EP3962459A1

EP3962459A1 - Pharmaceutical compositions comprising tolperisone and nimesulide combinations

Info

Publication number: EP3962459A1
Application number: EP20798008.7A
Authority: EP
Inventors: Seyhan TURKKAN
Original assignee: Sanovel Ilac Sanayi ve Ticaret AS
Current assignee: Sanovel Ilac Sanayi ve Ticaret AS
Priority date: 2019-04-30
Filing date: 2020-03-23
Publication date: 2022-03-09
Also published as: TR201906487A1; EP3962459A4; WO2020222714A1

Abstract

The present invention relates to pharmaceutical combinations comprising tolperisone or a pharmaceutically acceptable salt thereof and nimesulide or a pharmaceutically acceptable salt thereof in a single dosage form.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING TOLPERISONE AND

NIMESULIDE COMBINATIONS

DESCRIPTION

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 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. 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.

Nimesulide is a selective COX-2 inhibitor that has been used for the treatment of acute pain, the symptomatic treatment of osteoarthritis, and primary dysmenorrhoea in adolescents and adults above 12 years old. Its chemical name is N-(4-nitro-2-phenoxyphenyl) methanesulfonamide and its chemical structure is shown in the Formula 2.

Formula 2. Nimesulide In the state of art, there is no formulation suggesting the direct combination of tolperisone and nimesulide. However, there are some patent documents in which muscle relaxants and NSAIDs are combined. For example, in the patent application numbered W02007037667A1 , a ternary combination of NSAIDs, muscle relaxants and analgesics is mentioned. It is also stated that the mentioned formulation further comprises one or more additive necessary for the formulation.

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.

However; in combination formulations, the drug-drug interaction creates a significant drawback since it makes difficult to obtain a stable and highly efficient dosage form. The term “drug-drug interaction” refers to the influence of one drug upon another, e.g., where a second drug stimulates catabolism of the first drug, thereby reducing efficacy of the first drug, or where a second drug inhibits catabolism of the first drug, thereby increasing its efficacy or its toxicity. A synergistic interaction may be beneficial for patients but may also increase the risk of overdose. It is possible to take advantage of positive drug interactions. However, the negative interactions are usually of more interest because of their pathological significance, and also because they are often unexpected, and may even go undiagnosed. By studying the conditions that favor the appearance of pharmacodynamic interactions it should be possible to prevent them, or at least diagnose them in time.

On the other hand, pharmacokinetic drug-drug interactions are more common and more readily predictable than pharmacodynamic interactions. The most serious pharmacokinetic interactions are those in which one drug changes the rate of elimination of another. This can occur by one drug altering the rate of biotransformation or renal elimination of the other. If there is an effect in clearance, there will eventually be a change in the steady-state plasma concentration of the drug that could result in a decline in the therapeutic response and bioavailability. Furthermore, different drugs expose different physical characteristics depending on the granulation technique by which they are treated. For instance; the wet granulation method may increase the dissolution rate of a drug while causing a significant decrease in the stability of the other drug because of the difference between the hygroscopicity levels of the drugs. In such cases, it would be wiser to process these drugs separately and then combine them into a dosage form.

Considering the state of art, there is still a need for a dosage form, comprising tolperisone and nimesulide combination which eliminates the drug-drug interactions, and which enhances the stability and the therapeutic effect of the drugs on spasmodic and arthritic disorders.

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 thereof and nimesulide or a pharmaceutically acceptable salt thereof, eliminating all aforesaid problems and bringing additional advantages over the relevant prior art.

Another object of the present invention is to develop compositions of tolperisone and nimesulide ensuring high stability and bioavalibility.

A further object of the present invention is to develop compositions of tolperisone and nimesulide 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 nimesulide for use in the treatment and prevention of spasmodic and arthritic disorders.

Another object of the present invention is to provide a bilayer tablet dosage form comprising tolperisone and nimesulide which eliminates the drug-drug interactions and thus increases the total efficacy of the drugs.

Another object of the present invention is to provide a method for the preparation of bilayer tablet dosage forms comprising tolperisone and nimesulide which comprises wet granulation step for nimesulide layer and dry granulation step for tolperisone layer. 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 thereof and nimesulide or a pharmaceutically acceptable salt thereof.

According to the preferred embodiment, said tolperisone salt is tolperisone hydrochloride.

According to one preferred embodiment, the amount of tolperisone hydrochloride 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 15-25% by weight in the total composition.

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.

In the preferred embodiment of the invention, the weight ratio of nimesulide to tolperisone hydrochloride 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 to 1 :2.

These selections of ratios are surprisingly providing a synergistically enhanced bioavailability

According to the preferred embodiment, tolperisone hydrochloride is present in an amount of 1 to 500 mg, more preferably 5 to 250 mg in the total composition.

Accorrding to the preferred embodiment, nimesulide is present in an amount of 1 to 300 mg, more preferably 50 to 150 mg in the total composition.

According to one embodiment, the composition comprises tolperisone hydrochloride in an amount of 150 mg and nimesulide in an amount of 100 mg. 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, 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 bilayer tablet, more preferably in the form of a film-coated bilayer tablet.

According to this preferred embodiment, the composition comprises

-a first layer comprising nimesulide and

-a second layer comprising tolperisone hydrochloride.

Although nimesulide and tolperisone hydrochloride can work together to show synergistic indications, they are completely different compounds both structurally and chemically. These differences can cause interactions between them and decreases in the efficacy and stability of the dosage form comprising them.

Within the scope of this invention, it is possible to combine nimesulide and tolperisone hydrochloride in a single dosage form while maintaining the stability and enhancing the bioavailability by the mentioned bilayer form.

The first layer further comprises at least one excipient selected from diluents, binders, lubricants, disintegrants or mixtures thereof.

According to one embodiment of the invention, the first layer comprises at least one diluent which is selected from the group comprising lactose monohydrate, lactose, microcrystalline cellulose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, polysaccharides, 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 first layer comprises lactose monohydrate and microcrystalline cellulose as diluents. The amount of lactose monohydrate in the first layer is between 5-50%, preferably 10-40%, more preferably 15-30% by weight of the total composition.

The amount of microcrystalline cellulose in the first layer is between 5-50%, preferably 5- 40%, more preferably 10-20% by weight of the total composition.

According to one embodiment of the invention, the first layer 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 first layer comprises sodium starch glycolate as disintegrant. The amount of sodium starch glycolate in the first layer is between 0.5-30%, preferably 1 -10% by weight of the total composition.

According to one embodiment, the first layer 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 first layer comprises hydroxypropyl cellulose (HPC) as binder. The amount of HPC in the first layer is between 0.01 -5%, preferably 0.05-0.5% by weight of the total composition. However, this amount is remarkably low, it is surprisingly efficacious to provide a compact and stable layer. According to one embodiment, the first layer comprises at least one lubricant which is 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 first layer comprises magnesium stearate as lubricant. The amount of magnesium stearate in the first layer is between 0.1 - 10%, preferably 0.5-5% by weight of the total composition.

The second layer further comprises at least one excipient selected from diluents, disintegrants, binders, lubricants, glidants, buffering agents or mixtures thereof.

According to one embodiment of the invention, the second layer comprises at least one diluent which is selected from the group comprising lactose monohydrate, lactose, microcrystalline cellulose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, polysaccharides, 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 second layer comprises microcrystalline cellulose as diluent. The amount of microcrystalline cellulose in the second layer is between 5-50%, preferably 5-40%, more preferably 10-20% by weight of the total composition.

According to one embodiment of the invention, the second layer comprises at least one disintegrant which is selected from the group comprising pregelatinized starch, 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 second layer comprises pregelatinized starch as disintegrant. The amount of pregelatinized starch in the second layer is between 0.5-30%, preferably 1 -10% by weight of the total composition.

According to one embodiment, the second layer 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 second layer comprises glyceryl behenate or hydroxypropyl cellulose as binder. The amount of glyceryl behenate or HPC in the second layer is between 0.1 -10%, preferably 0.2-5% by weight of the total composition. However, this amount is remarkably low, it is surprisingly efficacious to provide a compact and stable layer.

According to one embodiment, the second layer 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, malic acid, maleic acid or mixtures thereof.

According to the preferred embodiment of the invention, the second layer comprises citric acid anhydrate as buffering agent. The amount of citric acid anhydrate in the second layer is between 0.1 -10%, preferably 0.1 -5% by weight of the total composition.

According to one embodiment, the second layer comprises at least one lubricant and/or 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 second layer comprises stearic acid, magnesium stearate and talc as lubricants.

The amount of stearic acid in the second layer is between 0.1 -10%, preferably 0.5-5% by weight of the total composition.

The amount of magnesium stearate in the second layer is between 0.01 -5%, preferably 0.05- 1 % by weight of the total composition.

The amount of talc in the second layer is between 0.01 -5%, preferably 0.05-1 % by weight of the total composition.

According to the preferred embodiment of the invention, the second layer comprises colloidal silicon dioxide as glidant.

The amount of colloidal silicon dioxide in the second layer is between 0.05-5%, preferably 0.1 -1% by weight of the total composition.

According to one embodiment of the invention, the bilayer tablet composition comprises at least one coating 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.

The amount of the coating is between 0.1 -10%, preferably 1 -5% by weight of the total composition.

According to the preferred embodiment, the coating is in the form of an outer layer on the bilayer tablet and comprises hydroxypropylmethyl cellulose (HPMC), titanium dioxide, polyvinylpyrrolidone, polydextrose, polyethylene glycole, medium chain triglyceride (MCT), yellow iron oxide, black iron oxide and red iron oxide.

According to this embodiment, the composition comprises the following components by weight of the total composition:

— 1 -40% by weight of nimesulide,

— 5-50% by weight of lactose monohydrate,

— 5-50% by weight of microcrystalline cellulose,

— 0.5-30% by weight of sodium starch glycolate,

— 0.01 -5% by weight of hydroxypropyl cellulose,

— 0.1 -10% by weight of magnesium stearate in the first layer;

— 1 -50% by weight of tolperisone hydrochloride,

— 5-50% by weight of microcrystalline cellulose,

— 0.5-30% by weight of pregelatinized starch,

— 0.1 -10% by weight of glyceryl behenate,

— 0.1 -10% by weight of citric acid anhydrate,

— 0.1 -10% by weight of stearic acid,

— 0.01 -5% by weight of magnesium stearate,

— 0.01 -5% by weight of talc,

— 0.05-5% by weight of colloidal silicon dioxide in the second layer and

— 0.1 -10% by weight of coating.

These analytically selected ratios ensure the required effective doses for the treatment and prevention of spasmodic and arthritic disorders. Furthermore, these ratios enhance the stability, bioavailibility and dissolution profile of the dosage form subjected to the invention.

According to all these embodiments, the below given formulations can be used in the 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 bilayer tablet formulation

Example 2: Film-coated bilayer tablet formulation

The preparation method of the film-coated bilayer tablet form subjected to the invention comprises wet granulation steps to obtain a first layer composition and dry granulation steps to obtain a second layer composition.

Accordingly, a composition comprising nimesulide is obtained by wet granulation and a composition comprising tolperisone is obtained by dry granulation. These specifically designated methods surprisingly enhance the dissolution profiles of both nimesulide and tolperisone. Furthermore, it has been seen that the total stability of the dosage form is also increased. Wet granulation is the process of adding a liquid solution to powders involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent that must be volatile, so that it can be removed by drying, and be non-toxic. Water mixed into the powders can form bonds between powder particles that are strong enough to lock them together. However, once the water dries, the powders may fall apart. Therefore, water may not be strong enough to create and hold a bond. In such instances, a liquid solution that includes a binder is required. According to an embodiment of the invention, HPC is used as binder in the first layer in an amount of less than %5, preferably less than %0.5 by weight of the total composition.

The amount of binder which is needed in wet granulation to bond powder particles is much less than the amount which is needed in dry granulation. The lower the amount of the binder, the higher the dissolution rate. For this invention, since nimesulide is a non-hygroscopic compound, it can tolerate the risk of residual moisture arising from the wet granulation. Thus, a high dissolution rate of nimesulide is obtained while stability of the dosage form is maintained.

On the other hand, dry granulation is used to form granules without using a liquid solution, because the product to be granulated may be sensitive to moisture and heat or does not compress well. Forming granules without moisture involves compacting and size reduction of the mix to produce a granular, free flowing blend of uniform size. Thus, the primary powder particles are aggregated under high pressure using swaying or high shear mixer-granulators. Dry granulation can be done in two ways: either a large tablet (slug) is produced in a compactor or the powder is squeezed between two rollers to produce a sheet of materials. When a compactor is used for dry granulation, the powders may not possess enough natural flow to feed the product uniformly into the die cavity, resulting in varying degrees of densification. To prevent this, a sufficient amount of binder and lubricant is required.

For this invention, since tolperisone hydrochloride is a hygroscopic compound, it is preferable to perform dry granulation and to use an adequate amount of binder for obtaining the second layer composition. According to an embodiment of the invention, glyceryl behanate or HPC is used as binder and stearic acid, talc and magnesium stearate are used as lubricants in the second layer. It has been surprisingly seen that the selection of this binder and these lubricants reduces the required amount of binder and provides an enhanced dissolution profile for tolperisone and an enhanced stability for the dosage form.

The amount of glyceryl behenate or HPC in the second layer is between 0.1 -10%, preferably between 0.2-5% by weight of the total composition, which is rather low considering that a homogenous and stable composition (second layer which comprises tolperisone hydrochloride) is obtained by the dry granulation technique.

According to one embodiment of the invention, the above-mentioned film-coated bilayer tablet forms of the Example 1 and 2 are prepared by following these steps:

i. Mixing nimesulide, lactose monohydrate, microcrystalline cellulose and sodium starch glycolate

ii. Feeding the mixture into a fluid bed dryer

iii. Preparing a 0.45% (w/w) aqueous solution of hydroxypropyl cellulose

iv. Spray-granulating the mixture with the aqueous solution of hydroxypropyl cellulose v. Drying the granules

vi. Adding magnesium stearate into the granules and mixing the total first layer composition vii. Mixing tolperisone and glyceryl behenate and sieving this mixture

viii. Adding citric acid anhydrate, pregelatinized starch, colloidal silicon dioxide, talc, stearic acid, ¾ by weight of microcrystalline cellulose to the sieved mixture to prepare an intermediate mixture

ix. Compacting the intermediate mixture with a compactor and then sieving it through a 0.8-1 mm mesh

x. Adding ¼ by weight of microcrystalline cellulose and mixing

xi. Adding magnesium stearate and mixing the total second layer composition xii. Compressing the first layer composition and the second layer composition together one on the other into bilayer tablets preferably with a force of 100-200N

xiii. Preparing an aqueous solution of coating composition and coating the bilayer tablets with this solution in a way to form a film layer

Claims

1 . A pharmaceutical composition comprising tolperisone or a pharmaceutically acceptable salt thereof and nimesulide or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1 , wherein the said tolperisone salt is tolperisone hydrochloride.

3. The pharmaceutical composition according to claim 2, wherein the said composition comprises tolperisone hydrochloride in an amount of 1 -50%, preferably 5-40%, more preferably 15-25% by weight of the total composition.

4. The pharmaceutical composition according to claim 1 , 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.

5. 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.

6. The pharmaceutical composition according to claim 5, wherein the composition is in the form of a bilayer tablet.

7. The pharmaceutical composition according to claim 6, wherein the composition comprises;

-a first layer comprising nimesulide and

-a second layer comprising tolperisone hydrochloride.

8. The pharmaceutical composition according to claim 7, wherein the first layer further comprises at least one pharmaceutically acceptable excipient selected from diluents, binders, lubricants, disintegrants or mixtures thereof.

9. The pharmaceutical composition according to claim 8, wherein the first layer comprises hydroxypropyl cellulose as binder in an amount of 0.01 -5%, preferably 0.05-0.5% by weight of the total composition.

10. The pharmaceutical composition according to claim 7, wherein the second layer further 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 second layer comprises glyceryl behenate or hydroxypropyl cellulose as binder in an amount of 0.1 -10%, preferably 0.2-5% by weight of the total composition.

12. The pharmaceutical composition according to claim 10, wherein the second layer comprises stearic acid, talc and magnesium stearate as lubricants.

13. The pharmaceutical composition according to any one of the claims 7 to 12, wherein the composition comprises the following components by weight of the total composition:

— 1 -40% by weight of nimesulide,

— 5-50% by weight of lactose monohydrate,

— 5-50% by weight of microcrystalline cellulose,

— 0.5-30% by weight of sodium starch glycolate,

— 0.01 -5% by weight of hydroxypropyl cellulose,

— 0.1 -10% by weight of magnesium stearate in the first layer;

— 1 -50% by weight of tolperisone hydrochloride,

— 5-50% by weight of microcrystalline cellulose,

— 0.5-30% by weight of pregelatinized starch,

— 0.1 -10% by weight of glyceryl behenate,

— 0.1 -10% by weight of citric acid anhydrate,

— 0.1 -10% by weight of stearic acid,

— 0.01 -5% by weight of magnesium stearate,

— 0.01 -5% by weight of talc,

— 0.05-5% by weight of colloidal silicon dioxide in the second layer and

— 0.1 -10% by weight of coating

14. A process for preparing the pharmaceutical composition according to claim 13, comprising wet granulation steps to obtain a first layer composition and dry granulation steps to obtain a second layer composition.

15. A process for preparing the pharmaceutical composition according to claim 14, comprising the following steps: i. Mixing nimesulide, lactose monohydrate, microcrystalline cellulose and sodium starch glycolate

ii. Feeding the mixture into a fluid bed dryer

iii. Preparing a 0.45% (w/w) aqueous solution of hydroxypropyl cellulose iv. Spray-granulating the mixture with the aqueous solution of hydroxypropyl cellulose

v. Drying the granules

ix. Compacting the intermediate mixture with a compactor and then sieving it x. Adding ¼ by weight of microcrystalline cellulose and mixing

xi. Adding magnesium stearate and mixing the total second layer composition xii. Compressing the first layer composition and the second layer composition together one on the other into bilayer tablets