EP3723736A2 - Tolperisone and selective cox-2 inhibitor combinations - Google Patents

Tolperisone and selective cox-2 inhibitor combinations

Info

Publication number
EP3723736A2
EP3723736A2 EP18915012.1A EP18915012A EP3723736A2 EP 3723736 A2 EP3723736 A2 EP 3723736A2 EP 18915012 A EP18915012 A EP 18915012A EP 3723736 A2 EP3723736 A2 EP 3723736A2
Authority
EP
European Patent Office
Prior art keywords
weight
pharmaceutical composition
tablet
composition according
tolperisone
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.)
Pending
Application number
EP18915012.1A
Other languages
German (de)
French (fr)
Other versions
EP3723736A4 (en
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Seyhan TÜRKKAN
Melda MISIRLI
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
Publication of EP3723736A2 publication Critical patent/EP3723736A2/en
Publication of EP3723736A4 publication Critical patent/EP3723736A4/en
Pending 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to pharmaceutical combinations comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof and selective COX-2 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 were reduced, so were some of the good effects of prostaglandins such as protection of the stomach lining.
  • NSAIDs namely selective COX-2 inhibitors, which only target the COX-2 enzyme that is responsible for pain and inflammation, without impacting the production of protective factors for the stomach.
  • selective COX-2 inhibitors are much more safe drugs, comparing with the classical non-selective NSAIDs in the treatment of inflammatory diseases.
  • tolperisone and an active agent selected from NSAIDs or other than NSAIDs are also present in the prior art.
  • 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 selective COX-2 inhibitor combination which enhance the therapeutic effect on spasmodic and arthritic disorders and ensures the gastrointestinal and 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 selective COX-2 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 compositions of tolperisone and selective COX-2 inhibitors ensuring cardiovascular and gastrointestinal safety and patient compliance, accordingly.
  • a further object of the present invention is to develop compositions of tolperisone and selective COX-2 inhibitors ensuring high stability, bioavalibility.
  • a further object of the present invention is to develop compositions of tolperisone and selective COX-2 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 selective COX-2 inhibitor for use in the treatment and prevention of spasmodic and arthritic disorders.
  • 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 selective COX-2 inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof.
  • the said selective COX-2 inhibitor is selected from the group comprising nimesulide, etoricoxib, lumiracoxib, meloxicam, parecoxib, parecoxib sodium, celecoxib or valdecoxib or mixtures tehreof.
  • the said selective COX-2 inhibitor is nimesulide.
  • the oral pharmaceutical composition comprises tolperisone and nimesulide as combined active agents.
  • 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 weight ratio of nimesulide 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 :0.5 or 1 :1.5.
  • the amount of nimesulide 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 nimesulide is present between 10-20% by weight in the total composition.
  • tolperisone is present in an amount of 1 to 500 mg, more preferably 5 to 250 mg in the total composition.
  • nimesulide 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 monohydrate, microcrystalline cellulose, lactose, 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 monohydrate, microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, spray-dried mannitol, dextrose, sucrose, fructose, maltos
  • the oral pharmaceutical composition comprises three diluents which are lactose monohydrate, microcrystalline cellulose and lactose.
  • the amount of lactose monohydrate is between 1 -50%, preferably 5-30% and more preferably 10-20% by weight of the total composition.
  • the amount of microcrystalline cellulose is between 1 -50%, preferably 5-30% and more preferably 10-20% by weight of the total composition.
  • the amount of lactose 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 sodium starch glycolate, 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 sodium starch glycolate, croscarmellose sodium, sodium carbonate, hydroxylpropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidon), copovidon, polycarbophil, low
  • the oral pharmaceutical composition comprises one disintegrant which is sodium starch glycolate.
  • the amount of sodium starch glycolate is between 1 -30%, preferably 5-15% 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 0.01 -5%, preferably 0.05-0.5% 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 two lubricants which are sodium stearyl fumarate and talc.
  • the amount of sodium stearyl fumarate is between 0.1 -10%, preferably 1 -5% by weight of the total composition.
  • the amount of talc is between 0.05-5%, preferably 0.1 -1% 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 0.05-5%, preferably 0.1 -1 % by weight of the total composition.
  • the composition is in the form of of tablet, coated tablet, film-coated tablet, trilayer tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, tablet in tablet, inlay tablet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified release tablet, , gastric disintegrating tablet, pellet, sugar pellet, 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, coated tablet, 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 yellow which comprises hydroxypropylmethyl cellulose (hypromellose), hydroxypropyl cellulose, titanium dioxide, quinoline yellow dye (D&C yellow no.10).
  • the composition comprises;
  • microcrystalline cellulose — 1 -50% by weight of microcrystalline cellulose
  • Example 1 Film-coated tablet formulation
  • Example 2 Film-coated tablet formulation

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Abstract

The present invention relates to pharmaceutical combinations comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof and selective COX-2 inhibitors or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or rasemic mixtures thereof.

Description

TOLPERISONE AND SELECTIVE COX-2 INHIBITOR COMBINATIONS
Field of Invention
The present invention relates to pharmaceutical combinations comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof and selective COX-2 inhibitors or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or rasemic mixtures thereof.
The background of the invention
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.
Its chemical name is 2-methyl-1 -(4-methylphenyl)-3-piperidin-1 -ylpropan-1 -one and its chemical structure is shown in the Formula 1 .
Formula 1. Tolperisone On the other hand, non-steroidal anti-inflammatory drugs (NSAIDs) are a very commonly prescribed type of drug that can reduce pain, inflammation and also lower the body’s temperature during a fever. NSAIDs work by inhibiting an enzyme called cyclooxygenase (COX). This enzyme is essential for the production of chemicals called prostaglandins, which are substances that have a few different roles, one of which is to cause inflammation. By stopping the enzyme, fewer prostaglandins are produced leading to less inflammation and pain.
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.
One of the problems with most of the NSAIDs is that they block both types of the COX enzyme, so while inflammation and pain were reduced, so were some of the good effects of prostaglandins such as protection of the stomach lining. There are also NSAIDs, namely selective COX-2 inhibitors, which only target the COX-2 enzyme that is responsible for pain and inflammation, without impacting the production of protective factors for the stomach. Thus, it can be said that the selective COX-2 inhibitors are much more safe drugs, comparing with the classical non-selective NSAIDs in the treatment of inflammatory diseases.
Besides, recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of selective COX-2 inhibitors. However, the recent market removal of some selective COX-2 inhibitors such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity.
In the state of art, there are few patent documents suggesting combinations of muscle relaxants and NSAIDs. For example, in the patent application numbered WO860368, it is stated that formulations of muscle relaxants and analgesics provide greater benefit in patients with acute musculoskeletal problems than similar doses of analgesics alone. However, types of NSAIDs and the risks thereof are not emphasized and differentiated in this document. Even so, the danger of the use of non-selective NSAIDs in patients with gastrointestinal disease stories is included in the common general knowledge.
Specific combinations of tolperisone and an active agent selected from NSAIDs or other than NSAIDs are also present in the prior art. For instance, the patent document numbered EP1610785B1 reveals the combined effect of tolperisone and dextromethorphan on the treatment of spasticity and pain. In another patent document numbered EP1677787B1 , the combination of tolperisone and flupirtin is suggested for the treatment of pains accompanied by an increase in muscle tone.
Considering the state of art, there is still a need for a dosage form, comprising tolperisone and a selective COX-2 inhibitor combination which enhance the therapeutic effect on spasmodic and arthritic disorders and ensures the gastrointestinal and cardiovascular safety and compliance of the patient at the same time.
Objects and Brief Description of the Invention
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 selective COX-2 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 compositions of tolperisone and selective COX-2 inhibitors ensuring cardiovascular and gastrointestinal safety and patient compliance, accordingly.
A further object of the present invention is to develop compositions of tolperisone and selective COX-2 inhibitors ensuring high stability, bioavalibility.
A further object of the present invention is to develop compositions of tolperisone and selective COX-2 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 selective COX-2 inhibitor for use in the treatment and prevention of spasmodic and arthritic disorders.
Detailed description of the invention
In accordance with the objects outlined above, detailed features of the present invention are given herein.
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 selective COX-2 inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof.
According to the preferred embodiment of the invention, the said selective COX-2 inhibitor is selected from the group comprising nimesulide, etoricoxib, lumiracoxib, meloxicam, parecoxib, parecoxib sodium, celecoxib or valdecoxib or mixtures tehreof.
According to the preferred embodiment of the invention, the said selective COX-2 inhibitor is nimesulide.
In the most preferred embodiment, the oral pharmaceutical composition comprises tolperisone and nimesulide as combined active agents.
According to one preferred embodiment, 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.
In the preferred embodiment of the invention, the weight ratio of nimesulide 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 :0.5 or 1 :1.5.
According to one preferred embodiment, the amount of nimesulide 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 nimesulide is present between 10-20% by weight in the total composition.
According to one embodiment, tolperisone is present in an amount of 1 to 500 mg, more preferably 5 to 250 mg in the total composition.
Accorrding this embodiment, nimesulide is present in an amount of 1 to 300 mg, more preferably 50 to 150 mg in the total composition.
According to the preferred embodiment of the invention, the composition comprises at least one pharmaceutically acceptable excipient selected from diluents, disintegrants, binders, lubricants, glidants, buffering agents or mixtures thereof.
According to one embodiment of the invention, the oral pharmaceutical composition comprises at least one diluent which is selected from the group comprising lactose monohydrate, microcrystalline cellulose, lactose, 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.
According to the preferred embodiment of the invention, the oral pharmaceutical composition comprises three diluents which are lactose monohydrate, microcrystalline cellulose and lactose.
The amount of lactose monohydrate is between 1 -50%, preferably 5-30% and more preferably 10-20% by weight of the total composition.
The amount of microcrystalline cellulose is between 1 -50%, preferably 5-30% and more preferably 10-20% by weight of the total composition.
The amount of lactose is between 1 -50%, preferably 5-30% and more preferably 10-20% by weight of the total composition.
According to one embodiment of the invention, the oral pharmaceutical composition comprises at least one disintegrant which is selected from the group comprising sodium starch glycolate, 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.
According to the preferred embodiment of the invention, the oral pharmaceutical composition comprises one disintegrant which is sodium starch glycolate. The amount of sodium starch glycolate is between 1 -30%, preferably 5-15% by weight of the total composition.
According to one embodiment, 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 methyl cellulose, polaxomer, polyethylene glycol (PEG), sugars, glycose syrups, natural gums, tragacanth gum, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose or mixtures thereof.
According to the preferred embodiment of the invention, the oral pharmaceutical composition comprises one binder which is hydroxypropyl cellulose (HPC). The amount of HPC is between 0.01 -5%, preferably 0.05-0.5% by weight of the total composition.
According to one embodiment, 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.
According to the preferred embodiment of the invention, 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.
According to one embodiment, 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.
According to the preferred embodiment of the invention, the solid oral pharmaceutical composition comprises two lubricants which are sodium stearyl fumarate and talc.
The amount of sodium stearyl fumarate is between 0.1 -10%, preferably 1 -5% by weight of the total composition.
The amount of talc is between 0.05-5%, preferably 0.1 -1% by weight of the total composition.
According to the preferred embodiment of the invention, the solid oral pharmaceutical composition comprises one glidant which is colloidal silicon dioxide.
The amount of colloidal silicon dioxide is between 0.05-5%, preferably 0.1 -1 % by weight of the total composition.
According to these embodiments, the composition is in the form of of tablet, coated tablet, film-coated tablet, trilayer tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, tablet in tablet, inlay tablet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified release tablet, , gastric disintegrating tablet, pellet, sugar pellet, 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, coated tablet, film-coated tablet; more preferably film-coated tablet.
According to one embodiment of the invention, 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.
According to one embodiment, coating layer is Opadry II yellow which comprises hydroxypropylmethyl cellulose (hypromellose), hydroxypropyl cellulose, titanium dioxide, quinoline yellow dye (D&C yellow no.10).
According to these embodiment, the composition comprises;
— 1 -50% by weight tolperisone,
— 1 -40% by weight of nimesulide,
— 1 -50% by weight of lactose monohydrate,
— 1 -50% by weight of microcrystalline cellulose,
— 1 -50% by weight of lactose,
— 1 -30% by weight of sodium starch glycolate,
— 0.01 -5% by weight of hydroxypropyl cellulose,
— 0.5-10% by weight of citric acid anhydrate,
— 0.1 -10% by weight of sodium stearyl fumarate,
— 0.05-5% by weight of talc,
— 0.05-5% by weight of colloidal silicon dioxide,
— 1 -5% by weight of coating.
These analytically selected ratios ensure the required effective doses for the treatment, cardiovascular and gastrointestinal safety and patient compliance, accordingly. Furthermore, they enhance the stability, bioavailibility and dissolution profile of the film- coated tablet subjected to the invention. According to all these embodiments, the below given formulations can be used in the solid oral pharmaceutical composition subjected to the invention. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
Example 1 : Film-coated tablet formulation
Example 2: Film-coated tablet formulation
The preparation method of the above-mentioned film-coated tablet form of the Example 1 and 2 subjected to the invention is prepared by following these steps:
- Mixing nimesulide, lactose monohydrate, microcrystalline cellulose and %60-70 by weight of sodium starch glycolate
- Feeding the mixture into a fluid bed dryer
- Spray-granulating the mixture with 0.45% (w/w) aqueous solution of hydroxypropyl cellulose
- Drying the granules
- Mixing tolperisone, lactose, %30-40 by weight of sodium starch glycolate and colloidal silicon dioxide and sieving this mixture
- Adding the granules into this mixture and mixing together
- Adding talc and sodium stearyl fumarate respectively and mixing the final mixture
- Compressing the final mixture into tablets
- Preparing an aqueous solution of coating material and coating the tablets with this solution in a way to form a film layer

Claims

1. A pharmaceutical composition comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof in combination with a selective COX-2 inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof.
2. The pharmaceutical composition according to claim 1 , wherein the selective COX- 2 inhibitor is selected from the group comprising nimesulide, etoricoxib, lumiracoxib, meloxicam, parecoxib, parecoxib sodium, celecoxib or valdecoxib or mixtures thereof.
3. The pharmaceutical composition according to claim 2, wherein the selective COX- 2 inhibitor is nimesulide.
4. The pharmaceutical composition according to any preceding claims, wherein the said composition comprises tolperisone and nimesulide.
5. The pharmaceutical composition according to claim 4, wherein the weight ratio of nimesulide to tolperisone is in the range of 1 :0.025 to 1 :50 and preferably 1 :0.1 to 1 :5.
6. The pharmaceutical composition according to claim 5, wherein the weight ratio of nimesulide to tolperisone is 1 :0.5 or 1 :1.5.
7. The pharmaceutical composition according to claim 4, wherein the said composition comprises tolperisone in an amount of 1 -50%, preferably 5-40%, more preferably 15-35% by weight of the total composition.
8. The pharmaceutical composition according to claim 4, wherein the said composition comprises nimesulide in an amount of 1 -40%, preferably 5-30%, more preferably 10-20% by weight of the total composition.
9. The pharmaceutical composition according to any preceding claims, wherein the composition comprises at least one pharmaceutically acceptable excipient selected from diluents, disintegrants, binders, lubricants, glidants, buffering agents or mixtures thereof.
10. The pharmaceutical composition according to claim 9, wherein the composition comprises one disintegrant which is sodium starch glycolate.
1 1. The pharmaceutical composition according to claim 10, wherein the amount of sodium starch glycolate is between 1 -30%, preferably 5-15% by weight of the total composition.
12. The pharmaceutical composition according to claim 9, wherein the composition comprises one binder which is hydroxypropyl cellulose (HPC).
13. The pharmaceutical composition according to claim 12, wherein the amount of hydroxypropyl cellulose is between 0.01 -5%, preferably 0.05-0.5% by weight of the total composition.
14. The pharmaceutical composition according to claim 9, wherein the 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.
15. The pharmaceutical composition according to claim 14, wherein the composition comprises two lubricants which are sodium stearyl fumarate and talc.
16. The pharmaceutical composition according to claim 15, wherein the amount of sodium stearyl fumarate is between 0.1 -10%, preferably 1 -5% by weight of the total composition.
17. The pharmaceutical composition according to claim 15, wherein the amount of talc is between 0.05-5%, preferably 0.1 -1 % by weight of the total composition.
18. The pharmaceutical composition according to claim 14, wherein the composition comprises one glidant which is colloidal silicon dioxide.
19. The pharmaceutical composition according to claim 18, wherein the amount of colloidal silicon dioxide is between 0.05-5%, preferably 0.1 -1 % by weight of the total composition.
20. The pharmaceutical composition according to any preceding claims, wherein the composition is in the form of tablet, coated tablet, film-coated tablet, trilayer tablet, bilayer tablet, multilayer tablet, orally disintegrating tablet, mini tablet, tablet in tablet, inlay tablet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified release tablet, , gastric disintegrating tablet, pellet, sugar pellet, pill, capsule, oral granule, powder, coated bead system, microsphere, dragee, sachet or orally administrable film.
21 . The pharmaceutical composition according to claim 20, wherein the composition is in the form of a tablet or coated tablet or film-coated tablet.
22. The pharmaceutical composition according to claim 21 , wherein the composition is in the form of a film-coated tablet.
23. The pharmaceutical composition according to any preceding claims, wherein the composition comprises;
- 1 -50% by weight tolperisone,
- 1 -40% by weight of nimesulide,
- 1 -50% by weight of lactose monohydrate,
- 1 -50% by weight of microcrystalline cellulose,
- 1 -50% by weight of lactose,
- 1 -30% by weight of sodium starch glycolate,
- 0.01 -5% by weight of hydroxypropyl cellulose,
- 0.5-10% by weight of citric acid anhydrate,
- 0.1 -10% by weight of sodium stearyl fumarate,
- 0.05-5% by weight of talc,
- 0.05-5% by weight of colloidal silicon dioxide,
- 1 -5% by weight of coating.
24. A process for preparing the pharmaceutical composition according to claim 23, comprising the following steps:
- Mixing nimesulide, lactose monohydrate, microcrystalline cellulose and %60-70 by weight of sodium starch glycolate
- Feeding the mixture into a fluid bed dryer
- Spray-granulating the mixture with 0.45% (w/w) aqueous solution of hydroxypropyl cellulose
- Drying the granules
- Mixing tolperisone, lactose, %30-40 by weight of sodium starch glycolate and colloidal silicon dioxide and sieving this mixture
- Adding the granules into this mixture and mixing together
- Adding talc and sodium stearyl fumarate respectively and mixing the final mixture
- Compressing the final mixture into tablets
- Preparing an aqueous solution of coating material and coating the tablets with this solution in a way to form a film layer
EP18915012.1A 2017-12-13 2018-12-12 Tolperisone and selective cox-2 inhibitor combinations Pending EP3723736A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/20289A TR201720289A2 (en) 2017-12-13 2017-12-13 Tolperizon and Selective COX-2 Inhibitor Combinations
PCT/TR2018/050798 WO2019203751A2 (en) 2017-12-13 2018-12-12 Tolperisone and selective cox-2 inhibitor combinations

Publications (2)

Publication Number Publication Date
EP3723736A2 true EP3723736A2 (en) 2020-10-21
EP3723736A4 EP3723736A4 (en) 2021-07-14

Family

ID=67952522

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18915012.1A Pending EP3723736A4 (en) 2017-12-13 2018-12-12 Tolperisone and selective cox-2 inhibitor combinations

Country Status (3)

Country Link
EP (1) EP3723736A4 (en)
TR (1) TR201720289A2 (en)
WO (1) WO2019203751A2 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201906487A1 (en) * 2019-04-30 2020-11-23 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi PHARMACEUTICAL COMPOSITIONS CONTAINING TOLPERISONE AND NIMESULIDE COMBINATIONS

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040204413A1 (en) * 2001-01-26 2004-10-14 Joaquina Faour Pharmaceutical compositions containing a COX-II inhibitor and a muscle relaxant
HUP0300929A3 (en) * 2003-04-09 2005-06-28 Richter Gedeon Vegyeszet Analgetic and/or muscle relaxant pharmaceutical composition
GEP20135986B (en) * 2009-03-09 2013-12-10 Shashikant Prabhudas Kurani Novel sustained release composition of compounds selected from class of centrally acting muscle relaxants

Also Published As

Publication number Publication date
EP3723736A4 (en) 2021-07-14
WO2019203751A3 (en) 2019-11-28
WO2019203751A2 (en) 2019-10-24
TR201720289A2 (en) 2019-06-21

Similar Documents

Publication Publication Date Title
TWI704915B (en) Pharmaceutical compositions comprising dimethyl fumarate and uses thereof
WO2012156981A1 (en) Pharmaceutical compositions of lurasidone
WO2018122384A1 (en) Oral pharmaceutical compositions comprising tadalafil and dapoxetine
WO2017208136A1 (en) Pharmaceutical composition of dapagliflozin co-crystal
US20140343076A1 (en) Pharmaceutical compositions of lurasidone
WO2019203751A2 (en) Tolperisone and selective cox-2 inhibitor combinations
EP3723755A2 (en) Combinations comprising a skeletal muscle relaxant agent and a multiple sclerosis treating agent
WO2020005189A2 (en) Solid oral pharmaceutical compositions comprising teriflunomide
EP3338767A1 (en) Capsule compositions comprising donepezil and memantine
WO2019190432A2 (en) Tolperisone and non-selective cox inhibitor combinations
WO2018099895A1 (en) Solid oral pharmaceutical compositions comprising tenofovir and emtricitabine
US20170312236A1 (en) Pharmaceutical compositions of flurbiprofen and tramadol
US20120121722A1 (en) Atazanavir formulations
WO2012059937A1 (en) Modifies release pharmaceutical compositons for nsaids
EP3962459A1 (en) Pharmaceutical compositions comprising tolperisone and nimesulide combinations
CA3085823A1 (en) Pharmaceutical compositions of flurbiprofen and 5-ht1 - receptor agonists
EP3318279A1 (en) Solid oral pharmaceutical compositions of lurasidone hydrochloride
US10034855B2 (en) Solid composition of pyrrole carboxamide
US20170189374A1 (en) Zaltoprofen and muscle relaxant combinations
EP3810112A2 (en) A combination comprising fingolimod and modafinil
WO2014035355A1 (en) Pharmaceutical combination comprising idebenone and memantine
WO2024084496A1 (en) Pharmaceutical compositions comprising acalabrutinib maleate
EP3810110A2 (en) A combination comprising fingolimod and amantadine
EA045272B1 (en) SOLID PHARMACEUTICAL COMPOSITION BASED ON LURAZIDONE HYDROCHLORIDE FOR ORAL USE
WO2019203748A2 (en) The composition comprising raloxifene with at least one antipsychotic agent

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200710

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20210616

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/20 20060101AFI20210610BHEP

Ipc: A61K 31/4453 20060101ALI20210610BHEP

Ipc: A61K 31/18 20060101ALI20210610BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20230629

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230708