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