INHIBITOR COMBINATION

Field of Invention

The present invention relates to topical pharmaceutical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or rasemic mixture thereof and a selective COX-2 inhibitor 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 Tolperisone is a preferable muscle relaxant to be applied in the human therapy due to its advantageous side effect profile and safe administration. In contrast to other central muscle relaxant tolperisone has no sedative effect; 900 mg can be taken daily without significant adverse reaction. Albeit that many pharmaceutical preparations containing tolperisone are available on the world market, there is no data regarding topical dosage forms incorporating tolperisone in the literature. The lack of tolperisone topical preparation on the pharmaceutical market seems to be the result of the chemical instability of the compound, which complicates the formulation of transdermal compositions containing 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.

Topical NSAIDs have a moderate effect on pain relief, with efficacy similar to that of oral NSAIDs, with the advantage of a better risk/benefit ratio. They are applied in cases such as acute musculoskeletal pain to unbroken skin where it hurts as gels, creams, sprays, or plasters. Topical NSAIDs penetrate the skin, enter tissues or joints, and reduce processes causing pain in the tissue. Drug levels in the blood with topical NSAIDs are very much lower than with the same drug taken by mouth. This minimises the risk of harmful effects such as gastrointestinal bleeding.

In the United States, several topical NSAID products are approved to treat painful conditions including diclofenac sodium 1 % gel (Voltaren Gel®; Endo Pharmaceuticals), diclofenac sodium topical solution 1.5% w/w in 45.5% dimethyl sulfoxide (PENNSAID®; Mallinckrodt, Inc.), and diclofenac epolamine 1.3% (Flector Patch®; Alpharma Pharmaceuticals LLC, a subsidiary of Pfizer, Inc.). Topical NSAIDs are also recommended as an early treatment option for the symptomatic management of osteoarthritis (OA), and may be used ahead of oral NSAIDs due to their superior safety profile.

In real-life studies, topical and oral NSAIDs demonstrate an equivalent effect on knee pain over 1 year of treatment, with fewer adverse events due to lower systemic absorption of topical NSAIDs compared with oral NSAIDs. As a result, topical NSAIDs may be the preferred treatment option, especially in patients aged ³75 years, and those with co-morbidities or at an increased risk of cardiovascular, gastrointestinal, or renal side effects. Furthermore, using topical NSAIDs in inflammatory rheumatic diseases leads to a 40% reduction in the need for concomitant oral NSAIDs. When selecting a topical NSAID, absorption and bioavailability are important since analgesic activity of the drug is correlated with its pharmacokinetic profile.

In the patent literature, there are a few mentions of liquid or gel forms of tolperisone and NSAID combinations. It is desired to develop methods of administration other than oral administration which will eliminate both the first-pass effect of the drug and the potential damage to gastrointestinal tracts. For this reason, intensive studies have been conducted to provide stable formulation enabling topical and/or percutaneous administrations.

For example, patent document numbered EP029541 1 (A1) asserts a percutaneous formulation of tolperisone or eperisone which presents remarkably improved skin penetration. This effect is provided by the addition of monoglycerides of aliphatic acids and/or esters of lactic acids with an aliphatic alcohol to the tolperisone/eperison and propylene glycol solution.

In another patent document numbered W02009081217 (A1), a tolperisone and NSAID combination is mentioned and it is stated that the formulation also comprises a gel forming macromolecule, a solvent, a thickening agent, a penetration enhancer and a pH adjuvant. Propylene glycol and dimethyl sulfoxide are the preferable solvents according to the document and this preference is supported by the examples. Formulations subjected to the invention comprises dimethyl sulfoxide which is also a penetration enhancer in an amount of %47-78 and propylene glycol in an amount of %20-90 by weight of the total composition.

Another important point is that the above-mentioned side effects such as gastrointestinal damage and cardiovascular risks are binding for NSAIDs which block both COX-1 and COX-2 enzymes. However, 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. A topical dosage form which includes only COX-2 inhibitor as NSAID shall completely eliminate these side effects

However, the state of art does not include any mention or motivation to combine tolperisone and a selective COX-2 inhibitor in order to provide maximum safety. Another challange with topical formulations is to provide an effective penetration through the skin, for this reason it is essential to use a penetration enhancer. However, most of them are potentially toxic if they are used over an amount. For instance, dimethyl sulfoxide which is commonly used as penetration enhancer and solvent in the topical formulations has low systemic toxicity but causes local toxic effects. It is explicitly stated that dimethyl sulfoxide acts as a primary irritant on skin, causing redness, burning, itching, and scaling; it also causes urticaria. Systemic symptoms include nausea, vomiting, chills, cramps, and lethargy; dimethyl sulfoxide can also cause increases in intraocular pressure. In 1965, the FDA banned investigation in humans of dimethyl sulfoxide owing to the appearance of changes in the refractive index of the lens of the eye in experimental animals (Handbook of Pharmaceutical Excipients edited by Raymond C. Rowe, Paul J. Sheskey and Marian E. Quinn, sixth edition, page 239).

In addition to that, it is known that dimethyl sulfoxide can react with oxidizing materials (Handbook of Pharmaceutical Excipients edited by Raymond C. Rowe, Paul J. Sheskey and Marian E. Quinn, sixth edition, page 239). On the other hand, in the prior art, dimethyl sulfoxide is usually used with propylene glycol which is known as being inclined to oxidize and as giving undesired products such as propionaldehyde, lactic acid, pyruvic acid, and acetic acid. Propylene glycol is also incompatible with oxidizing reagents. So, it is obvious that maintenance of the stability is also an issue to overcome for the kind of topical combinations, according to the prior art. Besides, propylene glycol is regarded as minimally irritant for skin. There have been some reports of contact dermatitis associated with propylene glycol. Parenteral administration may cause pain or irritation when propylene glycol is used in high concentration (Handbook of Pharmaceutical Excipients edited by Raymond C. Rowe, Paul J. Sheskey and Marian E. Quinn, sixth edition, page 592).

Considering the state of art, there is still a need for a non-toxic topical combination of tolperisone and selective COX-2 inhibitors which ensures the required dosage to treat pain or inflammation caused by sport injuries, arthritis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, menstruation, hereditary polyps of the colon, migraine, spasticity, muscle spasm and which provides improved stability, enhanced penetration capability and increased patient compliance at the same time.

Objects and Brief Description of the Invention

The main object of the present invention is to obtain topical pharmaceutical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer of rasemic mixture thereof and a selective COX-2 inhibitor 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 topical pharmaceutical compositions comprising tolperisone hydrochloride and nimesulide.

Another object of the present invention is to obtain topical pharmaceutical compositions of tolperisone and nimesulide which ensures the required dosage and penetration capability to treat pain and the inflammation.

Another object of the present invention is to obtain topical pharmaceutical compositions of tolperisone and nimesulide providing improved stability and patient compliance.

Another object of the present invention is to obtain topical pharmaceutical compositions of tolperisone and nimesulide which is not toxic and not skin irritant.

Another object of the present invention is to obtain topical pharmaceutical compositions of tolperisone and nimesulide, wherein the composition is free of propylene glycol.

Another object of the present invention is to obtain topical pharmaceutical compositions of tolperisone and nimesulide wherein the composition comprises a penetration enhancer in an amount of lower than %40, pereferably lower than %20 by weight of the total composition.

Another object of the present invention is to obtain topical pharmaceutical compositions of tolperisone and nimesulide in gel form.

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 topical 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, 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.

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

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

According to one preferred embodiment, the amount of tolperisone hydrochloride is between 0.1-50% by weight of the total composition. Preferably this amount is between 0.5-20% by weight of the total composition. More preferably tolperisone hydrochloride is present between 1-10% by weight in the total composition.

According to one preferred embodiment, the amount of nimesulide is between 0.1-20% by weight of the total composition. Preferably this amount is between 0.4-10% by weight of the total composition. More preferably it is present between 0.5-5% by weight in the total composition.

In the preferred embodiment of the invention, the weight ratio of tolperisone hydrochloride to nimesulide is in the range of 0.005: 1 to 500:1 , preferably 0.05: 1 to 50: 1 , more preferably 0.2: 1 to 20: 1. In the most preferred embodiment, this ratio is 5: 1.

According to another embodiment, the composition is free of propylene glycol.

Propylene glycol tends to oxidize and gives undesired products such as propionaldehyde, lactic acid, pyruvic acid, and acetic acid. It is also incompatible with oxidizing reagents and it is minimally irritant for skin. So, it is essential for the composition to be free of propylene glycole in order to be stable and non-irritant.

According to the preferred embodiment, the topical composition is in gel dosage form. According to the preferred embodiment of the invention, the composition comprises at least one pharmaceutically acceptable excipient selected from pH adjusting agents, aromatizers, penetration enhancers, solvents, gel forming agents, surfactants, humectants, preservatives or mixtures thereof.

Suitable penetration enhancers are selected from the group comprising fatty acids, fatty acid esters, polyoxylglyceride, N-substituted alkyl-azacycloalkyl-2-ones derivates, menthol, terpene, essential oils, phospholipides, sulfoxides, amino-acids and its derivates or mixture thereof.

According to the preferred embodiment, the topical pharmaceutical composition comprises a penetration enhancer which is dimethyl sulfoxide.

The amount of dimethyl sulfoxide is lower than %40, preferably lower than %20, more preferably between 5-15% by weight of the total composition.

Dimethyl sulfoxide is known to cause local toxic effects, to act as a primary irritant on skin and to react with oxidizing materials when used in high amounts, nevertheless it is commonly used in the state of the art in amounts higher that %40 by weight. For the composition subjected to the invention, it has been seen that dimethyl sulfoxide amounts lower than %40 is safe for skin and it has not any negative effect on the maintenance of the stability.

Suitable gel forming agents are selected from the group comprising carbomer, liquid paraffin, polyacrylamide, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, modified starch, acrylic acid/ethyl acrylate copolymers, polymethacrylate copolymers, tri hydroxy stearin, aluminum magnesium hydroxy stearate, poloxamer, polyvinyl alcohol, polyvinyl pyrrolidone, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, butyl hydroxybenzoate or mixtures thereof.

According to the preferred embodiment, the topical pharmaceutical composition comprises a gel forming agent which is hydroxypropyl cellulose.

The amount of hydroxypropyl cellulose is between 0.1-20%, preferably 0.5-10% and more preferably 1-5% by weight of the total composition. Suitable solvents are selected from the group comprising dimethyl sulfoxide, diethylene glycol monoethyl ether, propylene carbonate, polyethylene glycol, glycerine, ethanol or mixtures thereof.

According to the preferred embodiment, the topical pharmaceutical composition comprises at least one solvent selected from the group comprising dimethyl sulfoxide, polyethylene glycol and ethanol.

According to one embodiment, the topical pharmaceutical composition comprises two solvents which are polyethylene glycol and ethanol. Ethanol is also effective as a preservative and polyethylene glycol has also a role as a plasticizer.

The amount of polyethylene glycol is between 1-50%, preferably 5-40% and more preferably 15-30% by weight of the total composition.

The amount of ethanol is between 10-60%, preferably 20-50% and more preferably 30-50% by weight of the total composition.

Suitable surfactants are selected from the group comprising glyceryl oleate, tocopherol, ascorbyl palmitate, citric acid, polyethoxylated fatty acid esters, polyoxyethylene sorbitan esters, polyoxyethylene hydrogenated castor oil, sorbitan esters, sodium lauryl sulphate, docusate sodium, nonoxynol or mixtures thereof.

According to the preferred embodiment, the topical pharmaceutical composition comprises a surfactant which is polyoxyethylene sorbitan monooleate (polysorbate).

The amount of polysorbate is between 0.1 - 10%, preferably 0.5 - 4.0% by weight of the total composition.

In the preferred embodiment of the invention, the ratio of polyethylene glycole to polysorbate is in the range of 0.1 :1 to 500:1 , preferably 5: 1 to 100: 1 and more preferably 10: 1 to 50: 1.

In the preferred embodiment of the invention, the ratio of hydroxypropyl cellulose to polysorbate is in the range of 0.01 :1 to 200: 1 , preferably 0.1 :1 to 20: 1 and more preferably 0.5: 1 to 10: 1. In the most preferred embodiment, this ratio is 2.5:1. It has been seen that these specific ranges of the selected solvent, surfactant and gel forming agent surprisingly promote the penetration capability even in the case of dimethyl sulfoxide presence lower than %40 by weight which is preferable for the invention in order to provide a non-irritant and stable formulation. Thus, it is possible to enhance penetration capability and increase patient compliance at the same time.

Suitable humectants are selected from the group comprising propylene glycol, glycerin, butylene glycol, urea, tremella extract, sorbitol, dicyanamide, sodium lactate or mixtures thereof.

According to the preferred, the topical pharmaceutical composition comprises a humectant which is glycerine.

The amount of glycerine is between 0.5-50%, preferably 1-25% and more preferably 5-15% by weight of the total composition.

Suitable pH adjusting agents are selected from the group comprising pharmaceutically acceptable organic or inorganic acids or bases such as sodium hydroxide, tromethamine, hydrochloric acid, citric acid anhydrate or mixtures thereof.

According to the preferred, the topical pharmaceutical composition comprises a pH adjusting agent which is citric acid anhydrate.

The amount of citric acid anhydrate is between 0.1-20%, preferably 0.5-10%, more preferably 1-5% by weight of the total composition.

According to the preferred, the topical pharmaceutical composition further comprises an aromatizer which is menthol. The amount of menthol is between 0.1-20%, preferably 1-10% by weight of the total composition.

According to one embodiment, the composition comprises;

— 0.1-50% by weight tolperisone hydrochloride

— 0.1-20% by weight of nimesulide

— lower than 40% by weight of dimethyl sulfoxide

— 0.1-20% by weight of hydroxypropyl cellulose

— 1-50% by weight of polyethylene glycol

— 10-60% by weight of ethanol — 0.1-10% by weight of polysorbate

— 0.5-50% by weight of glycerine

— 0.1-20% by weight of citric acid anhydrate

— 0.1-20% by weight of menthol

These analytically selected ratios ensure the required effective doses for the treatment, toxic safety and patient compliance. Furthermore, they enhance the stability and the penetration capability while providing a uniform formulation. According to all these embodiments, the below given formulations can be used in the topical gel pharmaceutical compositions subjected to the invention.

Example 1 : Gel formulation of tolperisone hydrochloride and nimesulide combination

Example 2: Gel formulation of tolperisone hydrochloride and nimesulide combination

The preparation method of the above-mentioned gel forms given in examples 1 and 2 is prepared by following these steps:

- Mixing 70-90% by weight of the ethanol with dimethyl sulfoxide, citric acid anhydrate and menthol until a homogenous mixture is provided

- Adding tolperisone hydrochloride and nimesulide and mixing until they are solved

- Adding hydroxypropyl cellulose and mixing until it is swollen which takes approximately 60 minutes

- Adding glycerine, polysorbate and polyethylene glycole respectively and mixing the total mixture until it gets homogeneous which takes approximately 60 minutes

- Resting the total mixture

- Adding 10-30% by weight of ethanol and mixing the final mixture

- Filling the final mixture into tubes

According to a preferred embodiment, the topical pharmaceutical composition subjected to the invention is used in the treatment of pain or inflammation caused by sport injuries, arthritis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, menstruation, hereditary polyps of the colon, migraine, spasticity or muscle spasm.