WO2019190432A2

WO2019190432A2 - Tolperisone and non-selective cox inhibitor combinations

Info

Publication number: WO2019190432A2
Application number: PCT/TR2018/050801
Authority: WO
Inventors: Ali TÜRKYILMAZ; Nur PEHLIVAN AKALIN; Seyhan TÜRKKAN; Melda MISIRLI; Emine TUNCAY
Original assignee: Sanovel Ilac Sanayi ve Ticaret AS
Current assignee: Sanovel Ilac Sanayi ve Ticaret AS
Priority date: 2017-12-13
Filing date: 2018-12-12
Publication date: 2019-10-03
Anticipated expiration: 2020-06-13
Also published as: TR201720293A2; EP3723735A4; WO2019190432A3; EP3723735A2

Abstract

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.

Description

TOLPERISONE AND NON-SELECTIVE COX INHIBITOR COMBINATIONS

Field of Invention

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 Besides, 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 NSAIDs is that they 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. Recently, there has been an advent of 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. According to this distinction, NSAIDs are divided into two classes which are non- selective COX inhibitors and selective COX inhibitors.

On the other hand, a huge number of randomized controlled trials have been reporting that selective NSAIDs increase cardiovascular events. Patients with recent bypass surgery, unstable angina, myocardial infarction (Ml), ischemic cerebrovascular events, or any other active atherosclerotic process are at an increased risk for cardiovascular events with concurrent usage of selective COX inhibitors.

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 potential danger of the use of selective NSAIDs in patients who have cardiovascular risk factors is included in the common general knowledge. On the other hand, tolperisone is known as the most efficient muscle relaxant; 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 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.

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 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. 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 non-selective COX inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof.

According to the preferred embodiment of the invention, 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 or mixtures thereof.

According to the preferred embodiment of the invention, the non-selective COX inhibitor is flurbiprofen or ibuprofen or ketoprofen or fenoprofen or dexibuprofen or dexketoprofen or fenbufen or mixtures thereof.

According to the preferred embodiment of the invention, the non-selective COX inhibitor is flurbiprofen.

In the most preferred embodiment, the pharmaceutical composition comprises tolperisone and flurbiprofen as combined active agents.

According to preferred embodiment of the invention, 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.

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.

According to another preferred embodiment, 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.

According to one embodiment, tolperisone is present in an amount of 1 to 500 mg, more preferably 50 to 250 mg in the total composition.

Accorrding to another embodiment, flurbiprofen 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, 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.

According to the preferred embodiment of the invention, 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 amount of microcrystalline cellulose is between 1 -50%, preferably 5-40% and more preferably 20-30% 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 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 croscarmellose sodium. The amount of croscarmellose sodium is between 1 -20%, preferably 3-10% 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 1 -20%, preferably 3-10% 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 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.

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 0.1 -5%, preferably 0.5-2% by weight of the total composition.

According to these embodiments, 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. 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 white which comprises hydroxypropylmethyl cellulose (hypromellose), titanium dioxide, polyethylene glycol (PEG), magnesium stearate and glycerin.

According to these embodiment, the composition comprises;

— 1 -50% by weight tolperisone,

— 1 -40% by weight of flurbiprofen,

— 1 -50% by weight of lactose monohydrate,

— 1 -50% by weight of microcrystalline cellulose,

— 1 -20% by weight of croscarmellose sodium,

— 1 -20% by weight of hydroxypropyl cellulose,

— 0.5-10% by weight of citric acid anhydrate,

— 0.1 -10% by weight of sodium stearyl fumarate,

— 0.1 -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 safety and patient compliance. 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 forms of Example 1 and 2 subjected to the invention are prepared by following these steps:

- Mixing tolperisone, flurbiprofen, 50% by weight of lactose monohydrate, 90-91% by weight of microcrystalline cellulose, citric acid anhydrate, colloidal silicon dioxide

- Seiving the mixture

- Adding 9-10% by weight of microcrystalline cellulose, 50% by weight of lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose and mixing the total mixture

- Adding sodium stearyl fumarate 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 non-selective COX inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof.

2. The pharmaceutical composition according to claim 1 , wherein the 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 or mixtures thereof.

3. The pharmaceutical composition according to claim 2, wherein the non-selective COX inhibitor is flurbiprofen or ibuprofen or ketoprofen or fenoprofen or dexibuprofen or dexketoprofen or fenbufen or mixtures thereof..

4. The pharmaceutical composition according to claim 3, wherein the non-selective COX inhibitor is flurbiprofen.

5. The pharmaceutical composition according to any preceding claims, wherein the composition comprises tolperisone and flurbiprofen.

6. The pharmaceutical composition according to claim 5, wherein the weight ratio of flurbiprofen to tolperisone is in the range of 1 :0.025 to 1 :50, preferably 1 :0.1 to 1 :5.

7. The pharmaceutical composition according to claim 6, wherein the weight ratio of flurbiprofen to tolperisone is 1 :1.5.

8. The pharmaceutical composition according to claim 5, 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.

9. The pharmaceutical composition according to claim 5, wherein the said composition comprises flurbiprofen in an amount of 1 -40%, preferably 5-30%, more preferably 5-20% by weight of the total composition.

10. 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.

1 1. The pharmaceutical composition according to claim 10, wherein the composition comprises one disintegrant which is croscarmellose sodium.

12. The pharmaceutical composition according to claim 1 1 , wherein the amount of croscarmellose sodium is between 1 -20%, preferably 3-10% by weight of the total composition.

13. The pharmaceutical composition according to claim 10, wherein the composition comprises one lubricant which is sodium stearyl fumarate.

14. The pharmaceutical composition according to claim 13, wherein the amount of sodium stearyl fumarate is between 0.1 -10%, preferably 1 -5% by weight of the total composition.

15. 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.

16. The pharmaceutical composition according to claim 15, wherein the composition is in the form of a tablet or coated tablet or film-coated tablet.

17. The pharmaceutical composition according to claim 16, wherein the composition is in the form of a film-coated tablet.

18. The pharmaceutical composition according to any preceding claims, wherein the composition comprises;

— 1 -50% by weight tolperisone,

— 1 -40% by weight of flurbiprofen,

— 1 -50% by weight of lactose monohydrate,

— 1 -50% by weight of microcrystalline cellulose,

— 1 -20% by weight of croscarmellose sodium,

— 1 -20% by weight of hydroxypropyl cellulose,

— 0.5-10% by weight of citric acid anhydrate,

— 0.1 -10% by weight of sodium stearyl fumarate,

— 0.1 -5% by weight of colloidal silicon dioxide,

— 1 -5% by weight of coating.

19. A process for preparing the pharmaceutical composition according to claim 18, comprising the following steps:

— Mixing tolperisone, flurbiprofen, %50 by weight of lactose monohydrate, 90- 91 % by weight of microcrystalline cellulose, citric acid anhydrate, colloidal silicon dioxide

— Seiving the mixture

— Adding 9-10% by weight of microcrystalline cellulose, %50 by weight of lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose and mixing the total mixture

— Adding sodium stearyl fumarate 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