[go: up one dir, main page]

WO2020117161A1 - A combination comprising dimethyl fumarate and at least one muscle relaxant agent - Google Patents

A combination comprising dimethyl fumarate and at least one muscle relaxant agent Download PDF

Info

Publication number
WO2020117161A1
WO2020117161A1 PCT/TR2019/050957 TR2019050957W WO2020117161A1 WO 2020117161 A1 WO2020117161 A1 WO 2020117161A1 TR 2019050957 W TR2019050957 W TR 2019050957W WO 2020117161 A1 WO2020117161 A1 WO 2020117161A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical combination
tablets
combination according
dimethyl fumarate
amount
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.)
Ceased
Application number
PCT/TR2019/050957
Other languages
French (fr)
Inventor
Ahmet Toksoz
Zafer Toksoz
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.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret 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
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Priority to EP19891930.0A priority Critical patent/EP3890720A4/en
Publication of WO2020117161A1 publication Critical patent/WO2020117161A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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

Definitions

  • the present invention relates to a pharmaceutical combination comprising dimethyl fumarate and at least one muscle relaxant agent.
  • MS Multiple Sclerosis
  • CNS central nervous system
  • Myelin provides a covering or insulation for nerves, improves the conduction of impulses along the nerves and also is important for maintaining the health of the nerves.
  • inflammation causes the myelin to disappear. So, the electrical impulses become slower.
  • the nerves themselves are damaged. Patient suffers from a range of symptoms which affect their health-related quality of life such as pain, muscle spasticity and spasm, bladder problems and sleep disturbance.
  • MS Multiple sclerosis
  • MS is the most common autoimmune disorder affecting the central nervous system.
  • Multiple sclerosis also known as disseminated sclerosis or encephalomyelitis disseminata
  • MS is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental and sometimes psychiatric problems.
  • MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances.
  • DMF Dimethyl fumarate
  • E dimethyl (E)- butenedioate
  • MS multiple sclerosis
  • TECFIDERA ® Dimethyl Fumarate is marketed by BIOGEN under the trademark TECFIDERA ® .
  • This formulation, TECFIDERA ® is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of granulated dimethyl fumarate enterical coated minitablets.
  • the strategy to improve the current state of MS treatment is to combine therapies.
  • Muscle relaxants are used to relieve muscle spasms which may result from some conditions which affect the nervous system. Conditions which may cause muscle spasms include multiple sclerosis, motor neuron disease and cerebral palsy. Muscle spasms and tightness may also follow long-term injuries to the head or back. Muscle spasm can also occur as part of a more short-term condition or injury, such as low back pain or whiplash. Medication helps the muscles to relax, which may also reduce pain and discomfort.
  • the muscle relaxant agent is selected from the group comprising tolperisone or tizanidine or baclofen or thiocolchicoside or diazepam or metaxalone or methocarbamol or dantrolene or cyclobenzaprine or carisoprodol or tetrazepam or mixtures thereof.
  • Tolperisone is a centrally acting muscle relaxant that has been used for the symptomatic treatment of spasticity and muscle spasm. It acts as the reticular formation in the brain stem by blocking voltage-gated sodium and calcium channels and it is marketed under trade names including Biocalm, Muscodol, Mydeton, Mydocalm, Mydoflex, Myolax, Myoxan and Viveo.
  • tolperisone 2-methyl-1-(4-methylphenyl)-3-piperidin-1-ylpropan-1- one and its chemical structure is shown in the Formula II.
  • One of the other preferred muscle relaxant agent is tizanidine. Its chemical structure is shown in Formula III.
  • Tizanidine is a a2-adrenergic agonist and acts mainly at spinal and supraspinal levels to inhibit excitatory interneurons. It is used for the symptomatic relief of spasticity associated with multiple sclerosis or with spinal cord injury or disease.
  • the recommended dose of tizanidine is 2 mg, 4mg or 6 mg.
  • baclofen Another preferred muscle relaxant agent is baclofen.
  • the chemical name of baclofen is 4- amino-3-(4-chlorophenyl) butanoic acid and is generally represented as follows in Formula IV;
  • a further preferred muscle relaxant agent is thiocolchicoside. It is a muscle relaxant with anti inflammatory and analgesic effects and has been claimed to possess GABA-mimetic and glycinergic actions, in another way we can say that thiocolchicoside is a gamma-aminobutiric acid receptor agonist. Its chemical structure is shown in Formula V.
  • combining more than one molecule in one dosage form increases the patient’s compliance.
  • this combination increases the patients’ quality of life, combining more than one molecule in one dosage form also reduces undesired multiple sclerosis symptoms which can be muscle spasticity.
  • the muscle relaxant agents are tolperisone or tizanidine or baclofen or thiocolchicoside or mixtures thereof.
  • the main object of the present invention is to combine dimethyl fumarate with at least one muscle relaxant agent to eliminate multiple sclerosis symptoms, to provide rapid and effective treatment and to bring additional advantages over the relevant prior art.
  • Another object of the present invention is to obtain a stable combination formulation with synergistic effect for use in multiple sclerosis.
  • This invention also provides a pharmaceutical combination comprising an effective amount of dimethyl fumarate and an effective amount of at least one muscle relaxant agent for use in treating a human afflicted with multiple sclerosis, wherein dimethyl fumarate and at least one muscle relaxant agent are administered simultaneously, separately or sequentially.
  • tolperisone refers to tolperisone in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • tizanidine refers to tizanidine in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • baclofen refers to baclofen in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • thiocolchicoside refers to thiocolchicoside in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • Muscle relaxants are medicines that are used to prevent and reduce muscle spasms and tightness (spasticity). Muscle spasms occur when there is an uncontrolled (involuntary) contraction of a group of muscles. The muscles usually shorten (contract) suddenly; this is often painful. Spasticity occurs when some muscles contract tightly and can then become stiff and harder to use.
  • the pharmaceutical combination comprises dimethyl fumarate and at least one muscle relaxant agent.
  • the muscle relaxant agent is selected from the group comprising tolperisone or tizanidine or baclofen or thiocolchicoside or diazepam or metaxalone or methocarbamol or dantrolene or cyclobenzaprine or carisoprodol or tetrazepam or mixtures thereof.
  • the muscle relaxant agent is tolperisone or tizanidine or baclofen or thiocolchicoside or mixtures thereof which is used as adjunctive therapy in pain control and muscle spasticity.
  • an embodiment of this present invention is to combine dimethyl fumarate with tolperisone or tizanidine or baclofen or thiocolchicoside in a same and stable dosage form with desired dissolution profiles.
  • the pharmaceutical combination comprises dimethyl fumarate and tolperisone.
  • This invention provides a method of treating a human afflicted with multiple sclerosis comprising periodical administration of an effective amount of dimethyl fumarate and an effective amount of muscle relaxant agent to the subject together, wherein these effective amounts described below are effective to treat a human.
  • the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg and 300 mg and tolperisone in an amount of between 30 mg and 200 mg.
  • the weight ratio of dimethyl fumarate to tolperisone is between 0.5 - 10.0, preferably 0.8 -5.0.
  • the pharmaceutical combination comprises dimethyl fumarate and tizanidine.
  • the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and tizanidine in an amount of between 1 to 10 mg.
  • the weight ratio of dimethyl fumarate to tizanidine is between 10.0 - 300.0, preferably 30.0 -120.0.
  • the pharmaceutical combination comprises dimethyl fumarate and baclofen.
  • the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and baclofen in an amount of between 5 to 20 mg.
  • the weight ratio of dimethyl fumarate to baclofen is between 5.0 - 60.0, preferably 12.0 -24.0.
  • the pharmaceutical combination comprises dimethyl fumarate and thiocolchicoside.
  • the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and thiocolchicoside in an amount of between 1 to 15 mg.
  • the weight ratio of dimethyl fumarate to thiocolchicoside is between 6.0 - 300.0, preferably 15.0 -60.0.
  • said combination further comprises at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, solvents and co-solvents, rate controlling polymers, direct compression agent, surfactants, lubricants, glidants, sweeteners, stabilizers, coating agents, colouring agents, inert agents or mixtures thereof.
  • at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, solvents and co-solvents, rate controlling polymers, direct compression agent, surfactants, lubricants, glidants, sweeteners, stabilizers, coating agents, colouring agents, inert agents or mixtures thereof.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • Suitable disintegrants are selected from the group comprising polyvinil pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
  • polyvinil pyrrolidone crospovidone
  • povidone povidone
  • croscarmellose sodium cross-linked carboxymethyl cellulose
  • low-substituted hydroxypropyl cellulose pregelatinized
  • Suitable solvents or co-solvents are selected from the group comprising water, propylene glycol, glycerin, ethanol, polyethylene glycol or mixtures thereof.
  • Suitable rate controlling polymers are selected from the group comprising ethyl acrylate, ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose E4M, hydroxypropyl methylcellulose K100MCR, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, pectin, polyglucoronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, lambda carregeenan, io
  • Suitable direct compression agents are selected from the group comprising calcium hydrogen phosphate sodium alginate, pregelatinized starch, calcium citrate or mixtures thereof.
  • Suitable surfactants are selected from the group comprising sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, nonoxynol, polyoxyethylene stearates, polyethylene glycol, leucine, poloxamer 407, sodium benzoate, docusate sodium, alpha tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene hydrogenated castor oil or mixtures thereof.
  • Suitable lubricants are selected from the group comprising from magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch, talc or mixtures thereof.
  • Suitable sweeteners are selected from the group comprising aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose or sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
  • Suitable stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof.
  • Suitable coating agents are selected from the group comprising polymethacrylates, polyalkylacrylates copolymers, hydroxyl propyl methyl cellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol- polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.
  • Suitable colouring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
  • FD&C Food, Drug & Cosmetic
  • Suitable inert agents between the two molecules are selected from starch, lactose, sugar alcohol like D-mannitol, erythritol; low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof.
  • the pharmaceutical combination is administered orally.
  • the pharmaceutical combination is in the form of tablets, capsules, strips, syrups, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, suspensions or emulsions.
  • the pharmaceutical combination is in the form of tablets or capsules.
  • the pharmaceutical combination is in the form of a tablet.
  • the pharmaceutical combination is formulated as tablets comprising film-coated tablets, bilayer tablets, inlay tablets, orally disintegrating tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, gastric disintegrating tablets, chewable tablets, dispersing tablets or lozenges.
  • the pharmaceutical combination is in the form of a capsule.
  • modified release dosage form is selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof.
  • modified release dosage form is prepared using rate controlling polymers.
  • the combination is prepared using direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
  • the combination is for use in the treatment of multiple sclerosis in human.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a pharmaceutical combination comprising dimethyl fumarate and at least one muscle relaxant agent.

Description

A COMBINATION COMPRISING DIMETHYL FUMARATE AND AT LEAST ONE MUSCLE
RELAXANT AGENT
Field of the invention
The present invention relates to a pharmaceutical combination comprising dimethyl fumarate and at least one muscle relaxant agent.
Background of the invention
Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) resulting in loss of muscle control, balance, and sensation. Autoimmunity, infectious agents, environmental triggers and hereditary factors influential in disease development.
Myelin provides a covering or insulation for nerves, improves the conduction of impulses along the nerves and also is important for maintaining the health of the nerves. In multiple sclerosis, inflammation causes the myelin to disappear. So, the electrical impulses become slower. In addition, the nerves themselves are damaged. Patient suffers from a range of symptoms which affect their health-related quality of life such as pain, muscle spasticity and spasm, bladder problems and sleep disturbance.
Multiple sclerosis (MS) is the most common autoimmune disorder affecting the central nervous system. Multiple sclerosis, also known as disseminated sclerosis or encephalomyelitis disseminata, is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental and sometimes psychiatric problems. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances.
Dimethyl fumarate (DMF) corresponding to the compound dimethyl (E)- butenedioate (CeHsCU) is an anti-inflammatory mostly used for treating multiple sclerosis (MS). Its chemical structure is shown in the Formula I.
Figure imgf000003_0001
Formula I
Dimethyl Fumarate is marketed by BIOGEN under the trademark TECFIDERA®. This formulation, TECFIDERA®, is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of granulated dimethyl fumarate enterical coated minitablets.
There are various patents in the state of the art in relation to dimethyl fumarate which is first described in US6509376 B1 and also discloses its indication.
There is no known cure for MS until now. Current treatments typically focus on accelerating patient’s recovery from attacks, slowing the progression of the disease and restraining MS symptoms. Dimethyl fumarate alone does not provide adequate treatment.
In the present invention, the strategy to improve the current state of MS treatment is to combine therapies. Thus, there is no combination of dimethyl fumarate with at least one muscle relaxant agent, in the prior art.
Muscle relaxants are used to relieve muscle spasms which may result from some conditions which affect the nervous system. Conditions which may cause muscle spasms include multiple sclerosis, motor neuron disease and cerebral palsy. Muscle spasms and tightness may also follow long-term injuries to the head or back. Muscle spasm can also occur as part of a more short-term condition or injury, such as low back pain or whiplash. Medication helps the muscles to relax, which may also reduce pain and discomfort.
The muscle relaxant agent is selected from the group comprising tolperisone or tizanidine or baclofen or thiocolchicoside or diazepam or metaxalone or methocarbamol or dantrolene or cyclobenzaprine or carisoprodol or tetrazepam or mixtures thereof.
One of the preferred muscle relaxant agent is tolperisone. Tolperisone is a centrally acting muscle relaxant that has been used for the symptomatic treatment of spasticity and muscle spasm. It acts as the reticular formation in the brain stem by blocking voltage-gated sodium and calcium channels and it is marketed under trade names including Biocalm, Muscodol, Mydeton, Mydocalm, Mydoflex, Myolax, Myoxan and Viveo.
The chemical name of tolperisone is 2-methyl-1-(4-methylphenyl)-3-piperidin-1-ylpropan-1- one and its chemical structure is shown in the Formula II.
Figure imgf000004_0001
One of the other preferred muscle relaxant agent is tizanidine. Its chemical structure is shown in Formula III.
Figure imgf000004_0002
Tizanidine is a a2-adrenergic agonist and acts mainly at spinal and supraspinal levels to inhibit excitatory interneurons. It is used for the symptomatic relief of spasticity associated with multiple sclerosis or with spinal cord injury or disease. The recommended dose of tizanidine is 2 mg, 4mg or 6 mg.
Another preferred muscle relaxant agent is baclofen. The chemical name of baclofen is 4- amino-3-(4-chlorophenyl) butanoic acid and is generally represented as follows in Formula IV;
Figure imgf000004_0003
Formula IV A further preferred muscle relaxant agent is thiocolchicoside. It is a muscle relaxant with anti inflammatory and analgesic effects and has been claimed to possess GABA-mimetic and glycinergic actions, in another way we can say that thiocolchicoside is a gamma-aminobutiric acid receptor agonist. Its chemical structure is shown in Formula V.
Figure imgf000005_0001
It has also been found that the combination of a muscle relaxant agent with dimethyl fumarate is more effective compared to multiple sclerosis treating agent alone because, this combination also helps to reduce stiff muscles and spasms due to the disease. Furthermore, there is no combination of a muscle relaxant agent with multiple sclerosis treating agent in the prior art.
In the present invention, combining more than one molecule in one dosage form increases the patient’s compliance. However, while this combination increases the patients’ quality of life, combining more than one molecule in one dosage form also reduces undesired multiple sclerosis symptoms which can be muscle spasticity. Thus, there is a need to combine dimethyl fumarate with at least one muscle relaxant agent, preferably the muscle relaxant agents are tolperisone or tizanidine or baclofen or thiocolchicoside or mixtures thereof.
Detailed description of the Invention
The main object of the present invention is to combine dimethyl fumarate with at least one muscle relaxant agent to eliminate multiple sclerosis symptoms, to provide rapid and effective treatment and to bring additional advantages over the relevant prior art.
Another object of the present invention is to obtain a stable combination formulation with synergistic effect for use in multiple sclerosis. This invention also provides a pharmaceutical combination comprising an effective amount of dimethyl fumarate and an effective amount of at least one muscle relaxant agent for use in treating a human afflicted with multiple sclerosis, wherein dimethyl fumarate and at least one muscle relaxant agent are administered simultaneously, separately or sequentially.
The term“tolperisone” as used herein refers to tolperisone in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
The term“tizanidine” as used herein refers to tizanidine in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
The term“baclofen” as used herein refers to baclofen in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
The term“thiocolchicoside” as used herein refers to thiocolchicoside in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
Muscle relaxants are medicines that are used to prevent and reduce muscle spasms and tightness (spasticity). Muscle spasms occur when there is an uncontrolled (involuntary) contraction of a group of muscles. The muscles usually shorten (contract) suddenly; this is often painful. Spasticity occurs when some muscles contract tightly and can then become stiff and harder to use.
According to one embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate and at least one muscle relaxant agent.
According to one embodiment of the present invention, the muscle relaxant agent is selected from the group comprising tolperisone or tizanidine or baclofen or thiocolchicoside or diazepam or metaxalone or methocarbamol or dantrolene or cyclobenzaprine or carisoprodol or tetrazepam or mixtures thereof. Preferably, the muscle relaxant agent is tolperisone or tizanidine or baclofen or thiocolchicoside or mixtures thereof which is used as adjunctive therapy in pain control and muscle spasticity. Thus, an embodiment of this present invention is to combine dimethyl fumarate with tolperisone or tizanidine or baclofen or thiocolchicoside in a same and stable dosage form with desired dissolution profiles.
According to one embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate and tolperisone.
This invention provides a method of treating a human afflicted with multiple sclerosis comprising periodical administration of an effective amount of dimethyl fumarate and an effective amount of muscle relaxant agent to the subject together, wherein these effective amounts described below are effective to treat a human.
According to this embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg and 300 mg and tolperisone in an amount of between 30 mg and 200 mg.
According to one embodiment of the present invention, the weight ratio of dimethyl fumarate to tolperisone is between 0.5 - 10.0, preferably 0.8 -5.0.
According to another embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate and tizanidine.
According to this embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and tizanidine in an amount of between 1 to 10 mg.
According to one embodiment of the present invention, the weight ratio of dimethyl fumarate to tizanidine is between 10.0 - 300.0, preferably 30.0 -120.0.
According to another embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate and baclofen.
According to this embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and baclofen in an amount of between 5 to 20 mg. According to one embodiment of the present invention, the weight ratio of dimethyl fumarate to baclofen is between 5.0 - 60.0, preferably 12.0 -24.0.
According to another embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate and thiocolchicoside.
According to this embodiment of the present invention, the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and thiocolchicoside in an amount of between 1 to 15 mg.
According to one embodiment of the present invention, the weight ratio of dimethyl fumarate to thiocolchicoside is between 6.0 - 300.0, preferably 15.0 -60.0.
In a preferred embodiment according to the present invention, said combination further comprises at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, solvents and co-solvents, rate controlling polymers, direct compression agent, surfactants, lubricants, glidants, sweeteners, stabilizers, coating agents, colouring agents, inert agents or mixtures thereof.
Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
Suitable disintegrants are selected from the group comprising polyvinil pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
Suitable solvents or co-solvents are selected from the group comprising water, propylene glycol, glycerin, ethanol, polyethylene glycol or mixtures thereof.
Suitable rate controlling polymers are selected from the group comprising ethyl acrylate, ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose E4M, hydroxypropyl methylcellulose K100MCR, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, pectin, polyglucoronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, lambda carregeenan, iota carregeenan, furcellaran, xanthan gum, a polymer of acrylic acid, carbopol, agar, guar gum, psyllium seed gum, gellan gum, locust bean gum, tara gum, tamarind gum, gum arabic, curdlan, galactomannan, glucomannan, nitrocellulose, methylcellulose, proteoglycan, glycoprotein, actin, tubulin, hemoglobin, insulin, fibrin, albumin, myosin, collagen, casein, pullulan, chitosan, glycerol, propylene glycol, macrogols, phthalate esters, dibutyl sebacetate, citrate esters, triacetin, castor oil, acetylated monoglycerides, fractionated coconut oil, hydrogenated vegetable oil, hydrogenated castor oil, carnauba wax, candellia wax, beeswax, paraffin wax, stearic acid, glyceryl behenate, cetyl alcohol, cetostearyl alcohol or a mixtures thereof.
Suitable direct compression agents are selected from the group comprising calcium hydrogen phosphate sodium alginate, pregelatinized starch, calcium citrate or mixtures thereof.
Suitable surfactants are selected from the group comprising sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, nonoxynol, polyoxyethylene stearates, polyethylene glycol, leucine, poloxamer 407, sodium benzoate, docusate sodium, alpha tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene hydrogenated castor oil or mixtures thereof.
Suitable lubricants are selected from the group comprising from magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch, talc or mixtures thereof.
Suitable sweeteners are selected from the group comprising aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose or sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
Suitable stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof.
Suitable coating agents are selected from the group comprising polymethacrylates, polyalkylacrylates copolymers, hydroxyl propyl methyl cellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol- polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.
Suitable colouring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
Suitable inert agents between the two molecules are selected from starch, lactose, sugar alcohol like D-mannitol, erythritol; low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof.
According to one embodiment of the present invention, the pharmaceutical combination is administered orally. The pharmaceutical combination is in the form of tablets, capsules, strips, syrups, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, suspensions or emulsions. Preferably, the pharmaceutical combination is in the form of tablets or capsules.
According to another embodiment of the present invention, the pharmaceutical combination is in the form of a tablet. The pharmaceutical combination is formulated as tablets comprising film-coated tablets, bilayer tablets, inlay tablets, orally disintegrating tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, gastric disintegrating tablets, chewable tablets, dispersing tablets or lozenges.
According to another embodiment of the present invention, the pharmaceutical combination is in the form of a capsule.
According to an embodiment of this present invention, modified release dosage form is selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof. In one embodiment, modified release dosage form is prepared using rate controlling polymers.
The combination is prepared using direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
In this present invention, a desired dissolution of the combination is obtained and a desired content uniformity and a simple preparation process are in favor of industrial production.
In this present invention, the combination is for use in the treatment of multiple sclerosis in human.

Claims

1. A pharmaceutical combination comprising dimethyl fumarate and at least one muscle relaxant agent.
2. The pharmaceutical combination according to claim 1 , wherein the muscle relaxant agent is selected from the group comprising tolperisone or tizanidine or baclofen or thiocolchicoside or diazepam or metaxalone or methocarbamol or dantrolene or cyclobenzaprine or carisoprodol or tetrazepam or mixtures thereof.
3. The pharmaceutical combination according to claim 2, wherein the muscle relaxant agent is tolperisone or tizanidine or baclofen or thiocolchicoside or combinations thereof.
4. The pharmaceutical combination according to claim 3, wherein the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg and 300 mg and tolperisone in an amount of between 30 mg and 200 mg.
5. The pharmaceutical combination according to claim 4, wherein the weight ratio of dimethyl fumarate to tolperisone is between 0.5 - 10.0, preferably 0.8 -5.0.
6. The pharmaceutical combination according to claim 3, wherein the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and tizanidine in an amount of between 1 to 10 mg.
7. The pharmaceutical combination according to claim 6, wherein the weight ratio of dimethyl fumarate to tizanidine is between 10.0 - 300.0, preferably 30. -120.0.
8. The pharmaceutical combination according to claim 3, wherein the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and baclofen in an amount of between 5 to 20 mg.
9. The pharmaceutical combination according to claim 8, wherein the weight ratio of dimethyl fumarate to baclofen is between 5.0 - 60.0, preferably 12.0 -24.0.
10. The pharmaceutical combination according to claim 3, wherein the pharmaceutical combination comprises dimethyl fumarate in an amount of between 100 mg to 300 mg and thiocolchicoside in an amount of between 1 to 15 mg.
11. The pharmaceutical combination according to claim 10, wherein the weight ratio of dimethyl fumarate to thiocolchicoside is between 6.0 - 300.0, preferably 15.0 -60.0.
12. The pharmaceutical combination according to any one of the preceding claims, further comprising at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, solvents and co-solvents, rate controlling polymers, direct compression agents, surfactants, lubricants, glidants, sweeteners, stabilizers, coating agents, colouring agents, inert agents or mixtures thereof.
13. The pharmaceutical combination according to any one of the preceding claims, wherein the combination is administered orally.
14. The pharmaceutical combination according to claim 13, wherein the pharmaceutical combination is in the form of tablets, capsules, strips, syrups, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, suspensions or emulsions.
15. The pharmaceutical combination according to claim 14, wherein the pharmaceutical combination is in the form of a tablet.
16. The pharmaceutical combination according to claim 15, wherein the pharmaceutical combination is formulated as tablets comprising film-coated tablets, bilayer tablets, inlay tablets, orally disintegrating tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, gastric disintegrating tablets, chewable tablets, dispersing tablets or lozenges.
17. The pharmaceutical combination according to claim 14, wherein the pharmaceutical combination is in the form of a capsule.
18. A method for preparing the pharmaceutical combination according to any one of the preceding claims, comprising direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
19. The pharmaceutical combination according to any one of the preceding claims, for use in the treatment of multiple sclerosis in human.
PCT/TR2019/050957 2018-12-07 2019-11-15 A combination comprising dimethyl fumarate and at least one muscle relaxant agent Ceased WO2020117161A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP19891930.0A EP3890720A4 (en) 2018-12-07 2019-11-15 A combination comprising dimethyl fumarate and at least one muscle relaxant agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2018/18859A TR201818859A2 (en) 2018-12-07 2018-12-07 A combination comprising dimethyl fumarate and at least one muscle relaxant agent
TR2018/18859 2018-12-07

Publications (1)

Publication Number Publication Date
WO2020117161A1 true WO2020117161A1 (en) 2020-06-11

Family

ID=70975017

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2019/050957 Ceased WO2020117161A1 (en) 2018-12-07 2019-11-15 A combination comprising dimethyl fumarate and at least one muscle relaxant agent

Country Status (3)

Country Link
EP (1) EP3890720A4 (en)
TR (1) TR201818859A2 (en)
WO (1) WO2020117161A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016073510A1 (en) 2014-11-04 2016-05-12 Adamas Pharmaceuticals, Inc. Methods of administering amantadine compositions
WO2018082814A1 (en) * 2016-11-07 2018-05-11 Metriopharm Ag Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of chronic progressive multiple sclerosis
TR201720406A2 (en) * 2017-12-14 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi COMBINATIONS CONTAINING A SKELETAL MUSCLE LOAER AND A MULTIPLE SCLEROSIS THERAPY

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT500144A1 (en) * 2004-03-05 2005-11-15 Sanochemia Pharmazeutika Ag TOLPERISON-CONTAINING PHARMACEUTICAL PREPARATION WITH CONTROLLABLE ACTIVE INGREDIENTS FOR ORAL ADMINISTRATION
CN109453133A (en) * 2013-08-26 2019-03-12 前进制药知识产权有限公司 For with the pharmaceutical composition containing dimethyl fumarate of low daily dose application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016073510A1 (en) 2014-11-04 2016-05-12 Adamas Pharmaceuticals, Inc. Methods of administering amantadine compositions
WO2018082814A1 (en) * 2016-11-07 2018-05-11 Metriopharm Ag Use of 5-amino-2,3-dihydro-1,4-phthalazinedione in the treatment of chronic progressive multiple sclerosis
TR201720406A2 (en) * 2017-12-14 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi COMBINATIONS CONTAINING A SKELETAL MUSCLE LOAER AND A MULTIPLE SCLEROSIS THERAPY

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3890720A4

Also Published As

Publication number Publication date
EP3890720A4 (en) 2022-09-07
EP3890720A1 (en) 2021-10-13
TR201818859A2 (en) 2020-06-22

Similar Documents

Publication Publication Date Title
AU2017300185B2 (en) Extended release dosage forms of pregabalin
JPH02209A (en) Control release compound of carbidopa/levodopa
US20250228802A1 (en) Extended release midodrine hydrochloride compositions and methods of use
CN102716097A (en) Method for controlling medicament release rate of orally disintegrating tablet
JP2012514632A (en) Two-stage release pharmaceutical suspension
BRPI0614021A2 (en) pharmaceutical formulations and methods of use
WO2020122838A2 (en) A combination comprising a multiple sclerosis agent and at least one anti-epileptic agent
WO2019203752A2 (en) Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent
US20090175938A1 (en) Controlled Release Flurbiprofen and Muscle Relaxant Combinations
WO2020117161A1 (en) A combination comprising dimethyl fumarate and at least one muscle relaxant agent
WO2020122839A2 (en) A combination comprising a multiple sclerosis agent and at least one muscle relaxant agent
WO2016012398A1 (en) Zaltoprofen and muscle relaxant combinations
EP3810112A2 (en) A combination comprising fingolimod and modafinil
EP3810110A2 (en) A combination comprising fingolimod and amantadine
WO2019245512A2 (en) A combination comprising fingolimod and at least one anti-epileptic agent
WO2025250110A1 (en) The prolonged-release tablet comprising fampridine
WO2020139238A2 (en) Pharmaceutical combinations comprising fingolimod and a spasmolytic
TR2022010905A2 (en) A COMBINATION CONTAINING FAMPYRIDINE AND A CORTICOSTEROID AGENT
WO2019203748A2 (en) The composition comprising raloxifene with at least one antipsychotic agent
TR2021021540A2 (en) A COMBINATION COMPRISING IBUPROFEN AND AT LEAST ONE ATYPICAL ANTIPSYCHOTIC AGENT
WO2005016315A1 (en) Pharmaceutical compositions of nateglinide and a high amount of a water-soluble filler
TR2021021538A2 (en) A PHARMACEUTICAL COMBINATION CONTAINING IBUPROFEN AND AT LEAST ONE ATYPICAL ANTIPSYCHOTIC AGENT
AU2014222375A1 (en) Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters
EP2961393A1 (en) Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters
BR112019000636B1 (en) PREGABALIN EXTENDED-RELEASE DOSAGE FORMS

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19891930

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019891930

Country of ref document: EP

Effective date: 20210707