e.g. mice, rats, dogs etc.
  • the animals receive the compositions under investigation and after specified periods of time, the animals are sacrificed and the content of the active ingredient (or metabolite thereof, if relevant) is determined in plasma or specific organs or extracted from the intestinal contents.
  • Another test involves the use of a specific segment of an animal intestine.
  • the segment is placed in a suitable dissolution apparatus containing two compartments (a donor and a receiver) separated by the segment, and the composition under investigation is placed in a suitable medium in one compartment (the donor compartment).
  • the composition will release the active substance that subsequently is transported across the intestinal segment. Accordingly, at suitable time intervals, the concentration of the active substance (or, if relevant, the metabolite) is measured in the receiver compartment.
  • the in vivo release of the active substance is prolonged, slow and/or delayed compared with the commercially available Fumaderm® composition.
  • the term “prolonged” is intended to indicate that the active substance is released during a longer time period than Fumaderm® such as at least during a time period that is at least 1.2 times, such as, e.g., at least 1.5 times, at least 2 times, at least 3 times, at least 4 times or at least 5 times greater than that of Fumaderm®.
  • 100% of dimethylfumarate is released from Fumaderm® tablets 3 hours after the start of a suitable test
  • 100% of dimethylfumarate in a composition according to the invention is released at least 3.6 hours after the start of a suitable test.
  • the term “delayed” is intended to indicate that the release of the active substance starts at a later point in time compared with that of Fumaderm® (such as at 30 min or more later such as, e.g., 45 min or more later, 1 hour or more later or 1.5 hours or more later, alternatively, that the initial release during the first 2 hours is much less compared with that of Fumaderm® (i.e. less than 80% w/w such as, e.g., less than 70% w/w, less than 60% w/w or less than 50% of that of Fumaderm®).
  • a gastrointestinal (GI) side effect may include, but is not limited to diarrhea, stomach ache, stomach pain, abdominal pain, abdominal cramps, nausea, flatulence, tenesmus, meteorism, an increased frequency of stools, a feeling of fullness and upper abdominal cramps.
  • a reduction of GI related side effects is intended to denote a decrease in severity and/or incidence among a given treated patient population, compared to the GI side effects observed after administration of the composition according to the invention compared with that of Fumaderm®.
  • a reduction in GI related side effects according to this definition could thus be construed as a substantial reduction in incidence of any of the GI side effect listed above, such as at least a 10% reduction in incidence or more preferably at least 20% reduction in incidence or even more preferable a more than 30% reduction in incidence.
  • a reduction in GI related side effect can also be expressed as a substantial reduction in severity in any of the GI side effects listed above, such as a reduction in severity and/or frequency of diarrhea, stomach ache, stomach pain, abdominal pain, abdominal cramps, nausea, flatulence, tenesmus, meteorism, increased frequency of stools, a feeling of fullness or upper abdominal cramps.
  • the reduction of GI related side effects, as described above, can be monitored in a clinical trial setting, either comparing the administration of the composition according to the invention head on with Fumaderm® or with placebo.
  • PASI psoriasis area severity index
  • Patients with any type of psoriasis may be included (chronic plaque type, exanthematic guttate type, pustular type, psoriatic erythroderma or palmoplantar type), but in some cases only patients with the chronic plaque type are included.
  • About 15 to 20 patients in each treatment group are sufficient in most cases, but more preferably about 30 to 50 patients are included in each arm of the study.
  • Total study duration can be as short as one day to one week, but more preferably the study will run for 8 weeks to 12 weeks or up to 16 weeks.
  • the side effects can e.g.
  • the side effects can be assessed as the total number of times a certain side effect was reported in each group (irrespective of how many patients have experienced the side effect), or the side effects can be assessed as the number of patients that have experienced a certain side effect a certain number of times, such as at least once or at least twice or at least three times during the duration of the study.
  • the severity of a side effect can be monitored, or a certain severity of a side effect can be required for it to qualify as a side effect in the study.
  • a convenient way of assessing the severity of aside effect is via a visual analogue (VAS) scale.
  • VAS visual analogue
  • the active substance in a composition of the invention is any fumaric acid ester.
  • the fumaric acid ester is preferably selected from the group consisting of dimethylfumarate, diethylfumarate, dipropylfumarate, dibutylfumarate, dipentylfumarate, methyl-ethylfumarate, methyl-propylfumarate, methyl-butylfumarate, methyl-pentylfumarate, monomethylfumarate, monoethylfumarate, monopropylfumarate, monobutylfumarate and monopentylfumarate, including pharmaceutically acceptable salts thereof.
  • 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.
  • Suitable salts are e.g. metal salts such as a salt selected from alkali metal salts and alkaline earth metal salts including sodium, potassium, calcium, magnesium or zinc salt.
  • (C 1 -C 5 )alkyl refers to a branched or un-branched alkyl group having from one to five carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl and pentyl.
  • composition according to the invention comprises dimethylfumarate as the active substance.
  • composition according to the invention comprises monomethylfumarate as the active substance optionally in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
  • a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
  • composition according to the invention consists essentially of dimethylfumarate as the active substance.
  • composition according to the invention consists of dimethylfumarate as the active substance.
  • composition according to the invention consists essentially of monomethylfumarate as the active substance optionally in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
  • a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
  • composition according to the invention consists of monomethylfumarate as the active substance optionally in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
  • a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
  • composition according to the invention comprises dimethylfumarate and monomethylfumarate (optionally in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as the active substances, in a weight ratio between about 1:10 and about 10:1.
  • a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt
  • composition according to the invention consists essentially of dimethylfumarate and monomethylfumarate (optionally in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as the active substances, in a weight ratio between about 1:10 and about 10:1.
  • a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt
  • composition according to the invention consists of dimethylfumarate and monomethylfumarate (optionally in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as the active substances, in a weight ratio between about 1:10 and about 10:1.
  • a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt
  • the problem the invention solves is related to the appearance of gastro-intestinal side-effects upon oral administration of fumaric acid esters.
  • prolonging and/or delaying the release of the active substance from the composition it is envisaged that the local concentration of the active substance at specific sites of the gastro-intestinal tract is reduced (compared with that of Fumaderm®) which in turn leads to a reduction in gastro-intestinal side-effects.
  • compositions that enable a prolonged and/or a slow release of a fumaric acid ester as defined above are within the scope of the present invention.
  • SQZgelTM http://macromed.com, SQZgelTM's mechanism of action is a pH-sensitive polymer mixture combined with an outer coating. In the acidic environment of the stomach the polymer imbibes with water and swells, entrapping the drug.
  • Diffucaps Drug release profiles are created by layering active drug onto a neutral core such as sugar spheres, crystals or granules followed by a rate-controlling, functional membrane.
  • Diffucaps/Surecaps beads are small in size, approximately 1 mm or less in diameter. By incorporating beads of differing drug release profiles into hard gelatin capsules, combination release profiles can be achieved), Diffutabs (The Diffutab technology incorporates a blend of hydrophilic polymers that control drug release through diffusion and erosion of a matrix tablet), Minitabs (Eurand Minitabs are tiny (2 mm ⁇ 2 mm) tablets containing . . .
  • pellets suitable for use may have a mean particle size larger than 2000 ⁇ m. In another embodiment, pellets suitable for use may have a mean particle size of from about 0.01 ⁇ m to about 250 ⁇ m.
  • Another specific suitable formulation principle for use in the present context is formulation in a lipophilic environment such as, e.g., soft gelatin capsules.
  • a further specific example of a suitable formulation comprises the formulation of the active substance together with Vitamin E concentrate in soft or hard gelatin capsules.
  • This formulation in a modified form, is the basis of the commercial cyclosporine product, Neoral®, containing, among other things, corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL- ⁇ -tocopherol USP (part of the vitamin E family), gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium dioxide USP, carmine, and alcohol in addition to cyclosporine.
  • Neoral® containing, among other things, corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL- ⁇ -tocopherol USP (part of the vitamin E family), gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium dioxide USP, carmine, and alcohol in addition to cyclosporine.
  • the first releasing dose is compression coated on the core or air-suspension coated either with the enteric coat or on top of the enteric coat.
  • the first releasing dose is air-suspension coated with the enteric coat.
  • the first releasing dose is compression coated on the core, in order to avoid release of the composition according to the invention prior to the degradation of the enteric coat, such degradation typically occurring at pH values higher than those found in the gastric ventricle; i.e. the degradation of the enteric coat typically occurs after passage of the gastric ventricle.
  • a further example of a suitable formulation is an oral sustained drug delivery system.
  • a portion of the composition of the present invention is put in the core of a tablet.
  • the core can for example be made by conventional wet granulation or continuous granulation such as extrusion followed by compaction of the granulate into tablets.
  • the core is coated using an appropriate technology, preferably by airsuspension using ethylcellulose and a hydrophilic excipient such as hydroxyl propyl cellulose (HPC).
  • HPC hydroxyl propyl cellulose
  • the first releasing dose is compression coated on the core or air-suspension coated either with the enteric coat or on top of the enteric coat.
  • the first releasing dose is air-suspension coated with the enteric coat.
  • the first releasing dose is compression coated on the core, in order to avoid release of the composition according to the invention prior to the degradation of the enteric coat, such degradation typically occurring at pH values higher than those found in the gastric ventricle; i.e. the degradation of the enteric coat typically occurs after passage of the gastric ventricle.
  • a further example of a suitable formulation is obtained via crystal engineering, such as e.g. described in WO 03/080034, which is hereby incorporated by reference.
  • composition of the invention comprises the active substance in the form of micro-crystals with hydrophilic surfaces.
  • micro-crystals are filmcoated directly, in order to achieve a sustained release formulation.
  • a suitable formulation comprises complexation of the composition according to the present invention with genuine cyclodextrins and cyclodextrin-derivatives (e.g. alkyl- and hydroxyalkyl-derivatives or sulfobutyl-derivatives).
  • the complexation is achieved in accordance with well known methods. It is contemplated that such a complexation leads to a higher solubility and a higher dissolution rate of the composition according to the invention, compared to the composition prior to complexation. Furthermore, it is contemplated that such a complexation leads to a higher bioavailability of the composition according to the invention, compared to the composition prior to complexation.
  • ком ⁇ онентs include e.g. matrix tablets or dosage form containing a multiplicity of units each in the form of a matrix system.
  • the active substance is embedded in a matrix containing e.g. cellulose and cellulose derivatives including microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and methylcellulose, povidone, poly(ethyleneoxide) (PEO), polyethylene glycol (PEG), poly(vinyl alcohol) (PVA), xanthan gum, carrageenan and other synthetic materials.
  • PEO poly(ethyleneoxide)
  • PEG polyethylene glycol
  • PVA poly(vinyl alcohol)
  • xanthan gum xanthan gum
  • carrageenan and other synthetic materials.
  • Substances normally used as pharmaceutically acceptable excipients or additives may be added to a matrix composition.
  • compositions are e.g. hydrogels, i.e. monolithic systems wherein the active substance is embedded in a water-swellable network polymer.
  • Materials suitable for use include e.g. hydrophilic vinyl and acrylic polymers, polysaccharides like alginates, and polyethylene oxide).
  • a composition according to the invention has a pH controlled release (also known as a pH dependent release) of the fumaric acid ester.
  • a pH controlled release also known as a pH dependent release
  • the release is designed so that only a small amount, if any, of the fumaric acid ester is released in the stomach (pH up to about 3), whereas the fumaric acid ester is released in the intestines (pH shifts to about 6-7).
  • a pH controlled release can be obtained by providing a composition of the invention with an enteric coating (the whole composition or, if the composition is a multiparticulate composition, the individual units) or by providing a composition that releases the fumaric acid by a pH-dependent osmotic mechanism, or by employment of suitable enzymes.
  • compositions mentioned above having a pH independent release may also be formulated to release the fumaric acid ester e.g. by providing the composition with an outer layer of an enteric coating.
  • compositions may be formulated in such a manner that an initial delay in release of the fumaric acid ester is obtained.
  • a delay may be obtained e.g. by choosing an outermost coating that in a time-controlled manner degrades (e.g. erodes) and only when this outermost coating is eroded away, the release of the fumaric acid ester starts.
  • compositions provided with a diffusion coating such as a controlled release diffusion coating, matrix particulates or matrix tablets, hydrogels, pulsed dose drug delivery systems, co-formulation with vitamin E concentrate or ethanol, TPGS, corn oil and wax etc., including any of the formulation principles mentioned above.
  • 85% w/w such as, e.g., from about 50% to about 85% w/w, from about 60% to about 80% w/w, or about 75% of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • compositions provided with an enteric coating or hydrogels of a type described by Zentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No. 5,484,610), which hereby are incorporated by reference.
  • suitable formulation principles are e.g. compositions provided with an enteric coating or hydrogels of a type described by Zentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No. 5,484,610), which hereby are incorporated by reference.
  • Further examples of suitable formulation principles are e.g.
  • the invention relates to 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 or 6.8 as dissolution medium—is as follows:
  • the most about 98% w/w such as, e.g., from about 45% to about 98% w/w, from about 50% to about 98% w/w, from about 55% to about 98% w/w, from about 60% to about 98% w/w, from about 65% to about 98% w/w, from about 70% to about 98% w/w, from about 75% to about 95% w/w, from about 80% to about 95% w/w, from about 85% to about 95% w/w, or about 75% w/w, or about 80% w/w, or about 85% w/w, or about 90% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • 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, characterized in that it consists of a controlled-release dosage form adapted to release di-(C 1 -C 5 )alkylester and/or a mono-(C 1 -C 5 )alkylester of fumaric acid or a pharmaceutically acceptable salt thereof over a predetermined time period, according to a in vitro profile of dissolution when measured according to USP in 0.1 N hydrochloric acid during the first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or 6.8,
  • a controlled release 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, characterized in that it consists of a controlled-release dosage form adapted to release di-(C 1 -C 5 )alkylester and/or a mono-(C 1 -C 5 )alkylester of fumaric acid or a pharmaceutically acceptable salt thereof over a predetermined time period, according to a in vitro profile of dissolution when measured according to USP in 0.1 N hydrochloric acid during the first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or 6.8,
  • compositions provided with an enteric coating or hydrogels of a type described by Zentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No. 5,484,610), which hereby are incorporated by reference.
  • suitable formulation principles are e.g. compositions provided with an enteric coating or hydrogels of a type described by Zentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No. 5,484,610), which hereby are incorporated by reference.
  • Further examples of suitable formulation principles are e.g.
  • compositions provided with a diffusion coating such as a controlled release diffusion coating, matrix particulates or matrix tablets, hydrogels, pulsed dose drug delivery systems, co-formulation with vitamin E concentrate or ethanol, TPGS, corn oil and wax etc., including any of the formulation principles mentioned above, optionally with an enteric coating.
  • a diffusion coating such as a controlled release diffusion coating, matrix particulates or matrix tablets, hydrogels, pulsed dose drug delivery systems, co-formulation with vitamin E concentrate or ethanol, TPGS, corn oil and wax etc., including any of the formulation principles mentioned above, optionally with an enteric coating.
  • composition of the simulated gastric fluid can e.g. be found in the United States Pharmacopeia (USP) 2005:
  • 100 mL of synthetic/simulated gastric fluid contains 290 mg of NaCl, 70 mg of KCl, 27 mg of KH 2 PO 4 and enough HCl to adjust the pH to 2.0. In addition, it contains 100 mg pepsin and 300 mg of mucin.
  • composition of the simulated intestinal fluid can e.g. be found in the United States Pharmacopeia (USP) 2005:
  • 100 mL of synthetic/simulated intestinal fluid contains 30 mg of KCl, 50 mg of CaCl 2 , 20 mg of MgCl 2 and sufficient NaHCO 3 to adjust the pH to 7.5. Furthermore, it contains 30 mg of trypsin, 900 mg of pancreatin, 900 mg of lyophilized bile and 30 mg of urea.
  • the “half-change” method is carried out with the simulated gastric fluid and the simulated intestinal fluid as defined by the USP 2005.
  • the “half-change” method is carried out with the simulated gastric fluid and the simulated intestinal fluid as defined by the USP 2005, but without the proteins (i.e. without the pepsin in the simulated gastric fluid, and without the pancreatin in the simulated intestinal fluid).
  • 12% w/w such as, e.g., from about 12% to about 50% w/w, from about 15% to about 45% w/w, from about 20% to about 40% w/w, from about 20% to about 35% w/w, from about 22% to about 35% w/w, or about 25% w/w, or about 30% w/w of the total amount of the fumaric acid ester is released, and/or
  • 40% w/w such as, e.g., from about 10% to about 40% w/w, from about 15% to about 35% w/w, from about 20% to about 30% w/w, or about 25% w/w, or about 30% w/w of the total amount of the fumaric acid ester is released, and/or
  • At least about 81% w/w such as, e.g., from about 81% to about 96% w/w, from about 85% to about 95% w/w, from about 85% to about 90% w/w, or about 80% w/w, or about 85% w/w, or about 90% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • the most about 50% w/w such as, e.g., from about 20% to about 50% w/w, from about 25% to about 45% w/w, from about 30% to about 45% w/w, or about 40% w/w, or about 45% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • the composition within the first 7 hours after start of the test at least about 82% w/w such as, e.g., from about 82% to about 99% w/w, from about 85% to about 99% w/w, from about 85% to about 95% w/w, or about 90% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • 65% w/w such as, e.g., from about 25% to about 65% w/w, from about 30% to about 65% w/w, from about 35% to about 60% w/w, from about 40% to about 60% w/w, from about 50% to about 60% w/w, or about 55% w/w, or about 60% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • 85% w/w such as, e.g., from about 50% to about 85% w/w, from about 60% to about 80% w/w, or about 75% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • the most about 92% w/w such as, e.g., from about 30% to about 92% w/w, from about 35% to about 90% w/w, from about 40% to about 85% w/w, from about 45% to about 80% w/w, from about 50% to about 75% w/w, from about 55% to about 75% w/w, from about 60% to about 75% w/w, or about 65% w/w, or about 70% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more of the total amount of the fumaric acid ester contained in the composition is released.
  • the invention relates to 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 water as dissolution medium—is as follows:
  • 85% w/w such as, e.g., from about 50% to about 85% w/w such as, e.g., from about 60% to about 80% w/w, or about 75% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • compositions provided with a diffusion coating such as a controlled release diffusion coating, matrix particulates or matrix tablets, hydrogels, pulsed dose drug delivery systems, co-formulation with vitamin E concentrate or ethanol, TPGS, corn oil and wax etc., including any of the formulation principles mentioned above.
  • 85% w/w such as, e.g., from about 50% to about 85% w/w, from about 60% to about 80% w/w, or about 75% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • the invention relates to 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 or 6.8 as dissolution medium—is as follows:
  • the most about 98% w/w such as, e.g., from about 45% to about 98% w/w, from about 50% to about 98% w/w, from about 55% to about 98% w/w, from about 60% to about 98% w/w, from about 65% to about 98% w/w, from about 70% to about 98% w/w, from about 75% to about 95% w/w, from about 80% to about 95% w/w, from about 85% to about 95% w/w, or about 75% w/w, or about 80% w/w, or about 85% w/w, or about 90% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • the invention relates to 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 according to the “half-change” method—is as follows:
  • 99% w/w such as, e.g., from about 30% to about 99% w/w, from about 30% to about 95% w/w, from about 35% to about 90% w/w, from about 40% to about 85% w/w, from about 45% to about 80% w/w, from about 50% to about 75% w/w, from about 55% to about 75% w/w, from about 60% to about 75% w/w, or about 65% w/w, or about 70% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • 85% w/w such as, e.g., from about 50% to about 85% w/w, from about 60% to about 80% w/w, or about 75% w/w of the total amount of the fumaric acid ester contained in the composition is released, and/or
  • 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more of the total amount of the fumaric acid ester contained in the composition is released.
  • 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more of the total amount of the fumaric acid ester contained in the composition is released.
  • 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.
  • 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
  • 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
  • the C max of the monoalkylester of fumaric acid which appears in the plasma upon hydrolysis or metabolism of the dialkylester administered
  • a similar or equivalent dose is administered (i.e.
  • W 50 i.e. the time period in which the plasma concentration is 50% of C max or more
  • W 50 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 W 50 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.
  • 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®.
  • M t is the cumulative amount of drug released at any specified time point and M 0 is the dose of active substance incorporated in the pharmaceutical composition.
  • k 0 , k 1 and k H are rate constants for zero-order, first-order and Higuchi's equation, respectively.
  • One aspect of the invention relates to a zero-order dissolution release profile. Another aspect relates to a first-order dissolution release profile. A further aspect relates to a square-root (Higuchi's equation) dissolution release profile.
  • 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, is provided.
  • a controlled release pharmaceutical composition 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, is provided.
  • a controlled release pharmaceutical composition 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, is provided.
  • “pharmaceutically acceptable polymer(s)” comprises but are not limited to ethylcellulose, or methacrylic/acrylic acid copolymers, such as ammonio methacrylate copolymer type A and B or methacrylic acid copolymer A and B.
  • hydrophilic excipient(s) comprises but are not limited to polyethylene glycol (PEG), povidone, hydroxyl propyl cellulose (HPC), hydroxyethyl starch (HES) or hydroxypropyl methyl cellulose (HPMC) or a material with similar properties, or a combination thereof.
  • PEG polyethylene glycol
  • HPC hydroxyl propyl cellulose
  • HES hydroxyethyl starch
  • HPMC hydroxypropyl methyl cellulose
  • a controlled release pharmaceutical composition wherein the pharmaceutically acceptable polymer is ethyl cellulose, is provided.
  • a controlled release pharmaceutical composition wherein the hydrophilic excipient is hydroxyl propyl cellulose, is provided.
  • a controlled release pharmaceutical composition wherein the hydrophilic excipient is polyethylene glycol, is provided.
  • a controlled release pharmaceutical composition comprising as an active substance 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, is provided.
  • a controlled release pharmaceutical composition 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, is provided.
  • Granules may be prepared by mixing and/or granulating the active substance at a concentration of about 10 to about 90%, especially from about 50 to about 70%, with granulating excipients, such as pharmaceutical acceptable polymers, e.g. ethylcellulose such as Ethocel® NF premium, or methacrylic/acrylic acid copolymers, such as ammonio methacrylate copolymer type A and B (in a weight ratio of 1:9 to 9:1) or methacrylic acid copolymer A and B (in a weight ratio of 1:9 to 9:1), incorporated at a concentration between about 2 to about 40%.
  • pharmaceutical acceptable polymers e.g. ethylcellulose such as Ethocel® NF premium
  • methacrylic/acrylic acid copolymers such as ammonio methacrylate copolymer type A and B (in a weight ratio of 1:9 to 9:1) or methacrylic acid copolymer A and B (in a weight ratio
  • Hydrophilic excipients such as polyethylene glycol (PEG), povidone, hydroxyl propyl cellulose (HPC), hydroxyethyl starch (HES) or hydroxypropyl methyl cellulose (HPMC) at a concentration of about 1 to about 40% and/or pharmaceutical acceptable surfactants with HLB values above 8 at a concentration of about 0.01 to about 3% may be incorporated.
  • PEG polyethylene glycol
  • HPC hydroxyl propyl cellulose
  • HES hydroxyethyl starch
  • HPMC hydroxypropyl methyl cellulose
  • Crystallization is performed in any suitable organic solvent for re-crystallisation, such as isopropanol, at an appropriate temperature such as e.g. between +70° C. and ⁇ 20° C.
  • a hydrocolloid e.g. HPMC
  • a surfactant e.g. polysorbate
  • Any granulating/coating excipient such as pharmaceutically acceptable polymers, may be used e.g. ethylcellulose at a concentration of about 10 to about 50%, especially about 20 to about 35%, polymethacrylates such as ammonio methacrylate copolymer type A and B or methacrylic acid copolymer A and B.
  • a hydrophilic excipient mention can be made of e.g PEG 400.
  • a capsule e.g. a capsule of gelatine, HPMC or a starch derivative
  • a sachet may be filled with coated micro-crystals or coated granules and if necessary appropriate amounts of filling excipients such as sugaralcoholes e.g. mannitol, and/or glidants.
  • Tablets may be based on either micro-crystals or granules. When it comes to producing tablets in large scale, especially on a rotary machine, further excipients to increase flow ability or to improve tabletting-behaviour may be needed.
  • filling and binding excipients if required, mention can be made of e.g. microcrystalline cellulose, such as Avicel® 102, and cellulose at a concentration of about 1 to about 60%, crystalline, spray dried or granulated lactose monohydrate e.g.
  • Tablettose® as well as anhydrous lactose monohydrate, at a concentration of about 5 to about 60%, sugar alcohols, such as sorbitol and mannitol, at a concentration of about 0 to about 40% and modified starch at a concentration of about 0 to about 40%.
  • disintegration agents such as starch and starch-derivates such as sodium starch glycolate (at a concentration of about 0.2 to about 10%), crospovidone (at a concentration of about 0.2 to about 10%), sodium carboxymethylcellulose (at a concentration of about 0.1 to about 10%), glidants such as colloidal anhydrous and hydrous silica (at a concentration of about 0.2 to about 4%), and lubricants, e.g. magnesium stearate, calcium behenate, and calciumarachinate (at a concentration of about 0.2 to about 3%) or sodium stearyl fumarate (at a concentration of about 1 to about 8%) can be added.
  • kits containing two or more containers e.g. with compositions having various amounts of the fumaric acid included. Such kits are suitable for use in those situations where an increasing dosage is required over time.
  • a normal up-scale of the dosage is given in Table 2 below:
  • A corresponds to a low strength such as about 30 mg dimethylfumarate (or a corresponding effective dose of another fumaric acid ester)
  • B corresponds to a higher strength such as about 120 mg dimethylfumarate (or a corresponding effective dose of another fumaric acid ester)
  • a controlled release pharmaceutical composition 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, such as 90, 120, 180, 240 or 360 mg active substance, is provided.
  • the amount of active substance is 120, 180 or 240 mg active substance.
  • the amount of active substance is 180 or 360 mg.
  • the daily dosage of the controlled release pharmaceutical composition according to the invention that is administered to treat a patient depends on a number of factors among which are included, without limitation, weight and age and the underlying causes of the condition or disease to be treated, and is within the skill of a physician to determine.
  • the daily dosage can be e.g.
  • the controlled release pharmaceutical composition is in the form of a capsule.
  • the controlled release pharmaceutical composition in the form of a tablet is provided, such as a tablet which has a shape that makes it easy and convenient for a patient to swallow e.g. a tablet which has a rounded or a rod-like shape without any sharp edges.
  • a pharmaceutical composition in the form of a tablet designed to be divided into two or more parts is provided.
  • compositions according to the invention may be administered together with a meal or in relation to a meal such as e.g. in a time period corresponding to a range from at least about 30 minutes before a meal to about 2 hours after the meal, or the composition may be administered at any specific point(s) in time during the day.
  • the total daily dose is given at bedtime, such as up to or about 30 minutes before bedtime, up to or about 60 minutes before bedtime, up to or about 90 minutes before bedtime, up to or about 120 minutes before bedtime or up to or about 180 minutes before bedtime.
  • compositions and kits according to the invention are contemplated to be suitable to use in the treatment of one or more of the following conditions:
  • novel composition or kit according to the invention may be used in the treatment of
  • Psoriasis has been proposed to potentially be associated with Crohn's disease (Najarian D J, Gottling A B, Connections between psoriasis and Crohn's disease. J Am Acad Dermatol. 2003 June; 48(6):805-21), celiac disease (Ojetti V et al, High prevalence of celiac disease in psoriasis. Am J. Gastroenterol. 2003 November; 98(11):2574-5.), psychiatric or psychological disease, such as depression or a life crisis (Gupta M A, Gupta A K, Psychiatric and psychological co-morbidity in patients with dermatologic disorders: epidemiology and management. Am J Clin Dermatol.
  • the present invention thus relates in one aspect to 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 controlled release pharmaceutical composition according the
  • the present invention relates in another aspect to the use of a controlled release pharmaceutical composition according to the invention 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.
  • autoimmune diseases such as polyarth
  • the invention also relates to treating an individual suffering from one of the conditions in the abovementioned lists, more specifically psoriasis or psoriatic arthritis, with a composition or kit according to the invention, said individual further being in treatment with
  • a topical anti-psoriatic drug such as 1) vitamin D or derivatives thereof (calcipotriol, calcipotriene), 2) a corticosteroid (such as e.g. betamethasone, desoximethasone, fluocinolone, momethasone, hydrocortisone aceponate, fluticasone, clobethasol, clobethasone, hydrocortisone butyrate, desonide, triamcinolone or hydrocortisone), 3) tazaroten, 4) ditranol, 5) tacrolimus (FK-506), and other calcineurin inhibitors, such as pimecrolimus or 6) any combination of 1-5 and/or
  • a topical anti-psoriatic drug such as 1) vitamin D or derivatives thereof (calcipotriol, calcipotriene), 2) a corticosteroid (such as e.g. betamethasone, desoximethasone, fluocinolone, mometh
  • an oral anti-psoriatic drug such as 1) an oral retinoid (such as acitretin or etretinate) combined or not combined with PUVA, 2) cyclosporine and other calcineurin inhibitors, such as ISA247, tacrolimus and pimecrolimus, 3) methotrexate, 4) hydroxyurea, 5) azathioprine, 6) sulphasalazine, 7) a fumarate derivative (such as e.g.
  • rosiglitazone (Avandia) and other peroxisome proliferator-activated- ⁇ (PPAR ⁇ ) agonists or modulators, such as pioglitazone, farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10, MBX-1828, MBX-2044, CLX-0921, R-483, Jritazar, naveglitazar (LY-519818/LY-818), netoglitazone (MCC-555), CS-7017, troglitazone, ciglitazone, tesaglitazar, isaglitazone, balaglitazone, muraglitazar, TAK-654, LBM642, DRF 4158, EML 4156, T-174, TY-51501, TY-12780, VDO-52 or AMG-131(T131) or any combination of 1-8 and/or
  • a parenterally administered anti-psoriatic drug such as 1) alefacept (Amevive), 2) etanercept (Enbrel), 3) efalizumab (Raptiva), 4) onercept, 5) adalimumab (Humira) or any combination of 1-5 and/or
  • an inhibitor of TNF- ⁇ not mentioned in the list under section c) above e.g. CDP 870 or infliximab (Remicade)
  • an inhibitor of TNF- ⁇ not mentioned in the list under section c) above e.g. CDP 870 or infliximab (Remicade)
  • administered via an enteral or parenteral route e.g. CDP 870 or infliximab (Remicade)
  • An NSAID or a COX or a LOX inhibitor such as e.g. a COX-2 inhibitor or a COX/5-LOX inhibitor, and/or
  • an anti-diabetic or anti-obesity drug such as biguanides such as metformin; metformin XR; a sulphonylurea such as chlorpropamide, glipizide, gliclazide, glyburide/glibenclamide or glimepiride; Glucovance (metformin+glyburide); Metaglip (glipizide+metformin); a peroxisome proliferator-activated- ⁇ (PPAR ⁇ ) agonist or modulator, such as rosiglitazone (Avandia), pioglitazone, farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10, MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar, naveglitazar (LY-519818/LY-818), netoglitazone (MCC-555), CS-7017, troglitazone
  • a drug potentially useful in the treatment of substance abuse e.g. alcohol abuse such as naltrexone, acamprosate, disulphiram or Vivitrex (naltrexone long acting injection), and/or,
  • Suitable NSAIDs are piroxicam, diclofenac, nabumetone, propionic acids including naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates including mefenamic acid, paracetamol, indomethacin, sulindac, meloxicam, apazone, pyrazolones including phenylbutazone, salicylates including aspirin.
  • COX-2 inhibitors examples include rofecoxib (Vioxx), valdecoxib (Bextra), celecoxib (Celebrex), etoricoxib (Arcoxia), lumiracoxib (Prexige), parecoxib (Dynastat), deracoxib (Derain); tiracoxib, meloxicam, nimesolide, (1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran carboxylic acid (CT-3), 2(5H)-Furanone, 5,5-dimethyl (l-methylethoxy) [4(methylsulfonyl)phenyl]—(DFP); Carprofen (RIMADYL), (Acetyloxy)-benzoic acid, 3-[(nitrooxy)methyllphenyl ester (NCX4016), P54 (CAS Reg.
  • COX/5-LOX inhibitors examples include licofelone (ML-3000 or [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-yl]-acetic acid), di-tert-butylphenols, such as (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidence)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474), darbufelone or tebufelone and pharmacologically active metabolites as well as derivatives such as dihydro-dimethyl-benzofuran and PGV-20229, dihydro-dimethyl-benzofuran, thiophene derived compounds such as RWJ-63556, N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl)-butanamide (S
  • 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:
  • 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/or
  • 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/or
  • 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/or
  • a proton pump inhibitor 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/or
  • PPI proton pump inhibitor
  • an NSAID or a COX or a LOX inhibitor such as e.g. a COX-2 inhibitor or a COX/5-LOX inhibitor, and/or
  • pentoxifylline e.g. at a dose range of from 400 to 800 mg/day.
  • the active substance is a fumaric acid ester containing compound.
  • the fumaric ester containing compound is any and all of the salts contained in Fumaderm® or Fumaraat® or Panaclar® (BG-12) or described in U.S. Pat. No. 6,277,882, U.S. Pat. No. 6,355,676 or U.S. Pat. No. 6,509,376 or a formulation according to the present invention.
  • the active pharmaceutical ingredient may be provided in a formulation according to the present invention, or any Fumaderm® or Fumaraat® or Panaclar® formulation or as e.g. described in U.S. Pat. No. 6,277,882, U.S. Pat. No. 6,355,676 or U.S. Pat. No. 6,509,376.
  • 200 g granules are mixed with 150 g microcrystalline cellulose (e.g. Avicel® 102), 97.5 g lactose (e.g. Tablettose®), 10 g sodium carboxymethylcellulose (e.g. Ac-Di-Sol®) and 25 g starch for 30 min. Then 10 g magnesium stearate and 7.5 g amorphous silicium dioxide (e.g. Aerosil® 200) is added and the powder mixture is mixed for 5 min.
  • microcrystalline cellulose e.g. Avicel® 102
  • 97.5 g lactose e.g. Tablettose®
  • 10 g sodium carboxymethylcellulose e.g. Ac-Di-Sol®
  • 10 g magnesium stearate and 7.5 g amorphous silicium dioxide e.g. Aerosil® 200
  • This powder mixture is compressed to tablets in tabletting equipment (tablet diameter 10 mm, surface about 280-300 mm 2 ).
  • the tablets are enteric coated in a pan-coating or in a fluid-bed coating process as described in Example 4.
  • 200 g micro-crystals are mixed with 150 g microcrystalline cellulose (e.g. Avicel® 102), 130 g lactose (e.g. Tablettose®), 10 g of sodium carboxymethylcellulose (e.g. Ac-Di-Sol®) and 25 mg starch for 30 min. Then 10 g magnesium stearate and 7.5 g of amorphous silicium dioxide is added and the powder mixture is mixed for 5 min. This powder mixture is compressed to tablets in tabletting equipment (tablet diameter 10 mm, surface about 280-300 mm 2 ). The tablets are enteric coated in a pan-coating or in a fluid-bed coating process as described in Example 4.
  • microcrystalline cellulose e.g. Avicel® 102
  • lactose e.g. Tablettose®
  • 10 g of sodium carboxymethylcellulose e.g. Ac-Di-Sol®
  • 10 g magnesium stearate and 7.5 g of amorphous silicium dioxide is
  • Granules or micro-crystals are filled in HPMC capsules and these capsules are enteric coated as described in the following.
  • Eudragit® L30D-55 is sprayed at drying temperatures of 60° C. to 80° C. onto the capsules in an amount of 20 mg polymeric material per mm 2 .
  • Pigments and talc are added in an appropriate amount.
  • Eudragit® L30D-55 is sprayed at drying temperatures of 60° C. to 80° C. onto the tablets in an amount of 6 mg polymeric material per mm 2 . Pigments and talc are added in an appropriate amount.
  • micro-crystals prepared as described in Example 15, is filled in a hard-gelatine-capsule size 0.
  • the capsules are enteric coated by dipping them into a solution of 5% HPMCP (Pharmacoat HP 50®) in acetone four times each capsule-side.
  • dimethylfumarate in the following DMF
  • 1 g ethyl cellulose e.g. Ethocel® NF premium
  • 10 ml ethanol 96% passed through a sieve 1.0 mm and dried at 50° C. to 60° C. for 30 min.
  • PVA polyvinylacetate
  • a granulation process 50 g DMF is directly mixed with 5 g Eudragit® RL30D, passed through a sieve (1.00 mm) and dried at 80° C. After sieving the granules are coated in a fluid-bed coater (Mini-Glatt) with 15 g of a 1:1 mixture Eudragit® RL30D/RS30D. The coated granules can be manufactured to tablets and capsules using the same process as described in Examples 1 and 3.
  • ethyl cellulose e.g. Ethocel® NF premium
  • polyethylene glycole 6000 are added to the granulation liquid.
  • the mixture is passed through a sieve 1.00 mm and dried at 50° to 60° C. for 30 min.
  • After sieving the granules are coated in a fluid-bed coated (Mini-Glatt) with a 2:1 mixture of ethyl cellulose and polyethylene glycole 6000 in an amount of 20 mg per mm 2 granules surface area.
  • These granules can be manufactured to tablets or capsules using the processes described in Examples 1 and 3.
  • ethyl cellulose e.g. Ethocel® NF premium
  • ethanol 96% ethocel® NF premium
  • povidone e.g. Kollidon® 25
  • the mixture is passed through a sieve 1.00 mm and dried at 50° to 60° C. for 30 min. After sieving the granules are coated in a fluid-bed coated (Mini-Glatt) with a 3:2 mixture of ethyl cellulose and povidone in an amount of 20 mg per mm 2 granule surface area.
  • ethyl cellulose e.g. Ethocel® NF premium
  • HPC hydroxypropyl cellulose
  • the mixture is passed through a sieve 1.00 mm and dried at 50° to 60° C. for 30 min. After sieving, the granules are coated in a fluid-bed coater (mini-Glatt) with a 2:1 mixture of ethyl cellulose and HPC in an amount of 20 mg per mm 2 granule surface area.
  • a granulation process 50 g DMF is directly mixed with an appropriate amount of an aqueous dispersion of Eudragit® NE30D, passed through a sieve (1.00 mm) and dried at 80° C. After sieving the granules are coated in a fluid-bed coater (Mini-Glatt) with 15 g of a 1:1 mixture Eudragit® RL30D/RS30D. The coated granules can be manufactured to tablets and capsules using the processes described in Examples 1 and 3.
  • a granulation process 50 g DMF is directly mixed with an appropriate amount of an aqueous dispersion of Eudragit® RL30D, passed through a sieve (1.00 mm) and dried at 80° C. After sieving, the granules are coated in a fluid-bed coater (Mini-Glatt) with Eudragit® NE30D. The coated granules can be manufactured to tablets and capsules using the processes described in Examples 1 and 3.
  • a saturated solution of 50 g DMF in 300 ml 2-propanol is prepared at 60° C. and slowly cooled under permanent stirring. The precipitated crystals are filtered off and dried at 50° C. The crystals are sieved and the 315-710 ⁇ m fraction is used for a coating process in either a pan coater or a fluid-bed coater (Mini-Glatt).
  • a coating solution of 12 g ethyl cellulose (e.g. Ethocel® NF premium) and 3 g polyethylene glycole 400 in 500 g ethanol is sprayed at 60° C. onto the powder surface. After drying, the coated crystals are sieved through a 1.00 mm sieve. These coated DMF crystals can be manufactured to tablets and capsules using the processes described in Examples 2 and 3.
  • a granulation process 50 g DMF is mixed with 12 g Ethylcellulose (e.g. Ethocel® NF premium) and 3 g Polyethylenglycole 400 which is dissolved in 150 ml Ethanol 96%, passed through a 1.0 mm sieve, dried at 50° to 60° C. over 30 min and again passed through a sieve 1.0 mm.
  • a placebo granulate is prepared as follows: Tablettose® and Avicel® 102 are mixed in equal shares and granulated with 2% povidone (e.g. Kollidon® 25) dissolved in water (q.s.), passed through a 1.0 mm sieve, dried at 50° to 60° C.
  • the blend is compressed to tablets with a diameter of 10 mm, a weight of about 260 mg and a hardness of about 50 N.
  • the tablets are enteric coated using the processes described in Example 4.
  • a granulation process 50 g DMF is mixed with 12 g Ethylcellulose (e.g. Ethocel® NF premium) and 3 g Polyethylenglycole 400 which is dissolved in 150 ml Ethanol 96%, passed through a 1.0 mm sieve, dried at 50° to 60° C. over 30 min and again passed through a sieve 1.0 mm.
  • a placebo granulate is prepared as follows: Tablettose® and Avicel® 102 are mixed in equal shares and granulated with 2% povidone (e.g. Kollidon® 25) dissolved in water (q.s.), passed through a 1.0 mm sieve, dried at 50° to 60° C.
  • the blend is compressed to tablets with a diameter of 10 mm, a weight of about 260 mg and a hardness of about 50 N.
  • the tablets are enteric coated using the processes described in Example 4.
  • a saturated solution of 50 g DMF in 300 ml 2-propanol is prepared at 60° C. and slowly cooled under permanent stirring. The precipitated crystals are filtered off and dried at 50° C. The crystals are sieved and the 315-710 ⁇ m fraction is used for a coating process in either a pan coater or a fluid-bed coater (Mini-Glatt).
  • a coating solution of 12 g ethyl cellulose (e.g. Ethocel® NF premium) and 3 g povidone (PVP) in 500 g ethanol is sprayed at 60° C. onto the surface of the crystals. After drying the coated crystals are sieved through a 1.00 mm sieve.
  • the coated DMF crystals can be manufactured to tablets and capsules using the processes described in Example 2 and 3.
  • a saturated solution of 50 g DMF in 300 ml 2-propanol is prepared at 60° C. and slowly cooled under permanent stirring. The precipitated crystals are filtered off and dried at 50° C. The crystals are sieved and the 315-710 ⁇ m fraction is used for a coating process in either a pan coater or a fluid-bed coater (Mini-Glatt).
  • a coating solution of 12 g ethyl cellulose (e.g. Ethocel® NF premium) and 3 g hydroxylpropylcellulose (HPC) in 500 g ethanol is sprayed at 60° C. onto the powder surface. After drying the coated crystals are sieved through a 1.00 mm sieve.
  • These coated DMF crystals can be manufactured to tablets and capsules using the processes described in Examples 2 and 3.
  • DMF-crystals are prepared as described in Example 15, but 2% of ethyl cellulose, related to the mass of the crystals, is added directly to the 2-propanol before precipitation of the crystals.
  • DMF crystals prepared as described in Example 15 are directly mixed with 25% solid Eudragit® RS PO/Rt. PO in a ratio of 1:2 and manufactured to tablets as described in Example 2.
  • diethylfumarate (DEF) is mixed with 15% ethyl cellulose (e.g. Ethocel® NF premium) which is dissolved in an appropriate amount of ethanol 96%.
  • ethyl cellulose e.g. Ethocel® NF premium
  • polyethylene glycole 6000 is added to the granulation liquid.
  • the mixture is passed through a sieve 1.00 mm and dried at 50° to 60° C. for 30 min.
  • a granulate is prepared as described in Example 24 but instead of PEG 6000, 10% of povidone (e.g. Kollidon® 25) is added. This mixture can be manufactured to tablets or capsules using the processes described in Examples 1 and 3.
  • povidone e.g. Kollidon® 25
  • Example 15 50 g DMF crystals prepared as described in Example 15 are coated in a fluid-bed coater (Mini-Glatt) at a temperature of 80° C. with 20 g of an aqueous dispersion of a 1:1 mixture of Eudragit® RL30D/RS30D.
  • the coated crystals are enteric coated in a pan coater as described in the following.
  • Eudragit® L30D-55 are sprayed at drying temperatures of 60° C. to 80° C. onto the coated crystals in an amount of 6 mg polymeric material per mm 2
  • Ethylcellulose e.g. Ethocel® NF premium
  • 3 g hydroxypropyl cellulose e.g. Klucel®
  • Tablettose® and Avicel® 102 are mixed in equal shares and granulated with 2% povidone (Kollidon® 25) dissolved in water (q.s.). 60 parts of the DMF-granulate and 38 parts of the placebo-granulate are mixed for 30 minutes in a Turbula Shaker Mixer. One part Aerosil® 200 and one part magnesium stearate are added and the blend is mixed again for 5 minutes.
  • the amount of DMF is determined by HPLC (Kontron XXX) using a Merck LiChroCART RP8 5 ⁇ M, 20 cm column, tempered at 25° C.
  • the mobile phase consists of a mixture (35:65) of acetonitrile and 0.0725 mol/l NaH 2 PO 4 *H 2 O-buffer adjusted to pH 3.2 with phosphoric acid.
  • the UV detector is set at a wavelength of 230 nm and a flow rate of 1.0 ml per minute.
  • the DMF peak is detectable after a retention time of about 5 min.
  • the dissolution profile of capsules prepared as described in Example 5 is determined as described in Example 30.
  • the dissolution profile is shown in FIG. 1 .
  • the dissolution profile of the tablets (before the enteric coating is applied) prepared as described in example 16 is determined as described in Example 31.
  • the dissolution profile is shown in FIG. 2 .
  • the dissolution profile of the tablets (before the enteric coating is applied) prepared as described in example 17 is determined as described in Example 31.
  • the dissolution profile is shown in FIG. 3 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US11/576,871 2004-10-08 2005-10-07 Controlled release pharmaceutical compositions comprising a fumaric acid ester Abandoned US20140099364A2 (en)

Priority Applications (28)

Application Number Priority Date Filing Date Title
US11/576,871 US20140099364A2 (en) 2004-10-08 2005-10-07 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,147 US20130315993A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,220 US20130316003A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,250 US20140037740A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,117 US20140037720A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,712 US20140199386A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,823 US20150024049A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,756 US20140199393A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,480 US20170112793A2 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,584 US20140200272A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,651 US20140200273A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,673 US20140199388A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,399 US20140205659A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,503 US20140199390A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,685 US20140199392A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,321 US20140199387A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/581,966 US20170231941A1 (en) 2004-10-08 2017-04-28 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/728,872 US20180028483A1 (en) 2004-10-08 2017-10-10 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/834,870 US20180098957A1 (en) 2004-10-08 2017-12-07 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/988,628 US20180263947A1 (en) 2004-10-08 2018-05-24 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/046,509 US20180325855A1 (en) 2004-10-08 2018-07-26 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,559 US20190091193A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,503 US20190091192A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,403 US20190091191A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/294,038 US20190201368A1 (en) 2004-10-08 2019-03-06 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/525,392 US11052062B2 (en) 2004-10-08 2019-07-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US17/185,600 US20210220318A1 (en) 2004-10-08 2021-02-25 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US17/553,367 US20220105064A1 (en) 2004-10-08 2021-12-16 Controlled release pharmaceutical compositions comprising a fumaric acid ester

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
DKPA200401546 2004-10-08
DKPA200401546 2004-10-08
DKPA200401736 2004-11-10
DKPA200401736 2004-11-10
DKPA200500211 2005-02-11
DKPA200500211 2005-02-11
DKPA200500419 2005-03-23
DKPA200500419 2005-03-23
US69151305P 2005-06-16 2005-06-16
PCT/DK2005/000648 WO2006037342A2 (fr) 2004-10-08 2005-10-07 Compositions pharmaceutiques a liberation controlee renfermant un ester acide fumarique
US11/576,871 US20140099364A2 (en) 2004-10-08 2005-10-07 Controlled release pharmaceutical compositions comprising a fumaric acid ester

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/DE2005/000648 A-371-Of-International WO2005101333A1 (fr) 2004-04-13 2005-04-13 Systeme d'identification par radiofrequence (rfid) satisfaisant a la protection des donnees et reposant sur une fonctionnalite d'etiquette rfid controlee par le proprietaire
PCT/DK2005/000648 A-371-Of-International WO2006037342A2 (fr) 2004-10-08 2005-10-07 Compositions pharmaceutiques a liberation controlee renfermant un ester acide fumarique

Related Child Applications (16)

Application Number Title Priority Date Filing Date
US13/957,250 Continuation US20140037740A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,117 Continuation US20140037720A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,584 Continuation US20140200272A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,756 Continuation US20140199393A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,712 Continuation US20140199386A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,651 Continuation US20140200273A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,480 Continuation US20170112793A2 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,823 Continuation US20150024049A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,673 Continuation US20140199388A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,399 Continuation US20140205659A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,321 Continuation US20140199387A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,503 Continuation US20140199390A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,685 Continuation US20140199392A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,403 Division US20190091191A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,559 Division US20190091193A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,503 Division US20190091192A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester

Publications (2)

Publication Number Publication Date
US20090304790A1 US20090304790A1 (en) 2009-12-10
US20140099364A2 true US20140099364A2 (en) 2014-04-10

Family

ID=50726313

Family Applications (29)

Application Number Title Priority Date Filing Date
US11/576,871 Abandoned US20140099364A2 (en) 2004-10-08 2005-10-07 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,250 Abandoned US20140037740A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,117 Abandoned US20140037720A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,147 Abandoned US20130315993A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,220 Abandoned US20130316003A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,712 Abandoned US20140199386A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,651 Abandoned US20140200273A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,584 Abandoned US20140200272A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,756 Abandoned US20140199393A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,823 Abandoned US20150024049A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,480 Abandoned US20170112793A2 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,685 Abandoned US20140199392A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,503 Abandoned US20140199390A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,321 Abandoned US20140199387A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,399 Abandoned US20140205659A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,673 Abandoned US20140199388A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/581,966 Abandoned US20170231941A1 (en) 2004-10-08 2017-04-28 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/728,872 Abandoned US20180028483A1 (en) 2004-10-08 2017-10-10 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/834,870 Abandoned US20180098957A1 (en) 2004-10-08 2017-12-07 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/988,628 Abandoned US20180263947A1 (en) 2004-10-08 2018-05-24 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/046,509 Abandoned US20180325855A1 (en) 2004-10-08 2018-07-26 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,559 Abandoned US20190091193A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,503 Abandoned US20190091192A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,403 Abandoned US20190091191A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/227,287 Active US11229619B2 (en) 2004-10-08 2018-12-20 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/294,038 Abandoned US20190201368A1 (en) 2004-10-08 2019-03-06 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/525,392 Active US11052062B2 (en) 2004-10-08 2019-07-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US17/185,600 Abandoned US20210220318A1 (en) 2004-10-08 2021-02-25 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US17/553,367 Abandoned US20220105064A1 (en) 2004-10-08 2021-12-16 Controlled release pharmaceutical compositions comprising a fumaric acid ester

Family Applications After (28)

Application Number Title Priority Date Filing Date
US13/957,250 Abandoned US20140037740A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,117 Abandoned US20140037720A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,147 Abandoned US20130315993A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US13/957,220 Abandoned US20130316003A1 (en) 2004-10-08 2013-08-01 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,712 Abandoned US20140199386A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,651 Abandoned US20140200273A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,584 Abandoned US20140200272A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,756 Abandoned US20140199393A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,823 Abandoned US20150024049A1 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/209,480 Abandoned US20170112793A2 (en) 2004-10-08 2014-03-13 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,685 Abandoned US20140199392A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/212,503 Abandoned US20140199390A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,321 Abandoned US20140199387A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,399 Abandoned US20140205659A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US14/213,673 Abandoned US20140199388A1 (en) 2004-10-08 2014-03-14 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/581,966 Abandoned US20170231941A1 (en) 2004-10-08 2017-04-28 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/728,872 Abandoned US20180028483A1 (en) 2004-10-08 2017-10-10 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/834,870 Abandoned US20180098957A1 (en) 2004-10-08 2017-12-07 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US15/988,628 Abandoned US20180263947A1 (en) 2004-10-08 2018-05-24 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/046,509 Abandoned US20180325855A1 (en) 2004-10-08 2018-07-26 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,559 Abandoned US20190091193A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,503 Abandoned US20190091192A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/204,403 Abandoned US20190091191A1 (en) 2004-10-08 2018-11-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/227,287 Active US11229619B2 (en) 2004-10-08 2018-12-20 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/294,038 Abandoned US20190201368A1 (en) 2004-10-08 2019-03-06 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US16/525,392 Active US11052062B2 (en) 2004-10-08 2019-07-29 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US17/185,600 Abandoned US20210220318A1 (en) 2004-10-08 2021-02-25 Controlled release pharmaceutical compositions comprising a fumaric acid ester
US17/553,367 Abandoned US20220105064A1 (en) 2004-10-08 2021-12-16 Controlled release pharmaceutical compositions comprising a fumaric acid ester

Country Status (19)

Country Link
US (29) US20140099364A2 (fr)
EP (9) EP2801355B1 (fr)
JP (5) JP2008515822A (fr)
CY (5) CY1113792T1 (fr)
DE (4) DE14172396T1 (fr)
DK (4) DK2801355T3 (fr)
ES (5) ES2523796T1 (fr)
FR (1) FR15C0074I2 (fr)
HK (1) HK1108836A1 (fr)
HR (1) HRP20170677T1 (fr)
HU (3) HUE028342T2 (fr)
LT (2) LT2801354T (fr)
LU (1) LU92871I2 (fr)
ME (2) ME02253B (fr)
PL (4) PL2801354T3 (fr)
PT (4) PT2801355E (fr)
RS (2) RS54187B1 (fr)
SI (4) SI2801354T1 (fr)
WO (1) WO2006037342A2 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070142905A1 (en) * 2005-12-16 2007-06-21 Medtronic Vascular, Inc. Medical devices to treat or inhibit restenosis
US20100130607A1 (en) * 2007-02-08 2010-05-27 Ralf Gold Neuroprotection in demyelinating diseases
US20110124615A1 (en) * 2003-09-09 2011-05-26 Fumapharm Ag Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
US20140193495A1 (en) * 2004-10-08 2014-07-10 Forward Pharma A/S Controlled release pharmaceutical compositions comprising a fumaric acid ester
US9302977B2 (en) 2013-06-07 2016-04-05 Xenoport, Inc. Method of making monomethyl fumarate
US9326947B1 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US9326965B2 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9422226B2 (en) 2011-06-08 2016-08-23 Biogen Ma Inc. Process for preparing high purity and crystalline dimethyl fumarate
US9421182B2 (en) 2013-06-21 2016-08-23 Xenoport, Inc. Cocrystals of dimethyl fumarate
US9452972B2 (en) 2008-08-19 2016-09-27 Xenoport, Inc. Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
US9566259B1 (en) 2015-08-31 2017-02-14 Banner Life Sciences Llc Fumarate ester dosage forms
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
US10085961B2 (en) 2015-06-01 2018-10-02 Sun Pharmaceutical Industries Limited Pharmaceutical compositions of dimethyl fumarate
US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
US10179118B2 (en) 2013-03-24 2019-01-15 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
US10399924B2 (en) 2012-12-21 2019-09-03 Biogen Ma Inc. Deuterium substituted fumarate derivatives
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
WO2023084320A1 (fr) * 2021-11-11 2023-05-19 V-Ensure Pharma Technologies Private Limited Compositions antidiabétiques reconstituables à usage unique
US11903918B2 (en) 2020-01-10 2024-02-20 Banner Life Sciences Llc Fumarate ester dosage forms with enhanced gastrointestinal tolerability

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19853487A1 (de) 1998-11-19 2000-05-25 Fumapharm Ag Muri Verwendung von Dialkylfumaraten
ITMI20022394A1 (it) 2002-11-13 2004-05-14 Bracco Spa Uso di triiodotironina 3-solfato come farmaco ad attivita' tireomimetica e relative formulazioni farmaceutiche.
ITMI20110713A1 (it) 2011-04-29 2012-10-30 Bracco Imaging Spa Processo per la preparazione di un derivato solfatato di3,5-diiodo-o-[3-iodofenil]-l-tirosina
US7981908B2 (en) * 2005-05-11 2011-07-19 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion
US7803817B2 (en) 2005-05-11 2010-09-28 Vecta, Ltd. Composition and methods for inhibiting gastric acid secretion
WO2007042034A1 (fr) * 2005-10-07 2007-04-19 Aditech Pharma Ab Compositions pharmaceutiques a liberation controlee comportant un ester de l'acide fumarique
WO2007042035A2 (fr) * 2005-10-07 2007-04-19 Aditech Pharma Ab Therapie de combinaison pour le traitement d'un trouble auto-immun et/ou inflammatoire et de conditions associees
CN101365432B (zh) * 2005-12-16 2011-06-22 默沙东公司 二肽基肽酶-4抑制剂与二甲双胍的组合的药物组合物
RU2467747C2 (ru) * 2006-07-25 2012-11-27 Векта Лтд. Композиции и способы для ингибирования секреции желудочной кислоты с использованием производных малых дикарбоновых кислот в сочетании с ppi
ES2916604T1 (es) 2007-02-08 2022-07-04 Biogen Ma Inc Ensayos de detección de nrf2 y métodos y composiciones relacionados
JP2012514623A (ja) * 2009-01-09 2012-06-28 フォーワード・ファルマ・アクティーゼルスカブ １またはそれ以上のフマル酸エステルを含む医薬組成物
HK1252751A1 (zh) * 2009-01-09 2019-05-31 Fwp Ip Aps 包含溶蝕骨架中的一種或多種富馬酸酯的藥物製劑
EP2564839B1 (fr) * 2009-01-09 2016-05-11 Forward Pharma A/S Formule pharmaceutique comportant un ou plusieurs esters d'acide fumarique dans une matrice érosive
JP2012525385A (ja) 2009-04-29 2012-10-22 バイオジェン・アイデック・エムエイ・インコーポレイテッド 神経変性および神経炎症の治療
RS54551B1 (en) 2010-02-12 2016-06-30 Biogen Ma Inc. NEUROPROTECTION IN DEMYELINING DISEASES
MX339408B (es) * 2010-03-09 2016-05-24 Alkermes Pharma Ireland Ltd Composiciones farmaceuticas entericas resistentes al alcohol.
DK2694471T3 (da) * 2011-04-08 2017-11-13 Bracco Imaging Spa Fremgangsmåde til fremstilling af et sulfateret derivat af 3,5-diiod-o-[3-iodphenyl]-l-tyrosin
EP2782561A1 (fr) * 2011-11-24 2014-10-01 Synthon BV Libération contrôlée de particules comprenant du diméthylfumarate
WO2013076216A1 (fr) 2011-11-24 2013-05-30 Synthon Bv Libération contrôlée de particules comprenant du diméthylfumarate
US9504679B2 (en) 2011-12-19 2016-11-29 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators
US20130158077A1 (en) 2011-12-19 2013-06-20 Ares Trading S.A. Pharmaceutical compositions
CN114146079A (zh) 2012-02-07 2022-03-08 比奥根玛公司 含有富马酸二甲酯的药物组合物
MX2014009511A (es) 2012-02-07 2014-10-24 Xenoport Inc Compuestos de fumarato de morfolinoalquilo, composiciones farmaceuticas y metodos de uso.
SG11201507371RA (en) 2013-03-14 2015-10-29 Alkermes Pharma Ireland Ltd Prodrugs of fumarates and their use in treating various deseases
US8669281B1 (en) 2013-03-14 2014-03-11 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US20150307914A9 (en) * 2013-08-01 2015-10-29 Xenoport, Inc. Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
EA201690102A1 (ru) * 2013-08-26 2016-06-30 Форвард Фарма А/С Фармацевтическая композиция, содержащая диметилфумарат, для введения в низкой суточной дозе
BR112016012179B1 (pt) * 2013-12-12 2023-04-18 Almirall, S.A. Composições farmacêuticas que compreendem fumarato de dimetila
EP3079663A1 (fr) 2013-12-13 2016-10-19 Biogen MA Inc. Forme pharmaceutique à libération contrôlée pour administration une fois par jour de fumarate de diméthyle
CA2940845C (fr) 2014-02-24 2019-09-24 Alkermes Pharma Ireland Limited Sulfonamide et promedicaments de fumarates de sulfinamide et leur utilisation dans le traitement de diverses maladies
EP3650042A1 (fr) 2014-03-14 2020-05-13 Biogen MA Inc. Fumarate de diméthyle et régimes de vaccination
US20150298008A1 (en) * 2014-04-16 2015-10-22 Zynga Inc. Systems and methods of incentivizing game play
CA2962916C (fr) * 2014-10-08 2021-06-15 Banner Life Sciences Llc Capsules molles enteriques a liberation controlee d'esters de fumarate
WO2016061393A1 (fr) 2014-10-15 2016-04-21 Xenoport, Inc. Composés de fumarate, compositions pharmaceutiques et procédés d'utilisation
MA40985A (fr) 2014-11-17 2017-09-26 Biogen Ma Inc Méthodes de traitement de la sclérose en plaques
MA40982A (fr) * 2014-11-19 2017-09-26 Biogen Ma Inc Formulation de bille pharmaceutique comprenant du fumarate de diméthyle
MA41139A (fr) 2014-12-11 2017-10-17 Actelion Pharmaceuticals Ltd Combinaison pharmaceutique comportant un agoniste sélectif du récepteur sip1
KR102283582B1 (ko) 2014-12-23 2021-07-30 한미약품 주식회사 푸마르산 에스테르를 함유하는 미니-정제 형태의 약제학적 제제
WO2016113754A2 (fr) * 2015-01-14 2016-07-21 Leiutis Pharmaceuticals Pvt, Ltd. Nouvelles formes posologiques orales de fumarate de diméthyle
EA037666B1 (ru) * 2015-02-08 2021-04-28 Алкермес Фарма Айрленд Лимитед Фармацевтическая композиция, содержащая 2-(2,5-диоксопирролидин-1-ил)этилметилфумарат, и ее применение в медицине
AU2016231883B2 (en) * 2015-03-17 2019-03-07 Hetero Labs Limited Pharmaceutical compositions of dimethyl fumarate
MA41785A (fr) * 2015-03-20 2018-01-23 Biogen Ma Inc Procédés et compositions pour l'administration intraveineuse de fumarates pour le traitement de maladies neurologiques
CN107920997A (zh) 2015-06-17 2018-04-17 比奥根Ma公司 富马酸二甲酯颗粒和其药物组合物
US10213411B2 (en) 2015-08-27 2019-02-26 Vijaykumar Rajasekhar Use of prodrugs of fumarates in treating heart failure diseases
WO2017060420A1 (fr) 2015-10-07 2017-04-13 Neurovive Pharmaceutical Ab Métabolites à base d'acide fumarique protégé destinés au traitement de maladies auto-immunes
EP3407873B1 (fr) * 2016-01-28 2024-08-21 Zaklady Farmaceutyczne Polpharma S.A. Procès pour la formation des particules de diméthylfumarate
US10463642B2 (en) 2016-02-01 2019-11-05 Vijaykumar Rajasekhar Methods of treating heart failure diseases using prodrugs of methyl hydrogen fumarate
MA44010A (fr) 2016-02-11 2018-12-19 Biogen Ma Inc Formulations pharmaceutiques de billes comprenant du diméthylfumarate
CN110636838A (zh) 2017-06-23 2019-12-31 阿尔米雷尔有限公司 包含反丁烯二酸二甲酯的药物组合物
US11013723B1 (en) 2018-10-16 2021-05-25 Celgene Corporation Solid forms of a thiazolidinone compound, compositions and methods of use thereof
US11014897B1 (en) 2018-10-16 2021-05-25 Celgene Corporation Solid forms comprising a thiazolidinone compound, compositions and methods of use thereof
US11186556B1 (en) 2018-10-16 2021-11-30 Celgene Corporation Salts of a thiazolidinone compound, solid forms, compositions and methods of use thereof
US11014940B1 (en) 2018-10-16 2021-05-25 Celgene Corporation Thiazolidinone and oxazolidinone compounds and formulations
TR201818293A2 (tr) * 2018-11-30 2020-06-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Di̇meti̇l fumarat i̇çeren geci̇kmeli̇ salim sağlayan kapsül
RU2742745C1 (ru) * 2019-09-24 2021-02-10 Акционерное общество "Исследовательский Институт Химического Разнообразия" Лекарственная форма в виде капсулы, содержащая таблетки с диметилфурмаратом
AU2021208602A1 (en) 2020-05-06 2022-12-15 Imcyse Sa Combination treatment for fumarate-related diseases
FR3122850A1 (fr) * 2021-05-11 2022-11-18 Faurecia Sièges d'Automobile Siège de véhicule pliable
CN117597106A (zh) 2021-05-28 2024-02-23 美国安进公司 阿普斯特配制品
US20240010618A1 (en) * 2021-12-23 2024-01-11 Glenmark Lofe Science Limited Process for the preparation of brivaracetam
CN116524199B (zh) * 2023-04-23 2024-03-08 江苏大学 一种基于PReNet渐进式网络的图像去雨方法及装置

Family Cites Families (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2764609A (en) * 1953-07-24 1956-09-25 Monsanto Chemicals Isomerization of dialkyl maleates to dialkyl fumarates
US3078302A (en) * 1958-09-25 1963-02-19 Monsanto Chemicals Production of dialkyl fumarates
GB1153927A (en) 1966-08-25 1969-06-04 Wilhelm Hoerrmann Medicinal Composition Suitable For Treating Diseases Of The Retina
US4952594A (en) * 1973-06-18 1990-08-28 Mercer James B Reagents and method for therapeutic treatment of multiple sclerosis
DE2530372A1 (de) 1975-07-08 1977-01-13 Walter Dr Schweckendiek Pharmazeutische zubereitungen zur behandlung von psoriasis
DE2703964A1 (de) 1975-07-08 1978-08-03 Walter Dr Schweckendiek Pharmazeutische zubereitungen zur behandlung von psoriasis
US4145438A (en) * 1975-09-10 1979-03-20 Fisons Limited Method for treatment of eczema or psoriasis
DE2621214C3 (de) 1976-05-13 1981-11-12 Koronis Gmbh Chemisch-Pharmazeutische Praeparate, 5441 Sassen Verwendung von Stabilisatoren in Arzneimitteln mit Fumarsäuremonoäthylester und desen Mineralsalzen
DE2732131A1 (de) 1977-07-15 1979-01-25 Bayer Ag Verfahren zur herstellung von seitenstaendige hydroxylgruppen aufweisenden isocyanat-polyadditionsprodukten
DE2749188C2 (de) 1977-11-03 1981-11-12 Bayer Ag, 5090 Leverkusen Vorrichtung zum automatischen Einführen eines schnellaufenden Fadens in einen Fadenführungskanal einer Fadenbehandlungsvorrichtung
DE2840498C2 (de) 1978-09-18 1980-04-10 Walter Dr. 6700 Ludwigshafen Schweckendiek Pharmazeutische Zubereitungen zur Behandlung von Psoriasis
US4302440B1 (en) * 1980-07-31 1986-08-05 Easily-swallowed, powder-free and gastric-disintegrable aspirin tablet thinly-coated with hydroxypropyl methylcellulose and aqueous spray-coating preparation thereof
US5149695A (en) * 1985-01-15 1992-09-22 Speiser Peter P Fumaric acid derivatives, process for the production thereof and pharmaceutical compositions containing same
CH664150A5 (de) * 1985-01-15 1988-02-15 Peter Paul Prof Dr Speiser Fumarsaeureprodrug, verfahren zu seiner herstellung und dieses enthaltende darreichungsformen.
US4693896A (en) 1985-10-07 1987-09-15 Fmc Corporation Ethylcellulose-coated, gastric-disintegrable aspirin tablet
US4855305A (en) 1987-03-23 1989-08-08 Applied Medical Research Compositions and methods of effecting contraception utilizing melatonin
DE3711155A1 (de) * 1987-04-02 1988-10-13 Bayer Ag Verfahren zur herstellung von maleinsaeuredimethylester
IL83775A (en) 1987-09-04 1991-12-15 Dexter Chemical Corp Amino acid esters and amides of fumaric acid and pharmaceutical compositions containing them for use in the treatment of psoriasis
US5242905A (en) * 1987-09-04 1993-09-07 Dexter Chemical Corporation Pharmaceutical compositions for the treatment of psoriasis
US5214196A (en) * 1987-09-04 1993-05-25 Dexter Chemical Corporation Diethyl ester of di-glycyl fumaramide
US4959389A (en) 1987-10-19 1990-09-25 Speiser Peter P Pharmaceutical preparation for the treatment of psoriatic arthritis
US5424332A (en) * 1987-10-19 1995-06-13 Speiser; Peter P. Pharmaceutical composition and process for the production thereof
US5023245A (en) * 1987-11-10 1991-06-11 Hauser-Kuhrts, Inc. Improved niacin formulation
US4911917A (en) * 1988-06-28 1990-03-27 Hauser-Kuhrts, Inc. Cholesterol-lowering combination comopsitions of magnesium salt and niacin
US4965252A (en) 1988-06-28 1990-10-23 Hauser-Kuhrts, Inc. Cholesterol-lowering combination compositions of guar gum and niacin
DE3834794A1 (de) 1988-10-12 1990-04-19 F Schielein Oral zu verabreichendes mittel zur behandlung von psoriasis
GB2253346A (en) 1991-02-22 1992-09-09 John Rhodes Delayed release oral dosage forms for treatment of intestinal disorders
US5484610A (en) 1991-01-02 1996-01-16 Macromed, Inc. pH and temperature sensitive terpolymers for oral drug delivery
US5246947A (en) * 1991-09-23 1993-09-21 Hoechst-Roussel Pharmaceuticals Incorporated Substituted pyridinylamino-1,2-benzisothiazoles and their use for treating depression
FR2694693B1 (fr) 1992-07-28 1994-10-28 Abrax Bio Labs Sa Composition pharmaceutique à base de flavopéréirine et son utilisation dans un traitement contre le virus VIH.
DE69425453T2 (de) * 1993-04-23 2001-04-12 Novartis Ag, Basel Wirkstoffabgabevorrichtung mit gesteuerter Freigabe
US5434185A (en) 1993-05-17 1995-07-18 The University Of Kentucky Research Foundation Method for inhibiting angiogenesis with aurintricarboxylic acid, its analogues or salts
DK0758244T4 (da) * 1994-05-06 2008-06-16 Pfizer Doseringsformer af azithromycin med styret frigivelse
US5589504A (en) * 1994-07-26 1996-12-31 Cornell Research Foundation, Inc. Treatment of newborn jaundice
FR2725623A1 (fr) 1994-10-18 1996-04-19 Flamel Tech Sa Microcapsules medicamenteuses et/ou nutritionnelles pour administration per os
US5716625A (en) 1994-12-21 1998-02-10 Cosmederm Technologies Formulations and methods for reducing skin irritation
US6139850A (en) * 1994-12-21 2000-10-31 Cosmederm Technologies Formulations and methods for reducing skin irritation
US5804203A (en) 1994-12-21 1998-09-08 Cosmederm Technologies Topical product formulations containing strontium for reducing skin irritation
EP0737471A3 (fr) * 1995-04-10 2000-12-06 L'oreal Utilisation d'un sel d'une métal alcalino-terreux comme inhibiteur de TNF-alpha dans une composition unique et composition obtenue
EP0821587A4 (fr) 1995-04-19 1999-05-19 Lipoprotein Technologies Inc Compositions, trousses et procedes d'administration d'antilipemiques et medicaments contre l'agregation plaquettaire
FR2749759B1 (fr) * 1996-06-17 1999-11-26 Adir Utilisation de sels de strontium pour l'obtention de compositions pharmaceutiques destinees au traitement de l'arthrose
GB9613470D0 (en) 1996-06-27 1996-08-28 Ciba Geigy Ag Small solid oral dosage form
AU3889197A (en) 1996-07-26 1998-02-20 Douglas V Faller Compositions comprising an inducing agent and an anti-viral agent for the treat ment of blood, viral and cellular disorders
WO1998035666A1 (fr) 1997-02-13 1998-08-20 Nanosystems Llc Preparation de pastilles de naproxene nanoparticulaire
DE19721099C2 (de) * 1997-05-20 1999-12-02 Fumapharm Ag Muri Verwendung von Fumarsäurederivaten
NZ333474A (en) * 1998-01-02 1999-06-29 Mcneil Ppc Inc A chewable tablet containing ibuprofen, fumaric acid and a non hydrocolloid binder e.g. a wax or a fat
SK284839B6 (sk) 1998-01-22 2005-12-01 Zentaris Gmbh Použitie miltefozínu na výrobu lieku a farmaceutická kombinácia na liečenie leishmanózy
DE19814358C2 (de) 1998-03-31 2002-01-17 Fumapharm Ag Muri Verwendung von Alkylhydrogenfumaraten zur Behandlung von Psoriasis, psoriatischer Arthritis, Neurodermitis und Enteritis regionalis Crohn
CA2327685C (fr) * 1998-04-03 2008-11-18 Bm Research A/S Composition a liberation lente
US20050220909A1 (en) * 2004-03-30 2005-10-06 Theoharides Theoharis C Composition for protection against superficial vasodilator flush syndrome
DE19839566C2 (de) 1998-08-31 2002-01-17 Fumapharm Ag Muri Verwendung von Fumarsäurederivaten in der Transplantationsmedizin
DE19848260C2 (de) 1998-10-20 2002-01-17 Fumapharm Ag Muri Fumarsäure-Mikrotabletten
DE19853487A1 (de) * 1998-11-19 2000-05-25 Fumapharm Ag Muri Verwendung von Dialkylfumaraten
KR100297705B1 (ko) * 1999-03-29 2001-10-29 김덕중 낮은 온저항과 높은 항복전압을 갖는 전력용 반도체소자
US6537584B1 (en) 1999-11-12 2003-03-25 Macromed, Inc. Polymer blends that swell in an acidic environment and deswell in a basic environment
DE10000577A1 (de) * 2000-01-10 2001-07-26 Fumapharm Ag Muri Verwendung von Fumarsäurederivaten zur Behandlung mitochondrialer Krankheiten
KR20010112941A (ko) * 2000-02-15 2001-12-22 오하시 미츠오 푸마르산에스테르류의 제조방법
CN1951899B (zh) * 2000-02-16 2012-02-01 布里格姆及妇女医院股份有限公司 阿司匹林触发的脂质介体
IT1317042B1 (it) * 2000-06-14 2003-05-26 Biosalts Srl Fumarati doppi di una carnitina e creatina, e integratori alimentari,dietetici e farmaci che li contengono.
EP1172101A1 (fr) * 2000-06-20 2002-01-16 Helsinn Healthcare S.A. L'utilisation de nimesulide pour le traitement du psoriasis et de l'arthrite psoriatique
US6812248B2 (en) * 2000-07-05 2004-11-02 John Hopkins University School Of Medicine Prevention and treatment of degenerative diseases by glutathione and phase II detoxification enzymes
AU2002224417A1 (en) * 2000-10-18 2002-04-29 Immunex Corporation Methods for treating il-18 mediated disorders
DE10101307A1 (de) 2001-01-12 2002-08-01 Fumapharm Ag Muri Fumarsäurederivate als NF-kappaB-Inhibitor
ATE447945T1 (de) * 2001-01-12 2009-11-15 Biogen Idec Internat Gmbh Verwendung von fumarsäureamiden
SE0100200D0 (sv) 2001-01-24 2001-01-24 Astrazeneca Ab New film coating
AU2002325192B2 (en) 2001-07-06 2008-05-22 Veloxis Pharmaceuticals, Inc. Controlled agglomeration
NO20014746D0 (no) 2001-09-28 2001-09-28 Clas M Kjoelberg Smertelindrende middel
US7206276B2 (en) * 2001-10-12 2007-04-17 Konica Corporation Objective lens, optical element, optical pick-up apparatus and optical information recording and/or reproducing apparatus equipped therewith
US20030152622A1 (en) * 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
AR037356A1 (es) 2001-11-13 2004-11-03 Pharmacia Corp Forma de dosificacion oral de una prodroga de sulfonamida
US6613800B1 (en) * 2001-12-03 2003-09-02 Steven A. Smith Method and compositions for treating psoriasis, eczema, seborrhea and arthritis
KR100540035B1 (ko) 2002-02-01 2005-12-29 주식회사 태평양 다단계 경구 약물 방출 제어 시스템
AU2003225837B2 (en) 2002-03-15 2008-11-06 Forest Laboratories Holdings Limited NE and 5-HT reuptake inhibitors for treating visceral pain syndromes
DE10214031A1 (de) 2002-03-27 2004-02-19 Pharmatech Gmbh Verfahren zur Herstellung und Anwendung von Mikro- und Nanoteilchen durch aufbauende Mikronisation
US20030185915A1 (en) * 2002-03-28 2003-10-02 Jaime Carlo Synergetic composition for the treatment of psoriasis and other skin disorders and method therefor
DE10217314A1 (de) * 2002-04-18 2003-11-13 Fumapharm Ag Muri Carbocyclische und Oxacarboncyclische Fumarsäure-Oligomere
US20030219456A1 (en) * 2002-05-21 2003-11-27 Taing Ok Method of utilization of zygosaccharomyces rouxii
US20040038904A1 (en) * 2002-05-21 2004-02-26 Angela Ogden Method of treating multiple sclerosis
US6830759B2 (en) 2002-06-28 2004-12-14 Ajinomoto Co., Inc. Antidiabetic preparation for oral administration
ES2263058T3 (es) 2002-08-19 2006-12-01 Glaxo Group Limited Derivados de pirimidina como inhibidores selectivos de cox-2.
US20070053994A1 (en) 2003-03-27 2007-03-08 Egil Jellum Anti-inflammatory treatment
AU2004237438B2 (en) 2003-05-07 2011-01-20 Osteologix A/S Strontium combinations for prophylaxis/treatment of cartilage and/or bone conditions
US20060216358A1 (en) 2003-05-07 2006-09-28 Christian Hansen Controlled release composition containing a strontium salt
CA2519189C (fr) 2003-05-07 2012-07-17 Osteologix A/S Sels de strontium solubles dans l'eau pour le traitement de maladies des cartilages et/ou des os
AR041089A1 (es) 2003-05-15 2005-05-04 Merck & Co Inc Procedimiento y composiciones farmaceutiicas para tratar aterosclerosis, dislipidemias y afecciones relacionadas
ES2336913T3 (es) 2003-08-08 2010-04-19 Biovail Laboratories International Srl Comprimido de liberacion modificada de hidrocloruro de bupropion.
SI1663197T1 (sl) 2003-09-09 2008-06-30 Biogen Idec Internat Gmbh Uporaba derivatov fumarne kisline za zdravljenje sräśne insuficience in astme
AU2005231145B8 (en) 2004-03-31 2010-11-11 Bpsi Holdings, Inc. Enteric coatings for orally ingestible substrates
TW200603792A (en) 2004-04-23 2006-02-01 Pharmacia & Upjohn Co Llc Monotherapy for the treatment of psoriasis with cyclooxygenase-2 selective inhibitors
CN1245873C (zh) 2004-08-21 2006-03-22 王立峰 富马酸二甲酯微胶囊及其制备方法
CN101056624A (zh) 2004-10-08 2007-10-17 Adi技术制药股份公司 包含富马酸酯的控释药物组合物
PT2801355E (pt) 2004-10-08 2015-09-18 Forward Pharma As Composições farmacêuticas de libertação controlada compreendendo um éster de ácido fumárico
EP1812374A1 (fr) 2004-11-10 2007-08-01 Aditech Pharma AB Nouveaux sels de monoalkylesters d'acide fumarique et leur utilisation pharmaceutique
US20080004344A1 (en) * 2004-11-10 2008-01-03 Aditech Pharma Ab Novel Salts of Fumaric Acid Monoalkylesters and Their Pharmaceutical Use
DE102005022845A1 (de) * 2005-05-18 2006-11-23 Fumapharm Ag Thiobernsteinsäurederivate und deren Verwendung
US20070071819A1 (en) * 2005-05-30 2007-03-29 Kesarwani Amit K Multiple unit modified release compositions of carbamazepine and process for their preparation
EP1959969A2 (fr) 2005-07-01 2008-08-27 The Johns Hopkins University Compositions et procedes pour traiter ou prevenir des troubles associes au stress oxydatif
WO2007006307A2 (fr) 2005-07-07 2007-01-18 Aditech Pharma Ab Nouveaux sels de monoalkylesters d'acide fumarique et leur utilisation pharmaceutique
WO2007006308A1 (fr) 2005-07-07 2007-01-18 Aditech Pharma Ab Nouveaux esters de glucopyranose et esters de glucofuranose d'alkyl-fumarates et leur utilisation pharmaceutique
WO2007042034A1 (fr) 2005-10-07 2007-04-19 Aditech Pharma Ab Compositions pharmaceutiques a liberation controlee comportant un ester de l'acide fumarique
WO2007042035A2 (fr) * 2005-10-07 2007-04-19 Aditech Pharma Ab Therapie de combinaison pour le traitement d'un trouble auto-immun et/ou inflammatoire et de conditions associees
EP1994168A4 (fr) * 2006-02-15 2009-05-27 Md Bioalpha Co Ltd Procédé de contrôle du ratio nad(p)/nad(p)h par une oxydoréductase
WO2007148744A1 (fr) 2006-06-21 2007-12-27 Santen Pharmaceutical Co., Ltd. Agent prophylactique ou thérapeutique pur un trouble cornéen/conjonctival comprenant un dérivé de l'acide fumarique en tant que principe actif
RU2459626C2 (ru) 2006-09-01 2012-08-27 Гайлид Сайэнсиз, Инк. Способы и композиции, повышающие переносимость пациентом методов визуализации миокарда
ES2916604T1 (es) 2007-02-08 2022-07-04 Biogen Ma Inc Ensayos de detección de nrf2 y métodos y composiciones relacionados
ES2599227T3 (es) 2007-02-08 2017-01-31 Biogen Ma Inc. Neuroprotección en enfermedades desmielinizantes
WO2008129698A1 (fr) 2007-04-12 2008-10-30 Panasonic Corporation Système d'alimentation et procédé de chargement d'un bloc de batterie
RU2009141539A (ru) 2007-04-25 2011-05-27 Тева Фармасьютикал Индастриес Лтд. (Il) Комплекс фармацевтического наполнителя
US20080274182A1 (en) 2007-05-03 2008-11-06 Regina Helena Alida Boekema Tablet coatings made from modified carboxymethylcellulose materials
WO2009005803A1 (fr) 2007-07-01 2009-01-08 Joseph Peter Habboushe Comprimé de combinaison avec une couche extérieure pouvant être mâchée
KR20090028047A (ko) * 2007-09-13 2009-03-18 경북대학교 산학협력단 디메틸푸마레이트의 신규 용도
CN101318901A (zh) 2008-06-17 2008-12-10 健雄职业技术学院 一种富马酸二甲酯的合成新工艺
PL2334378T3 (pl) * 2008-08-19 2014-09-30 Xenoport Inc Proleki wodorofumaranu metylu, ich kompozycje farmaceutyczne i sposoby zastosowania
EP2564839B1 (fr) 2009-01-09 2016-05-11 Forward Pharma A/S Formule pharmaceutique comportant un ou plusieurs esters d'acide fumarique dans une matrice érosive
JP2012514623A (ja) 2009-01-09 2012-06-28 フォーワード・ファルマ・アクティーゼルスカブ １またはそれ以上のフマル酸エステルを含む医薬組成物
CN101475477A (zh) 2009-01-23 2009-07-08 上海化学试剂研究所 反丁烯二酸二甲酯的制备方法
WO2010113096A1 (fr) * 2009-03-30 2010-10-07 Tel Hashomer Medical Research Infrastructure And Services Ltd. Méthodes pour prévoir l'évolution clinique de la sclérose en plaque et la traiter
JP2012525385A (ja) * 2009-04-29 2012-10-22 バイオジェン・アイデック・エムエイ・インコーポレイテッド 神経変性および神経炎症の治療
CN101701943A (zh) 2009-11-05 2010-05-05 宁波中普检测技术服务有限公司 气相色谱-质谱联用测定产品中富马酸二甲酯的方法
RS54551B1 (en) 2010-02-12 2016-06-30 Biogen Ma Inc. NEUROPROTECTION IN DEMYELINING DISEASES
JP2014515373A (ja) 2011-05-26 2014-06-30 バイオジェン・アイデック・エムエイ・インコーポレイテッド 多発性硬化症の治療方法およびミエリン量を保存および／または増加させる方法
PL2718257T3 (pl) 2011-06-08 2018-04-30 Biogen Ma Inc. Sposób przygotowywania dimetylofumaranu krystalicznego o wysokiej czystości
WO2013076216A1 (fr) 2011-11-24 2013-05-30 Synthon Bv Libération contrôlée de particules comprenant du diméthylfumarate
CN114146079A (zh) 2012-02-07 2022-03-08 比奥根玛公司 含有富马酸二甲酯的药物组合物
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
KR102092289B1 (ko) * 2013-06-03 2020-03-23 삼성전자주식회사 전자 기기 및 이의 문서 작성 방법
EP3079663A1 (fr) 2013-12-13 2016-10-19 Biogen MA Inc. Forme pharmaceutique à libération contrôlée pour administration une fois par jour de fumarate de diméthyle
EP3110408B1 (fr) 2014-02-28 2019-01-16 Banner Life Sciences LLC Capsules molles entériques à libération contrôlée d'esters de fumarate
US9636318B2 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US9326947B1 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
CA2962916C (fr) 2014-10-08 2021-06-15 Banner Life Sciences Llc Capsules molles enteriques a liberation controlee d'esters de fumarate
WO2017040272A1 (fr) 2015-08-31 2017-03-09 Banner Life Sciences Llc Formes posologiques d'ester de fumarate
WO2017151184A1 (fr) 2016-02-29 2017-09-08 Banner Life Sciences Llc Formes posologiques d'ester de fumarate
US10523918B2 (en) 2017-03-24 2019-12-31 Samsung Electronics Co., Ltd. System and method for depth map

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110124615A1 (en) * 2003-09-09 2011-05-26 Fumapharm Ag Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
US8980832B2 (en) 2003-09-09 2015-03-17 Biogen Idec International Gmbh Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
US20140193495A1 (en) * 2004-10-08 2014-07-10 Forward Pharma A/S Controlled release pharmaceutical compositions comprising a fumaric acid ester
US20140199392A1 (en) * 2004-10-08 2014-07-17 Forward Pharma A/S Controlled release pharmaceutical compositions comprising a fumaric acid ester
US11052062B2 (en) 2004-10-08 2021-07-06 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US11229619B2 (en) 2004-10-08 2022-01-25 Biogen Swiss Manufacturing Gmbh Controlled release pharmaceutical compositions comprising a fumaric acid ester
US20070142905A1 (en) * 2005-12-16 2007-06-21 Medtronic Vascular, Inc. Medical devices to treat or inhibit restenosis
US20100130607A1 (en) * 2007-02-08 2010-05-27 Ralf Gold Neuroprotection in demyelinating diseases
US9452972B2 (en) 2008-08-19 2016-09-27 Xenoport, Inc. Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
US9422226B2 (en) 2011-06-08 2016-08-23 Biogen Ma Inc. Process for preparing high purity and crystalline dimethyl fumarate
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
US10940117B2 (en) 2012-08-22 2021-03-09 Arbor Pharmaceuticals, Llc Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US10716760B2 (en) 2012-08-22 2020-07-21 Arbor Pharmaceuticals, Llc Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US10399924B2 (en) 2012-12-21 2019-09-03 Biogen Ma Inc. Deuterium substituted fumarate derivatives
US10179118B2 (en) 2013-03-24 2019-01-15 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
US11938111B2 (en) 2013-03-24 2024-03-26 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
US9302977B2 (en) 2013-06-07 2016-04-05 Xenoport, Inc. Method of making monomethyl fumarate
US9421182B2 (en) 2013-06-21 2016-08-23 Xenoport, Inc. Cocrystals of dimethyl fumarate
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9682057B2 (en) 2013-09-06 2017-06-20 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US10918616B2 (en) 2014-02-28 2021-02-16 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10918615B2 (en) 2014-02-28 2021-02-16 Banner Life Sciences Llc Fumarate esters
US9820960B2 (en) 2014-02-28 2017-11-21 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9326947B1 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US9326965B2 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
US10105337B2 (en) 2014-02-28 2018-10-23 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10105336B2 (en) 2014-02-28 2018-10-23 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9511043B2 (en) 2014-02-28 2016-12-06 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9814691B2 (en) 2014-02-28 2017-11-14 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US9517209B2 (en) 2014-02-28 2016-12-13 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10918617B2 (en) 2014-02-28 2021-02-16 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US11135296B2 (en) 2014-03-24 2021-10-05 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of fumaric acid esters
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
US10085961B2 (en) 2015-06-01 2018-10-02 Sun Pharmaceutical Industries Limited Pharmaceutical compositions of dimethyl fumarate
US10105335B2 (en) 2015-08-31 2018-10-23 Banner Life Sciences Llc Fumarate ester dosage forms
US9814692B2 (en) 2015-08-31 2017-11-14 Banner Life Sciences Llc Fumarate ester dosage forms
US10945985B2 (en) 2015-08-31 2021-03-16 Banner Life Sciences Llc Fumarate ester dosage forms
US9636319B1 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US9566259B1 (en) 2015-08-31 2017-02-14 Banner Life Sciences Llc Fumarate ester dosage forms
US9636318B2 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US11590095B2 (en) 2015-08-31 2023-02-28 Banner Life Sciences Llc Fumarate ester dosage forms
US9820961B2 (en) 2015-08-31 2017-11-21 Banner Life Sciences Llc Fumarate ester dosage forms
US11903918B2 (en) 2020-01-10 2024-02-20 Banner Life Sciences Llc Fumarate ester dosage forms with enhanced gastrointestinal tolerability
WO2023084320A1 (fr) * 2021-11-11 2023-05-19 V-Ensure Pharma Technologies Private Limited Compositions antidiabétiques reconstituables à usage unique

Also Published As

Publication number Publication date
US20090304790A1 (en) 2009-12-10
US20140200272A1 (en) 2014-07-17
ES2525495T1 (es) 2014-12-23
US11052062B2 (en) 2021-07-06
ES2525497T3 (es) 2015-10-09
US20180098957A1 (en) 2018-04-12
US20190091191A1 (en) 2019-03-28
CY1116599T1 (el) 2016-08-31
US20130315993A1 (en) 2013-11-28
CY2015045I2 (el) 2016-08-31
HUE031950T2 (en) 2017-08-28
US20180325855A1 (en) 2018-11-15
EP2792349A2 (fr) 2014-10-22
EP3470064A1 (fr) 2019-04-17
US20180028483A1 (en) 2018-02-01
SI2801354T1 (sl) 2017-07-31
DK2801355T3 (en) 2015-07-06
HRP20170677T1 (hr) 2017-09-08
US11229619B2 (en) 2022-01-25
RS55936B1 (sr) 2017-09-29
US20140193495A1 (en) 2014-07-10
EP2801354B1 (fr) 2017-02-08
US20140037720A1 (en) 2014-02-06
DK2316430T3 (da) 2012-07-23
LT1799196T (lt) 2016-09-12
US20140199390A1 (en) 2014-07-17
HK1108836A1 (zh) 2008-05-23
DE14172396T1 (de) 2015-01-08
DK1799196T3 (en) 2016-08-15
EP3093012A1 (fr) 2016-11-16
JP2008515822A (ja) 2008-05-15
FR15C0074I2 (fr) 2016-04-22
FR15C0074I1 (fr) 2015-12-25
US20140199387A1 (en) 2014-07-17
PT1799196T (pt) 2016-08-31
PL1799196T3 (pl) 2016-12-30
JP2018087220A (ja) 2018-06-07
US20140200273A1 (en) 2014-07-17
HUS1500057I1 (hu) 2016-04-28
PT2801355E (pt) 2015-09-18
US20210220318A1 (en) 2021-07-22
US20140037740A1 (en) 2014-02-06
EP3459532A1 (fr) 2019-03-27
PT2801354T (pt) 2017-06-05
PL2801354T3 (pl) 2017-08-31
EP2801354A1 (fr) 2014-11-12
CY1117937T1 (el) 2017-05-17
EP2316430B8 (fr) 2012-07-11
US20170231941A1 (en) 2017-08-17
JP2013064007A (ja) 2013-04-11
WO2006037342A3 (fr) 2006-07-20
ES2387192T3 (es) 2012-09-17
EP2801355A1 (fr) 2014-11-12
EP2965751A1 (fr) 2016-01-13
HUE028342T2 (en) 2016-12-28
JP2019147832A (ja) 2019-09-05
US20190091192A1 (en) 2019-03-28
US20190091193A1 (en) 2019-03-28
US20140199393A1 (en) 2014-07-17
ME02746B (fr) 2018-01-20
RS54187B1 (en) 2015-12-31
LU92871I9 (fr) 2019-02-27
JP2015227350A (ja) 2015-12-17
US20130316003A1 (en) 2013-11-28
US20140199386A1 (en) 2014-07-17
US20190117613A1 (en) 2019-04-25
EP2316430A1 (fr) 2011-05-04
EP2792349A3 (fr) 2014-12-17
DE14172390T1 (de) 2014-12-31
PL2316430T3 (pl) 2012-11-30
US20180263947A1 (en) 2018-09-20
ES2582942T3 (es) 2016-09-16
CY1113792T1 (el) 2016-07-27
JP6896792B2 (ja) 2021-06-30
SI1799196T1 (sl) 2016-10-28
EP1799196B1 (fr) 2016-06-22
US20190201368A1 (en) 2019-07-04
LU92871I2 (fr) 2016-01-13
EP2316430B1 (fr) 2012-06-06
ES2525497T1 (es) 2014-12-23
US20140199392A1 (en) 2014-07-17
WO2006037342A2 (fr) 2006-04-13
SI2316430T1 (sl) 2012-09-28
US20150024049A1 (en) 2015-01-22
US20190343787A1 (en) 2019-11-14
CY2015045I1 (el) 2016-08-31
ES2525495T3 (es) 2017-07-26
PT2316430E (pt) 2012-06-26
EP1799196A2 (fr) 2007-06-27
US20170112793A2 (en) 2017-04-27
US20170014367A2 (en) 2017-01-19
DK2801354T3 (en) 2017-05-15
ES2523796T1 (es) 2014-12-01
US20140205659A1 (en) 2014-07-24
US20160271093A2 (en) 2016-09-22
US20160136125A2 (en) 2016-05-19
DE202005022112U1 (de) 2014-04-24
DE14172398T1 (de) 2015-01-08
ME02253B (fr) 2015-12-31
LT2801354T (lt) 2017-06-26
US20220105064A1 (en) 2022-04-07
US20140199388A1 (en) 2014-07-17
EP2801355B1 (fr) 2015-05-20
CY1118887T1 (el) 2018-01-10
PL2801355T3 (pl) 2015-10-30
SI2801355T1 (sl) 2015-09-30

Similar Documents

Publication Publication Date Title
US11052062B2 (en) Controlled release pharmaceutical compositions comprising a fumaric acid ester

Legal Events

Date Code Title Description
AS Assignment

Owner name: ADITECH PHARMA AB, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NILSSON, HENRIK;SCHOENHARTING, FLORIAN;MUELLER, BERND W.;AND OTHERS;REEL/FRAME:019484/0642;SIGNING DATES FROM 20070416 TO 20070618

Owner name: ADITECH PHARMA AB, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NILSSON, HENRIK;SCHOENHARTING, FLORIAN;MUELLER, BERND W.;AND OTHERS;SIGNING DATES FROM 20070416 TO 20070618;REEL/FRAME:019484/0642

AS Assignment

Owner name: ADITECH PHARMA AG,SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ADITECH PHARMA AB;REEL/FRAME:023179/0978

Effective date: 20090826

Owner name: ADITECH PHARMA AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ADITECH PHARMA AB;REEL/FRAME:023179/0978

Effective date: 20090826

AS Assignment

Owner name: FORWARD PHARMA A/S, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ADITECH PHARMA AG;REEL/FRAME:025140/0486

Effective date: 20101001

STCV Information on status: appeal procedure

Free format text: APPLICATION INVOLVED IN COURT PROCEEDINGS

AS Assignment

Owner name: FORWARD PHARMA OPERATIONS APS, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FORWARD PHARMA A/S;REEL/FRAME:042903/0352

Effective date: 20170630

AS Assignment

Owner name: FWP IP APS, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FORWARD PHARMA OPERATIONS APS;REEL/FRAME:042987/0578

Effective date: 20170630

AS Assignment

Owner name: BIOGEN SWISS MANUFACTURING GMBH, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FWP IP APS;REEL/FRAME:048691/0028

Effective date: 20190325

STCV Information on status: appeal procedure

Free format text: COURT PROCEEDINGS TERMINATED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- AFTER EXAMINER'S ANSWER OR BOARD OF APPEALS DECISION