[go: up one dir, main page]

WO2019203752A2 - Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent - Google Patents

Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent Download PDF

Info

Publication number
WO2019203752A2
WO2019203752A2 PCT/TR2018/050800 TR2018050800W WO2019203752A2 WO 2019203752 A2 WO2019203752 A2 WO 2019203752A2 TR 2018050800 W TR2018050800 W TR 2018050800W WO 2019203752 A2 WO2019203752 A2 WO 2019203752A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical combination
tablets
combination according
weight
tizanidine
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/TR2018/050800
Other languages
French (fr)
Other versions
WO2019203752A3 (en
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Arzu Palantöken
Sibel ZENGINER
Merve PEKER
Emine TUNCAY
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 EP18915063.4A priority Critical patent/EP3723755A4/en
Publication of WO2019203752A2 publication Critical patent/WO2019203752A2/en
Publication of WO2019203752A3 publication Critical patent/WO2019203752A3/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
    • 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
    • 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
    • A61K31/185—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
    • A61K31/33—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to combinations which comprise at least one skeletal muscle relaxant agent and at least one multiple sclerosis treating agent.
  • MS Multiple Sclerosis
  • CNS central nervous system
  • spasticity a condition called spasticity. It happens mostly in the muscles of the legs and arms, and it may keep you from moving your limbs freely. Certain things can trigger them, and they can make the daily activities difficult.
  • fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1 ,3-diol.
  • Fingolimod is used in the treatment of the relapsing form of multiple sclerosis. May also be used in chronic inflammatory demyelinating polyneuropathy and shown as Formula I.
  • fingolimod derivatives first disclosed in US5604229.
  • the use of fingolimod derivatives as immunodepressant and a preventive or remedy for autoimmune diseases is disclosed in EP0627406 (B1 ).
  • the use of fingolimod derivatives in the prevention or treatment of chronic rejection in a recipient of organ or tissue alio- or xenotransplant is disclosed in EP0941082 (B1 ).
  • Skeletal muscle relaxant agents are often prescribed for musculoskeletal conditions including low back pain, neck pain, fibromyalgia, tension headaches, and myofascial pain syndrome.
  • the goals of treatment include managing muscle pain and improving functional status so the patient can return to work or resume previous activities.
  • Tizanidine, baclofen, diazepam, methocarbamol, dantrolene, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, orphenadrine are known as skeletal muscle relaxant agent.
  • tizanidine is 5-chloro-N-(4,5-dihydro-1 H-imidazol-2-yl)-2,1 ,3- benzothia-diazol-4-amine. It is a centrally acting skeletal muscle relaxant that acts mainly at spinal and supraspinal levels to inhibit excitatory interneurons and shown in Formula II.
  • baclofen 4-amino-3-(4-chlorophenyl) butanoic acid and is generally represented as follows in Formula III;
  • the main object of the present invention is to provide combinations of a skeletal muscle relaxant agent and multiple sclerosis treating agent, eliminating multiple sclerosis symptoms which is stiff muscles and spasms and bringing additional advantages over the relevant prior art.
  • Another object of the present invention is to obtain excellent content uniformity and a desired dissolution.
  • Another object of the present invention is to provide a pharmaceutical formulation that allows to obtain safe and efficient plasma levels of each pharmacological agents.
  • skeletal muscle relaxant agent refers to skeletal muscle relaxant agent in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.
  • Skeletal muscle relaxant agents are a diverse group of medicines that have the ability to relax or reduce tension in muscle. The agents work in the brain or spinal cord to block over-excited neuronal (nerve) pathways.
  • Some of skeletal muscle relaxant agents are tizanidine, baclofen, methocarbamol, dantrolene, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone and orphenadrine.
  • multiple sclerosis treating agent refers to multiple sclerosis treating agent in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof. Multiple sclerosis treating agents are used in multiple sclerosis to modify the disease course, treat relapses and manage symptoms. Some of multiple sclerosis treating agents are fingolimod, dimethyl fumarate, teriflunomide, dalfampridine, glatiramer.
  • combining more than one molecule in one dosage form increases the patient’s compliance.
  • this combination is increasing the patients’ quality of life, combining more than one molecule in one dosage form is also reduce undesired multiple sclerosis symptoms which can be stiff muscles and spasms.
  • molecules should be compatible with each other to achieve desired stability and dissolution for the patient’s compliance.
  • One embodiment of this invention is to provide a pharmaceutical combination comprises at least one skeletal muscle relaxant agent and at least one multiple sclerosis treating agent. Along with the other essential components of comprehensive MS care, these combinations help people to manage their MS and enhance their comfort and quality of life.
  • suitable multiple sclerosis treating agents are selected from the group comprising fingolimod, dimethyl fumarate, teriflunomide, dalfampridine, glatiramer or mixtures thereof.
  • suitable skeletal muscle relaxant agents are selected from group comprising tizanidine, baclofen, methocarbamol, dantrolene, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone and orphenadrine or mixtures thereof.
  • skeletal muscle relaxant agent is tizanidine or baclofen.
  • the amount of tizanidine is between 0.3%-40.0% by weight of the total composition.
  • the amount of baclofen is between 0.3%-40.0% by weight of the total composition.
  • the amount of tizanidine or baclofen provides effective treatment.
  • the combination is selected from tizanidine with fingolimod, tizanidine with dimethyl fumarate, tizanidine with teriflunomide, tizanidine with dalfampridine, tizanidine with glatiramer.
  • the combination is selected from baclofen with fingolimod, baclofen with dimethyl fumarate, baclofen with teriflunomide, baclofen with dalfampridine, baclofen with glatiramer.
  • the combination comprises at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, diluents, dispersing agents, lubricants/glidants, surfactant, plasticizers, melting components, inert agent, stabilizers, rate controlling polymers, coating agents, coloring agents or mixtures thereof.
  • pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, diluents, dispersing agents, lubricants/glidants, surfactant, plasticizers, melting components, inert agent, stabilizers, rate controlling polymers, coating agents, coloring agents or mixtures thereof.
  • Suitable fillers are selected from group comprising microcrystalline cellulose, calcium hydrogen phosphate dihydrate, ammonium alginate, calcium carbonate, dibasic calcium phosphate, calcium sulfate, cellulose, cellulose acetate, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, polysorbate
  • the amount of fillers is between 20.0%- 85.0% by weight of the total composition. Preferably, it is between 30.0%-75.0% by weight of the total composition, more preferably it is between 35.0%-70.0% by weight of the total composition.
  • binders are used in this invention to achieve the desired dissolution of the combination.
  • Suitable binders are selected from the group comprising polyethylene glycols, dibasic calcium phosphate, polyvinylpyrrolidone (povidone), sugars, glucose syrup, natural gums, gelatin, collagen, gelatin, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, starch, corn starch , pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, liquid glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin,
  • the amount of binders is between 0.5%- 8.0% by weight of the total composition. Preferably, it is between 0.5%-7.0% by weight of the total composition, more preferably it is between 0.5%-6.0% by weight of the total composition.
  • Suitable disintegrants are selected from the group comprising cross-linked 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, polyacrylate potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
  • cross-linked polyvinil pyrrolidone crospovidone
  • povidone cross-linked carboxymethyl cellulose
  • croscarmellose sodium cross-linked carboxymethyl cellulose
  • low-substituted hydroxypropyl cellulose pregelatinized starch
  • Suitable diluents 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 dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.
  • Suitable lubricants/glidants are selected from the group comprising sodium stearyl fumarate, 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, glyceryl palmito sulphate, sodium lauryl sulphate, aluminium silicate, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.
  • Suitable surfactants are selected from the group comprising sodium lauryl sulfate, cetylpyridinium chloride, docusate sodium, lauric acid, polyoxyethylene sorbitan fatty acid esters (polysorbate), phospholipids, cetrimide or mixtures thereof.
  • Suitable plasticizers are selected from the group comprising polyethylene glycols of different molecular weights, triacetin, tributyl citrate, triethyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols, propylene glycol or mixtures thereof.
  • Suitable melting components are selected from the group comprising gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene-polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylated monoglyceride, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalylethly glycolate, glycerin, propylene glycol, triacetin, triacetin citrate, tripropionin or mixtures thereof.
  • gelucire stearyl macrogolglyceride
  • poloxamer polyoxyethylene-polyoxypropylene block copolymer
  • polyethylene glycol povidone
  • povidone soluplus
  • cationic methacrylate copovidone
  • Suitable inert agents between the two molecules wherein the inert agent is selected from starch, lactose, D-mannitol, erythritol; lowsubstituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof.
  • Suitable stabilizers are selected from the group comprising sucrose, 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 rate controlling polymers are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone,, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, sodium alginate, alginic acid, pectin, polyglucoronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, lambda carregeenan, iota carregeenan, furcellaran, xant
  • Suitable coating agents are selected from the group comprising hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), 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 coloring 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
  • the pharmaceutical combination is administered orally.
  • the pharmaceutical combination is in the form of capsules, tablets, strips, syrups, powders, pastilles, sachet, effervescent compositions, pills, hard or soft gelatin capsules, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions or emulsions.
  • the pharmaceutical combination is in the form of capsules or tablets or pastilles or strips. According to one embodiment of the present invention, the pharmaceutical combination is in the form of capsule.
  • the pharmaceutical combination is in the form of tablet.
  • the pharmaceutical combination is formulated as tablets comprising compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges.
  • the pharmaceutical combination may comprise a film coating as necessary.
  • said tablets or capsules comprises at least one type of particle. Furthermore, each particle comprises at least one active agent.
  • At least one type of particle is mini capsule, mini-tablet, pellets, agglomerates, granules, powder, liposomes, sphericals or mixtures thereof.
  • An embodiment of this present invention is to combine skeletal muscle relaxant agent and multiple sclerosis treating agent in a same and stable dosage form with desired dissolution profiles.
  • compositions of invention may be developed as immediate release formulation, extended release formulation, sustained release formulation, controlled release formulation, modified release formulation, delayed release formulation or thereof combination.
  • composition comprising at least one of the following drug combinations for combined, separate or sequential administration: -tizanidine, fingolimod or their pharmaceutically acceptable salt, solvate or polymorph -tizanidine, dimethyl fumarate or their pharmaceutically acceptable salt, solvate or polymorph
  • the pharmaceutical combination of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
  • Example 1 Capsule comprising skeletal muscle relaxant agent and multiple sclerosis treating agent
  • the process for preparation of the combination comprises the following steps:
  • Example 2 Capsule comprising fingolimod and tizanidine
  • Example 3 Capsule comprising fingolimod and tizanidine
  • the process for preparation of the combination comprises the following steps:
  • Example 5 Capsule comprising fingolimod and baclofen
  • the process for preparation of the pharmaceutical combination comprises the following steps:
  • Example 6 Film-coated tablet comprising fingolimod and tizanidine
  • the pharmaceutical combinations mentioned above are prepared by following these steps: a. Mixing fingolimod, tizanidine, or pharmaceutically acceptable polymorphs thereof, microcrystalline cellulose, dibasic calcium phosphate, polyethylene glycol and pregelatinized starch.
  • Example 7 Film-coated tablet comprising fingolimod and baclofen
  • the pharmaceutical combinations mentioned above are prepared by following these steps: a. Mixing fingolimod, baclofen, or pharmaceutically acceptable polymorphs thereof, microcrystalline cellulose, dibasic calcium phosphate, polyethylene glycol and pregelatinized starch.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to combinations which comprise at least one skeletal muscle relaxant agent and at least one multiple sclerosis treating agent.

Description

COMBINATIONS COMPRISING A SKELETAL MUSCLE RELAXANT AGENT AND A MULTIPLE SCLEROSIS TREATING AGENT
Field of the invention
The present invention relates to combinations which comprise at least one skeletal muscle relaxant agent and at least one multiple sclerosis treating 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. However, there is substantial evidence indicating that dysregulated immune responses, including immune mechanisms directed against myelin proteins, have a role in triggering disease onset.
During an MS attack, inflammation occurs in areas of the white matter of CNS in patches known as“plaques”. This process is followed by destruction of myelin in the brain and spinal cord, leading to diminished or lost function.
Many people with multiple sclerosis have stiff muscles and spasms, a condition called spasticity. It happens mostly in the muscles of the legs and arms, and it may keep you from moving your limbs freely. Certain things can trigger them, and they can make the daily activities difficult.
There is no known cure for MS until now. However, there are therapies that may slow the development of the disease.
The chemical name of fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1 ,3-diol. Fingolimod is used in the treatment of the relapsing form of multiple sclerosis. May also be used in chronic inflammatory demyelinating polyneuropathy and shown as Formula I.
Figure imgf000003_0002
Formula I: Fingolimod
In the prior art, fingolimod derivatives first disclosed in US5604229. The use of fingolimod derivatives as immunodepressant and a preventive or remedy for autoimmune diseases is disclosed in EP0627406 (B1 ). The use of fingolimod derivatives in the prevention or treatment of chronic rejection in a recipient of organ or tissue alio- or xenotransplant is disclosed in EP0941082 (B1 ).
Skeletal muscle relaxant agents are often prescribed for musculoskeletal conditions including low back pain, neck pain, fibromyalgia, tension headaches, and myofascial pain syndrome. The goals of treatment include managing muscle pain and improving functional status so the patient can return to work or resume previous activities. Tizanidine, baclofen, diazepam, methocarbamol, dantrolene, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, orphenadrine are known as skeletal muscle relaxant agent.
The chemical name of tizanidine is 5-chloro-N-(4,5-dihydro-1 H-imidazol-2-yl)-2,1 ,3- benzothia-diazol-4-amine. It is a centrally acting skeletal muscle relaxant that acts mainly at spinal and supraspinal levels to inhibit excitatory interneurons and shown in Formula II.
Figure imgf000003_0001
Formula II: Tizanidine
The chemical name of baclofen is 4-amino-3-(4-chlorophenyl) butanoic acid and is generally represented as follows in Formula III;
Figure imgf000004_0001
Formula III: Baclofen
It has also been found that the combination of a skeletal muscle relaxant agent with multiple sclerosis treating agent 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 skeletal muscle relaxant agent with multiple sclerosis treating agent in the prior art.
Detailed Description of the Invention
The main object of the present invention is to provide combinations of a skeletal muscle relaxant agent and multiple sclerosis treating agent, eliminating multiple sclerosis symptoms which is stiff muscles and spasms and bringing additional advantages over the relevant prior art.
Another object of the present invention is to obtain excellent content uniformity and a desired dissolution.
Yet, another object of the present invention is to provide a pharmaceutical formulation that allows to obtain safe and efficient plasma levels of each pharmacological agents.
The term“combination” means that when drugs are administered together, a combined action is obtained which is higher than the individual actions of the respective drugs when they are used separately.
The term “skeletal muscle relaxant agent” as used herein refers to skeletal muscle relaxant agent in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof. Skeletal muscle relaxant agents are a diverse group of medicines that have the ability to relax or reduce tension in muscle. The agents work in the brain or spinal cord to block over-excited neuronal (nerve) pathways. Some of skeletal muscle relaxant agents are tizanidine, baclofen, methocarbamol, dantrolene, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone and orphenadrine.
The term“multiple sclerosis treating agent” as used herein refers to multiple sclerosis treating agent in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof. Multiple sclerosis treating agents are used in multiple sclerosis to modify the disease course, treat relapses and manage symptoms. Some of multiple sclerosis treating agents are fingolimod, dimethyl fumarate, teriflunomide, dalfampridine, glatiramer.
In this invention, combining more than one molecule in one dosage form increases the patient’s compliance. However, while this combination is increasing the patients’ quality of life, combining more than one molecule in one dosage form is also reduce undesired multiple sclerosis symptoms which can be stiff muscles and spasms. Moreover, in order to combine two different molecules in one dosage form, molecules should be compatible with each other to achieve desired stability and dissolution for the patient’s compliance.
One embodiment of this invention is to provide a pharmaceutical combination comprises at least one skeletal muscle relaxant agent and at least one multiple sclerosis treating agent. Along with the other essential components of comprehensive MS care, these combinations help people to manage their MS and enhance their comfort and quality of life.
According to one embodiment, suitable multiple sclerosis treating agents are selected from the group comprising fingolimod, dimethyl fumarate, teriflunomide, dalfampridine, glatiramer or mixtures thereof.
According to one embodiment, suitable skeletal muscle relaxant agents are selected from group comprising tizanidine, baclofen, methocarbamol, dantrolene, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone and orphenadrine or mixtures thereof. Preferably skeletal muscle relaxant agent is tizanidine or baclofen.
According to one embodiment, the amount of tizanidine is between 0.3%-40.0% by weight of the total composition. The amount of baclofen is between 0.3%-40.0% by weight of the total composition. The amount of tizanidine or baclofen provides effective treatment. According to one embodiment, the combination is selected from tizanidine with fingolimod, tizanidine with dimethyl fumarate, tizanidine with teriflunomide, tizanidine with dalfampridine, tizanidine with glatiramer.
According to one embodiment, the combination is selected from baclofen with fingolimod, baclofen with dimethyl fumarate, baclofen with teriflunomide, baclofen with dalfampridine, baclofen with glatiramer.
According to one embodiment of this present invention, the combination comprises at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, diluents, dispersing agents, lubricants/glidants, surfactant, plasticizers, melting components, inert agent, stabilizers, rate controlling polymers, coating agents, coloring agents or mixtures thereof.
Suitable fillers are selected from group comprising microcrystalline cellulose, calcium hydrogen phosphate dihydrate, ammonium alginate, calcium carbonate, dibasic calcium phosphate, calcium sulfate, cellulose, cellulose acetate, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, polysorbate, xylitol or mixtures thereof.
According to this embodiment of the invention, the amount of fillers is between 20.0%- 85.0% by weight of the total composition. Preferably, it is between 30.0%-75.0% by weight of the total composition, more preferably it is between 35.0%-70.0% by weight of the total composition.
The binders are used in this invention to achieve the desired dissolution of the combination. Suitable binders are selected from the group comprising polyethylene glycols, dibasic calcium phosphate, polyvinylpyrrolidone (povidone), sugars, glucose syrup, natural gums, gelatin, collagen, gelatin, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, starch, corn starch , pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, liquid glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, bentonite, laponit, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
According to this embodiment of the invention, the amount of binders is between 0.5%- 8.0% by weight of the total composition. Preferably, it is between 0.5%-7.0% by weight of the total composition, more preferably it is between 0.5%-6.0% by weight of the total composition.
Suitable disintegrants are selected from the group comprising cross-linked 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, polyacrylate potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
Suitable diluents 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 dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.
Suitable lubricants/glidants are selected from the group comprising sodium stearyl fumarate, 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, glyceryl palmito sulphate, sodium lauryl sulphate, aluminium silicate, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.
Suitable surfactants are selected from the group comprising sodium lauryl sulfate, cetylpyridinium chloride, docusate sodium, lauric acid, polyoxyethylene sorbitan fatty acid esters (polysorbate), phospholipids, cetrimide or mixtures thereof.
Suitable plasticizers are selected from the group comprising polyethylene glycols of different molecular weights, triacetin, tributyl citrate, triethyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols, propylene glycol or mixtures thereof.
Suitable melting components are selected from the group comprising gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene-polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylated monoglyceride, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalylethly glycolate, glycerin, propylene glycol, triacetin, triacetin citrate, tripropionin or mixtures thereof.
Suitable inert agents between the two molecules wherein the inert agent is selected from starch, lactose, D-mannitol, erythritol; lowsubstituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof.
Suitable stabilizers are selected from the group comprising sucrose, 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 rate controlling polymers are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone,, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, sodium alginate, alginic acid, pectin, polyglucoronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, lambda carregeenan, iota carregeenan, furcellaran, xanthan gum, a polymer of acrylic acid, agar, guar gum, psyllium seed gum, gellan gum, locust bean gum, tara gum, tamarind gum, gum arabic, curdlan, galactomannan, glucomannan, glyceryl behenate, nitrocellulose, methylcellulose, pullulan, chitosan, glycerol, propylene glycol, macrogols, phfchalate 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, cetyl alcohol, cetostearyl alcohol, gelucire (stearyl macrogolglyceride) or a mixtures thereof.
Suitable coating agents are selected from the group comprising hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), 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 coloring 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.
According to an embodiment of this present invention, the pharmaceutical combination is administered orally.
An embodiment of this present invention, the pharmaceutical combination is in the form of capsules, tablets, strips, syrups, powders, pastilles, sachet, effervescent compositions, pills, hard or soft gelatin capsules, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions or emulsions.
In this present, the pharmaceutical combination is in the form of capsules or tablets or pastilles or strips. According to one embodiment of the present invention, the pharmaceutical combination is in the form of capsule.
According to one embodiment of the present invention, the pharmaceutical combination is in the form of tablet.
An embodiment of this present invention, the pharmaceutical combination is formulated as tablets comprising compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges.
According to one embodiment of the present invention, the pharmaceutical combination may comprise a film coating as necessary.
According to one embodiment of the present invention, said tablets or capsules comprises at least one type of particle. Furthermore, each particle comprises at least one active agent.
According to one embodiment of the present invention, at least one type of particle is mini capsule, mini-tablet, pellets, agglomerates, granules, powder, liposomes, sphericals or mixtures thereof.
An embodiment of this present invention is to combine skeletal muscle relaxant agent and multiple sclerosis treating agent in a same and stable dosage form with desired dissolution profiles.
The compositions of invention may be developed as immediate release formulation, extended release formulation, sustained release formulation, controlled release formulation, modified release formulation, delayed release formulation or thereof combination.
The pharmaceutical combination wherein said composition comprises at least one of the following drug combinations for combined, separate or sequential administration: -tizanidine, fingolimod or their pharmaceutically acceptable salt, solvate or polymorph -tizanidine, dimethyl fumarate or their pharmaceutically acceptable salt, solvate or polymorph
-tizanidine, teriflunomide or their pharmaceutically acceptable salt, solvate or polymorph -tizanidine, dalfampridine or their pharmaceutically acceptable salt, solvate or polymorph -tizanidine, glatiramer or their pharmaceutically acceptable salt, solvate or polymorph -baclofen, fingolimod or their pharmaceutically acceptable salt, solvate or polymorph -baclofen, dimethyl fumarate or their pharmaceutically acceptable salt, solvate or polymorph
-baclofen, teriflunomide or their pharmaceutically acceptable salt, solvate or polymorph -baclofen, dalfampridine or their pharmaceutically acceptable salt, solvate or polymorph -baclofen, glatiramer or their pharmaceutically acceptable salt, solvate or polymorph
The pharmaceutical combination of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
It has surprisingly been found that solid dosage forms of excellent uniformity and showing improved dissolution can be obtained when skeletal muscle relaxant agent and multiple sclerosis treating agent are formulated together in wet granulation process. Wet granulation process efficiently counteracts segregation, so it can achieve good dissolution and disintegration properties.
In this present invention, a desired dissolution of the combination is obtained and have an excellent content uniformity which maintains simple preparation process, in favor of industrial production.
Example 1 : Capsule comprising skeletal muscle relaxant agent and multiple sclerosis treating agent
Figure imgf000011_0001
Figure imgf000012_0001
Process for example 1 :
The process for preparation of the combination comprises the following steps:
a) Adding multiple sclerosis treating agent, skeletal muscle relaxant agent, fillers and binders and then, mixing
b) Granulating the mixture with ethanokwater (1 :1 ) solution and then, drying and sieving
c) Adding a lubricant/glidant and mixing
d) Filling into capsules
Example 2: Capsule comprising fingolimod and tizanidine
Figure imgf000012_0002
Example 3: Capsule comprising fingolimod and tizanidine
Figure imgf000012_0003
Process for example 3:
The process for preparation of the combination comprises the following steps:
e) Adding fingolimod, tizanidine, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, polyethylene glycol and then, mixing
f) Granulating the mixture with ethanohwater (1 :1 ) solution and then, drying and sieving
g) Adding sodium stearyl fumarate and mixing
h) Filling into capsules Example 4: Capsule comprising fingolimod and baclofen
Figure imgf000013_0001
Example 5: Capsule comprising fingolimod and baclofen
Figure imgf000013_0002
Process for example 5:
The process for preparation of the pharmaceutical combination comprises the following steps:
a) Adding fingolimod, baclofen, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, polyethylene glycol and then, mixing
b) Granulating the mixture with ethanokwater (1 :1 ) solution and then, drying and sieving c) Adding sodium stearyl fumarate and mixing
d) Filling into capsules
Example 6: Film-coated tablet comprising fingolimod and tizanidine
Figure imgf000014_0001
The pharmaceutical combinations mentioned above are prepared by following these steps: a. Mixing fingolimod, tizanidine, or pharmaceutically acceptable polymorphs thereof, microcrystalline cellulose, dibasic calcium phosphate, polyethylene glycol and pregelatinized starch.
b. Adding talc in the mixture and mixing until a homogenous mixture is achieved. c. Adding sodium stearyl fumarate to the mixture and mixing for 1 -2 minutes.
d. Compressing the powder mixture to form tablets
e. Coating these tablets with PVA based coating agent.
Example 7: Film-coated tablet comprising fingolimod and baclofen
Figure imgf000014_0002
Figure imgf000015_0001
The pharmaceutical combinations mentioned above are prepared by following these steps: a. Mixing fingolimod, baclofen, or pharmaceutically acceptable polymorphs thereof, microcrystalline cellulose, dibasic calcium phosphate, polyethylene glycol and pregelatinized starch.
b. Adding talc in the mixture and mixing until a homogenous mixture is achieved. c. Adding sodium stearyl fumarate to the mixture and mixing for 1 -2 minutes.
d. Compressing the powder mixture to form tablets
e. Coating these tablets with PVA based coating agent.

Claims

1 . A pharmaceutical combination comprising at least one skeletal muscle relaxant agent and at least one multiple sclerosis treating agent.
2. The pharmaceutical combination according to claim 1 , wherein multiple sclerosis treating agents are selected from group comprising fingolimod, dimethyl fumarate, teriflunomide, dalfampridine, glatiramer or mixtures thereof.
3. The pharmaceutical combination according to claim 1 , wherein skeletal muscle relaxant agents are selected from group comprising tizanidine, baclofen, methocarbamol, dantrolene, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone and orphenadrine or mixtures thereof.
4. The pharmaceutical combination according to claim 3, wherein the skeletal muscle relaxant agent is tizanidine or baclofen.
5. The pharmaceutical combination according to claim 4, wherein the amount of tizanidine is between 0.3%-40.0% by weight of the total composition and the amount of baclofen is between 0.3%-40.0% by weight of the total composition.
6. The pharmaceutical combination according to claim 1 , wherein the combination is selected from tizanidine with fingolimod or tizanidine with dimethyl fumarate or tizanidine with teriflunomide or tizanidine with dalfampridine or tizanidine with glatiramer.
7. The pharmaceutical combination according to claim 1 , wherein the combination is selected from baclofen with fingolimod or baclofen with dimethyl fumarate or baclofen with teriflunomide or baclofen with dalfampridine or baclofen with glatiramer.
8. The pharmaceutical combination according to any preceding claims, wherein the combination comprising at least one pharmaceutically acceptable excipients which are selected from fillers, binders, disintegrants, diluents, dispersing agents, lubricants/glidants, surfactant, plasticizers, melting components, inert agent, stabilizers, rate controlling polymers, coating agents, coloring agents or mixtures thereof.
9. The pharmaceutical combination according to claim 8, wherein the binders are selected from the group comprising polyethylene glycols, dibasic calcium phosphate, polyvinylpyrrolidone (povidone), sugars, glucose syrup, natural gums, gelatin, collagen, gelatin, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, starch, corn starch , pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, liquid glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, bentonite, laponit, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
10. The pharmaceutical combination according to claim 9, wherein the amount of the binders is between 0.5% - 8.0% by weight of the total composition.
1 1. The pharmaceutical combination according to any preceding claims, wherein the pharmaceutical composition is administered orally.
12. The pharmaceutical combination according to claim 1 1 , wherein the pharmaceutical combination is in the form of capsules, tablets, strips, syrups, powders, pastilles, sachet, effervescent compositions, pills, hard or soft gelatin capsules, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions or emulsions.
13. The pharmaceutical combination according to claim 12, wherein the pharmaceutical combination is in the form of capsules or tablets or pastilles or strips.
14. The pharmaceutical combination according to claim 13, wherein the pharmaceutical combination is in the form of capsules.
15. The pharmaceutical combination according to claim 13, wherein the pharmaceutical combination is in the form of tablets.
16. The pharmaceutical combination according to claim 15, wherein said tablets are selected from a group comprising compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet or lozenges.
17. The pharmaceutical combination according to claim 14 or 15, wherein said tablets or capsules comprising at least one type of particle.
18. The pharmaceutical combination according to claim 17, wherein at least one type of particle is mini-capsule, mini-tablet, pellets, agglomerates, granules, powder, liposomes, sphericals or mixtures thereof.
19. The pharmaceutical combination according to claim 14, wherein the capsule comprising;
0.3%-30.0% by weight of fingolimod
5.0%-40.0% by weight of baclofen or tizanidine
30.0%-70.0% by weight of microcrystalline cellulose
20.0%-50.0% by weight of calcium hydrogen phosphate dihydrate
0.5%-8.0% by weight of polyethylene glycol
0.5%-8.0% by weight of sodium stearyl fumarate
20. A process for preparing the pharmaceutical combination according to claim 19, comprising the following steps: a) Adding fingolimod, tizanidine or baclofen, fillers and binders and then, mixing b) Granulating the mixture with ethanohwater (1 :1 ) solution, drying and sieving c) Adding a lubricant/glidant and mixing
d) Filling into capsules
21. The pharmaceutical combination according to claim 15, wherein the tablet
comprising;
0.3%-30.0% by weight of fingolimod
0.3%-40.0% by weight of baclofen or tizanidine
5.0%-70.0% by weight of microcrystalline cellulose
5.0%-50.0% by weight of dibasic calcium phosphate
0.5%-10.0% by weight of polyethylene glycol
1 .0% - 30.0% by weight of pregelatinized starch
0.5%-12.0% by weight of talc
0.5%-8.0% by weight of sodium stearyl fumarate
22. A process for preparing the pharmaceutical combination according to claim 21 , comprising the following steps: a. Mixing fingolimod, tizanidine or baclofen, microcrystalline cellulose, dibasic calcium phosphate, microcrystalline cellulose, polyethylene glycol and pregelatinized starch.
b. Adding talc in the mixture and mixing until a homogenous mixture is achieved. c. Adding sodium stearyl fumarate to the mixture and mixing
d. Compressing the powder mixture to form tablets
e. Coating these tablets with coating agent.
PCT/TR2018/050800 2017-12-14 2018-12-12 Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent Ceased WO2019203752A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18915063.4A EP3723755A4 (en) 2017-12-14 2018-12-12 Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/20406 2017-12-14
TR2017/20406A TR201720406A2 (en) 2017-12-14 2017-12-14 COMBINATIONS CONTAINING A SKELETAL MUSCLE LOAER AND A MULTIPLE SCLEROSIS THERAPY

Publications (2)

Publication Number Publication Date
WO2019203752A2 true WO2019203752A2 (en) 2019-10-24
WO2019203752A3 WO2019203752A3 (en) 2020-01-16

Family

ID=67900478

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2018/050800 Ceased WO2019203752A2 (en) 2017-12-14 2018-12-12 Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent

Country Status (3)

Country Link
EP (1) EP3723755A4 (en)
TR (1) TR201720406A2 (en)
WO (1) WO2019203752A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021181411A (en) * 2020-05-18 2021-11-25 東和薬品株式会社 Pharmaceutical composition containing fingolimod and manufacturing method and stabilizing method thereof
EP3893855A4 (en) * 2018-12-12 2022-08-17 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A combination comprising a multiple sclerosis agent and at least one muscle relaxant agent

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201818859A2 (en) * 2018-12-07 2020-06-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A combination comprising dimethyl fumarate and at least one muscle relaxant agent
TR201820976A2 (en) * 2018-12-28 2020-07-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi PHARMACEUTICAL COMBINATIONS WITH FINGOLIMOD AND A SPASMOLITHIC

Citations (1)

* 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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017031276A1 (en) * 2015-08-19 2017-02-23 The Regents Of The University Of California Methods of providing neuroprotective therapy related to administering an estrogen receptor beta ligand

Patent Citations (1)

* 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

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3893855A4 (en) * 2018-12-12 2022-08-17 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A combination comprising a multiple sclerosis agent and at least one muscle relaxant agent
JP2021181411A (en) * 2020-05-18 2021-11-25 東和薬品株式会社 Pharmaceutical composition containing fingolimod and manufacturing method and stabilizing method thereof

Also Published As

Publication number Publication date
WO2019203752A3 (en) 2020-01-16
EP3723755A2 (en) 2020-10-21
TR201720406A2 (en) 2019-07-22
EP3723755A4 (en) 2021-09-15

Similar Documents

Publication Publication Date Title
WO2008064202A2 (en) Modified-release formulations of calcium receptor-active compounds
WO2019203752A2 (en) Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent
US20100136119A1 (en) Controlled-release preparation containing cilostazol and process for the preparation thereof
JP2019513800A (en) Oral pharmaceutical composition of mesalazine
TWI491395B (en) Oral dosage formulation containing both immediate-release and sustained-release drugs for treating neurodegenerative disorders
JP2021506944A (en) Sustained release midodrine hydrochloride composition and usage
WO2017208136A1 (en) Pharmaceutical composition of dapagliflozin co-crystal
WO2022144919A1 (en) Extended release pharmaceutical compositions of riociguat
WO2007112574A1 (en) Extended release composition of venlafaxine
JP7021108B2 (en) Oral pharmaceutical composition of nicotinamide
US11576917B2 (en) Pharmaceutical compositions comprising Ibrutinib
WO2018095996A1 (en) Delayed release dosage forms comprising dimethyl fumarate
US20070134315A1 (en) Orally administrable extended release pellet and tablet formulations of a highly water soluble compound
EP2503996A2 (en) Controlled release pharmaceutical compositions of galantamine
US9561242B2 (en) Doxycycline composition
WO2019209217A2 (en) Modified release formulations of flurbiprofen
JP7352175B2 (en) tolvaptan formulation
US9566287B2 (en) Pharmaceutical composition of doxycycline with reduced food effect
US20160143923A1 (en) Low dose pharmaceutical composition of doxycycline
WO2019203748A2 (en) The composition comprising raloxifene with at least one antipsychotic agent
WO2024084496A1 (en) Pharmaceutical compositions comprising acalabrutinib maleate
EP3810112A2 (en) A combination comprising fingolimod and modafinil
WO2025032501A1 (en) Pharmaceutical composition comprising combination of levodopa and carbidopa
EP3810110A2 (en) A combination comprising fingolimod and amantadine
EP3886835A2 (en) The delayed release capsule comprising dimethyl fumarate

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018915063

Country of ref document: EP

Effective date: 20200714