WO2019190432A2 - Combinaisons de tolpérisone et d'inhibiteur de la cox non sélectif - Google Patents

Combinaisons de tolpérisone et d'inhibiteur de la cox non sélectif Download PDF

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Publication number
WO2019190432A2
WO2019190432A2 PCT/TR2018/050801 TR2018050801W WO2019190432A2 WO 2019190432 A2 WO2019190432 A2 WO 2019190432A2 TR 2018050801 W TR2018050801 W TR 2018050801W WO 2019190432 A2 WO2019190432 A2 WO 2019190432A2
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WO
WIPO (PCT)
Prior art keywords
weight
tablet
pharmaceutical composition
composition according
tolperisone
Prior art date
Application number
PCT/TR2018/050801
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English (en)
Other versions
WO2019190432A3 (fr
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Seyhan TÜRKKAN
Melda MISIRLI
Emine TUNCAY
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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 Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to EP18911384.8A priority Critical patent/EP3723735A4/fr
Publication of WO2019190432A2 publication Critical patent/WO2019190432A2/fr
Publication of WO2019190432A3 publication Critical patent/WO2019190432A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
    • A61K31/435—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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to pharmaceutical combinations comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof and non-selective COX inhibitors or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or rasemic mixtures thereof.
  • a muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia.
  • the term "muscle relaxant” is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as centrally acting muscle relaxants, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxants, the term is commonly used to refer to spasmolytics only.
  • Tolperisone is a centrally acting muscle relaxant that has been used for the symptomatic treatment of spasticity and muscle spasm. It acts at the reticular formation in the brain stem by blocking voltage-gated sodium and calcium channels and it is marketed unders trade names including Biocalm, Muscodol, Mydeton, Mydocalm, Mydoflex, Myolax, Myoxan and Viveo.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX cyclooxygenase
  • COX-1 The cyclooxygenase (COX) enzyme is actually present in two different forms, COX-1 and COX-2, each with a similar but distinct set of actions.
  • COX-2 is the enzyme responsible for inflammation and fever, whereas COX-1 actually performs other functions such as protecting the gastric mucosa (the lining of the stomach) from the acid that the stomach naturally produces.
  • COX-1 also plays a role in making platelets stick together to form clots. Both reduce blood flow to the kidneys.
  • NSAIDs block both types of the COX enzyme, so while inflammation and pain are reduced, so are some of the good effects of prostaglandins such as protection of the stomach lining.
  • selective NSAIDs which only target the COX-2 enzyme that is responsible for pain and inflammation, without impacting the production of protective factors for the stomach.
  • NSAIDs are divided into two classes which are non- selective COX inhibitors and selective COX inhibitors.
  • EP1610785B1 reveals the combined effect of tolperisone and dextromethorphan on the treatment of spasticity and pain.
  • EP1677787B1 the combination of tolperisone and flupirtin is suggested for the treatment of pains accompanied by an increase in muscle tone.
  • a dosage form comprising tolperisone and a non-selective COX inhibitor combination which enhances the therapeutic effect on spasmodic and arthritic disorders and which ensures the cardiovascular safety and compliance of the patient at the same time.
  • the main object of the present invention is to obtain combinations comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer of rasemic mixture thereof and non-selective COX inhibitors or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers of rasemic mixtures thereof, eliminating all aforesaid problems and bringing additional advantages over the relevant prior art.
  • Another object of the present invention is to obtain combinations of tolperisone and non- selective COX inhibitors ensuring cardiovascular safety and patient compliance.
  • a further object of the present invention is to develop combinations of tolperisone and non-selective COX inhibitors ensuring high stability, bioavalibility.
  • a further object of the present invention is to develop combinations of tolperisone and non-selective COX inhibitors having an improved level of dissolution rate and solubility.
  • Another object of the present invention is to provide a tablet dosage form comprising tolperisone and a non-selective COX inhibitor.
  • the present invention relates to pharmaceutical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof in combination with a non-selective COX inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof.
  • the said non-selective COX inhibitor is selected from the group comprising amidopirin, antipirin, aseclofenac, azapropazone, benzydamine, dexibuprofen, dexketoprofen, diflunisal, diclofenac, etodolac, etofenamate, fenbufen, phenylbutazone, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, mefenamic acid, meclofenamate, metamizole, nabumetone, naproxen, oxaprozin, oxyfenbutasone, piroxicam, proquazone, sulindac, tenocsicam, thiaprofenic acid, tolfenamic acid or tolmetin
  • the non-selective COX inhibitor is flurbiprofen or ibuprofen or ketoprofen or fenoprofen or dexibuprofen or dexketoprofen or fenbufen or mixtures thereof.
  • the non-selective COX inhibitor is flurbiprofen.
  • the pharmaceutical composition comprises tolperisone and flurbiprofen as combined active agents.
  • the weight ratio of flurbiprofen to tolperisone is in the range of 1 :0.025 to 1 :50 and preferably 1 :0.1 to 1 :5. In the most preferred embodiment, this ratio is 1 :1.5.
  • the amount of tolperisone is between 1 -50% by weight of the total composition. Preferably this amount is between 5-40% by weight of the total composition. More preferably tolperisone is present between 15-35% by weight in the total composition.
  • the amount of flurbiprofen is between 1 -40% by weight of the total composition. Preferably this amount is between 5-30% by weight of the total composition. More preferably flurbiprofen is present between 5-20% by weight in the total composition.
  • tolperisone is present in an amount of 1 to 500 mg, more preferably 50 to 250 mg in the total composition.
  • flurbiprofen is present in an amount of 1 to 300 mg, more preferably 50 to 150 mg in the total composition.
  • the composition comprises at least one pharmaceutically acceptable excipient selected from diluents, disintegrants, binders, lubricants, glidants, buffering agents or mixtures thereof.
  • the oral pharmaceutical composition comprises at least one diluent which is selected from the group comprising lactose, lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate, mannitol, spray-dried mannitol, 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.
  • diluent which is selected from the group comprising lactose, lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate, mannitol, spray-dried mannitol, dextrose, sucrose, fructose, maltos
  • the oral pharmaceutical composition comprises two diluents which are lactose monohydrate and microcrystalline cellulose.
  • the amount of lactose monohydrate is between 1 -50%, preferably 5-30% and more preferably 10-20% by weight of the total composition.
  • the oral pharmaceutical composition comprises at least one disintegrant which is selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxylpropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidon), copovidon, polycarbophil, low-substitue poloxamer, alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, docusate sodium, guar gum, polyacrylin potasium, sodium alginate, sodium glysin carbonate, sodium lauryl sulphate or mixtures thereof.
  • disintegrant which is selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxylpropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidon), copovidon, polycarbophil, low-substitue poloxa
  • the oral pharmaceutical composition comprises one disintegrant which is croscarmellose sodium.
  • the amount of croscarmellose sodium is between 1 -20%, preferably 3-10% by weight of the total composition.
  • the oral pharmaceutical composition comprises at least one binder which is selected from the group comprising hydroxypropyl cellulose (HPC), copovidone, copolyvidone, polyvinylpyrrolidone (PVP), povidone K30, carnauba wax, hydroxypropyl methyl cellulose (hypromellose, HPMC), pullulan, polymethacrylate, glyceryl behenate, carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), ethyl cellulose, microcrystalline cellulose, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxyethyl methylcellulose (HPC
  • the oral pharmaceutical composition comprises one binder which is hydroxypropyl cellulose (HPC).
  • HPC hydroxypropyl cellulose
  • the amount of HPC is between 1 -20%, preferably 3-10% by weight of the total composition.
  • the oral pharmaceutical composition comprises at least one buffering agent which is selected from the group comprising citric acid anhydrate, alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof.
  • buffering agent which is selected from the group comprising citric acid anhydrate, alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydr
  • the oral pharmaceutical composition comprises one buffering agent which is citric acid anhydrate.
  • the amount of citric acid anhydrate is between 0.5-10%, preferably 1 -5% by weight of the total composition.
  • the oral pharmaceutical composition comprises at least one lubricant and one glidant which are selected from the group comprising sodium stearyl fumarate, colloidal silicon dioxide, sodium lauryl sulphate, magnesium stearate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.
  • lubricant and one glidant which are selected from the group comprising sodium stearyl fumarate, colloidal silicon dioxide, sodium lauryl sulphate, magnesium stearate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stea
  • the solid oral pharmaceutical composition comprises one lubricant which is sodium stearyl fumarate.
  • the amount of sodium stearyl fumarate is between 0.1 -10%, preferably 1 -5% by weight of the total composition.
  • the solid oral pharmaceutical composition comprises one glidant which is colloidal silicon dioxide.
  • the amount of colloidal silicon dioxide is between 0.1 -5%, preferably 0.5-2% by weight of the total composition.
  • the composition is in the form of tablet, coated tablet, film-coated tablet, trilayer tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, pellet, sugar pellet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified release tablet, gastric disintegrating tablet, tablet in tablet, inlay tablet, pill, capsule, oral granule, powder, coated bead system, microsphere, dragee, sachet or orally administrable film.
  • the composition is preferably in the form of a tablet or coated tablet or film-coated tablet; more preferably film-coated tablet.
  • the solid oral pharmaceutical composition comprises at least one coating layer to protect the composition against the moisture and maintain the stability.
  • Suitable coating ingredients are selected from the group comprising hydroxypropylmethyl cellulose (hypromellose), 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) and all kinds of OpadryTM, pigments, dyes, titanium dioxide, iron oxide or polymethylmetacrylate copolymers and mixtures thereof.
  • coating layer is Opadry II white which comprises hydroxypropylmethyl cellulose (hypromellose), titanium dioxide, polyethylene glycol (PEG), magnesium stearate and glycerin.
  • the composition comprises;
  • microcrystalline cellulose — 1 -50% by weight of microcrystalline cellulose
  • Example 1 Film-coated tablet formulation
  • Example 2 Film-coated tablet formulation
  • the preparation method of the above-mentioned film-coated tablet forms of Example 1 and 2 subjected to the invention are prepared by following these steps:
  • microcrystalline cellulose 50% by weight of lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose and mixing the total mixture

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

Abstract

La présente invention concerne des combinaisons pharmaceutiques comprenant de la tolpérisone ou un solvate, un polymorphe, un isomère, un énantiomère, un mélange racémique ou un sel pharmaceutiquement acceptable de celle-ci, et des inhibiteurs de la COX non sélectifs ou des solvates, des polymorphes, des isomères, des énantiomères, des sels ou des mélanges racémiques pharmaceutiquement acceptables de ceux-ci.
PCT/TR2018/050801 2017-12-13 2018-12-12 Combinaisons de tolpérisone et d'inhibiteur de la cox non sélectif WO2019190432A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18911384.8A EP3723735A4 (fr) 2017-12-13 2018-12-12 Combinaisons de tolpérisone et d'inhibiteur de la cox non sélectif

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/20293A TR201720293A2 (tr) 2017-12-13 2017-12-13 Tolperi̇zon ve non-selekti̇f cox i̇nhi̇bi̇törü kombi̇nasyonlari
TR2017/20293 2017-12-13

Publications (2)

Publication Number Publication Date
WO2019190432A2 true WO2019190432A2 (fr) 2019-10-03
WO2019190432A3 WO2019190432A3 (fr) 2019-11-21

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PCT/TR2018/050801 WO2019190432A2 (fr) 2017-12-13 2018-12-12 Combinaisons de tolpérisone et d'inhibiteur de la cox non sélectif

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EP (1) EP3723735A4 (fr)
TR (1) TR201720293A2 (fr)
WO (1) WO2019190432A2 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1362585A2 (fr) 2001-01-26 2003-11-19 Osmotica Corp. Compositions pharmaceutiques contenant un inhibiteur de cox-ii et un relaxant musculaire
WO2009081217A1 (fr) 2007-12-20 2009-07-02 Richter Gedeon Nyrt. Formulations pharmaceutiques contenant tolperisone
WO2010103544A2 (fr) 2009-03-09 2010-09-16 Dinesh Shantilal Patel Nouvelle composition à libération prolongée de composés choisis dans la classe des relaxants musculaires à action centrale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1362585A2 (fr) 2001-01-26 2003-11-19 Osmotica Corp. Compositions pharmaceutiques contenant un inhibiteur de cox-ii et un relaxant musculaire
WO2009081217A1 (fr) 2007-12-20 2009-07-02 Richter Gedeon Nyrt. Formulations pharmaceutiques contenant tolperisone
WO2010103544A2 (fr) 2009-03-09 2010-09-16 Dinesh Shantilal Patel Nouvelle composition à libération prolongée de composés choisis dans la classe des relaxants musculaires à action centrale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3723735A4

Also Published As

Publication number Publication date
TR201720293A2 (tr) 2019-06-21
EP3723735A2 (fr) 2020-10-21
EP3723735A4 (fr) 2021-11-10
WO2019190432A3 (fr) 2019-11-21

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