WO2020086046A2 - Topical compositions comprising tolperisone and flurbiprofen combination - Google Patents

Topical compositions comprising tolperisone and flurbiprofen combination Download PDF

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WO2020086046A2
WO2020086046A2 PCT/TR2019/050902 TR2019050902W WO2020086046A2 WO 2020086046 A2 WO2020086046 A2 WO 2020086046A2 TR 2019050902 W TR2019050902 W TR 2019050902W WO 2020086046 A2 WO2020086046 A2 WO 2020086046A2
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weight
pharmaceutical composition
topical pharmaceutical
composition according
flurbiprofen
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PCT/TR2019/050902
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French (fr)
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WO2020086046A3 (en
Inventor
Emine TUNCAY
Melda MISIRLI
Seyhan TURKKAN
Nur PEHLIVAN AKALIN
Ali Turkyilmaz
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Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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Publication of WO2020086046A2 publication Critical patent/WO2020086046A2/en
Publication of WO2020086046A3 publication Critical patent/WO2020086046A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to pharmaceutical topical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or racemic mixture thereof and flurbiprofen or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or racemic mixtures thereof.
  • a muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia.
  • the term "muscle relaxant” is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as centrally acting muscle relaxants, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxants, the term is commonly used to refer to spasmolytics only.
  • Tolperisone is a centrally acting muscle relaxant that has been used for the symptomatic treatment of spasticity and muscle spasm. It acts at the reticular formation in the brain stem by blocking voltage-gated sodium and calcium channels and it is marketed under trade names including Biocalm, Muscodol, Mydeton, Mydocalm, Mydoflex, Myolax, Myoxan and Viveo.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX cyclooxygenase
  • Tolperisone is a preferable muscle relaxant to be applied in 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.
  • 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.
  • patent document numbered EP0295411 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.
  • W02009081217 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.
  • 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).
  • 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.
  • propylene glycol is regarded as minimally irritant for skin.
  • 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).
  • the main object of the present invention is to obtain pharmaceutical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer of racemic mixture thereof and flurbiprofen or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers of racemic 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 combinations of tolperisone and flurbiprofen which is free of propylene glycol.
  • Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen which comprises a penetration enhancer in an amount of lower than %40, preferably lower than %20 by weight of the total composition.
  • Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen providing improved stability and patient compliance.
  • Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen ensuring high penetration capability.
  • Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen which is not toxic and not skin irritant.
  • Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen in a gel dosage rdform.
  • the present invention relates to topical pharmaceutical compositions comprising tolperisone hydrochloride in combination with flurbiprofen.
  • said composition is free of propylene glycole.
  • 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 preferable for the composition to be free of propylene glycole in order to be stable and non-irritant.
  • 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.
  • the amount of flurbiprofen 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 it is present between 1-10% by weight in the total composition.
  • the weight ratio of tolperisone hydrochloride to flurbiprofen is in the range of 0.002:1 to 500:1 , preferably 0.025:1 to 40:1 , more preferably 0.1 :1 to 10:1. In the most preferred embodiment, this ratio is 1 :1.
  • the topical composition is in a gel dosage form.
  • tolperisone is present in an amount of 100 to 5000 mg, more preferably 1000 to 2000 mg in the dosage form.
  • flurbiprofen is present in an amount of 100 to 5000 mg, more preferably 1000 to 2000 mg in the dosage form.
  • 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 or mixture thereof.
  • 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 than %40 by weight.
  • 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.
  • 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.
  • the topical pharmaceutical composition comprises at least one solvent which is selected from the group comprising dimethyl sulfoxide, polyethylene glycol and ethanol.
  • 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 30-45% 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.
  • 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% by weight of the total composition.
  • the ratio of polyethylene glycol 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.
  • 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.
  • Suitable humectants are selected from the group comprising propylene glycol, glycerin, butylene glycol, urea, tremella extract, sorbitol, dicyanamide, sodium lactate or mixtures thereof.
  • the topical pharmaceutical composition comprises a humectant which is glycerine.
  • 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.
  • 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.
  • 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.
  • the composition comprises;
  • Example 1 Gel formulation of tolperisone hydrochloride and flurbiprofen combination
  • Example 2 Gel formulation of tolperisone hydrochloride and flurbiprofen combination

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Abstract

The present invention relates to pharmaceutical topical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or racemic mixture thereof and a nonsteroidal anti-inflammatory drug or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or racemic mixtures thereof.

Description

TOPICAL COMPOSITIONS COMPRISING TOLPERISONE AND FLURBIPROFEN
COMBINATION
Field of Invention
The present invention relates to pharmaceutical topical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or racemic mixture thereof and flurbiprofen or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or racemic 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 under 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 Formula 1.
Figure imgf000002_0001
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 combined use of muscle relaxants and NSAIDs has already been studied in the state of the art for their coordinated effects on the pain-like complaints. Methocarbamol and ibuprofen combinations, thiocolchicoside and aceclofenac combinations, chlorzoxazone and aceclofenac/ibuprofen combinations are just some of them.
Tolperisone is a preferable muscle relaxant to be applied in 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.
However, in the patent literature, there are a few mentions of liquid or gel forms of tolperisone and its 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.
In the state of art, patent document numbered EP0295411 (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.
One of the challenges with topical formulations of tolperisone 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 NSAIDs 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 pharmaceutical compositions comprising tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer of racemic mixture thereof and flurbiprofen or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers of racemic 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 combinations of tolperisone and flurbiprofen which is free of propylene glycol.
Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen which comprises a penetration enhancer in an amount of lower than %40, preferably lower than %20 by weight of the total composition.
Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen providing improved stability and patient compliance.
Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen ensuring high penetration capability.
Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen which is not toxic and not skin irritant.
Another object of the present invention is to obtain topical combinations of tolperisone and flurbiprofen in a gel dosage rdform.
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 hydrochloride in combination with flurbiprofen.
According to the preferred embodiment, said composition is free of propylene glycole.
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 preferable for the composition to be free of propylene glycole in order to be stable and non-irritant.
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 flurbiprofen 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 it is present between 1-10% by weight in the total composition.
In the preferred embodiment of the invention, the weight ratio of tolperisone hydrochloride to flurbiprofen is in the range of 0.002:1 to 500:1 , preferably 0.025:1 to 40:1 , more preferably 0.1 :1 to 10:1. In the most preferred embodiment, this ratio is 1 :1.
According to the preferred embodiment, the topical composition is in a gel dosage form.
According to one embodiment, tolperisone is present in an amount of 100 to 5000 mg, more preferably 1000 to 2000 mg in the dosage form.
According to this embodiment, flurbiprofen is present in an amount of 100 to 5000 mg, more preferably 1000 to 2000 mg in the 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 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 than %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 which is selected from the group comprising dimethyl sulfoxide, polyethylene glycol and ethanol.
According to another 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 30-45% 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% by weight of the total composition.
In the preferred embodiment of the invention, the ratio of polyethylene glycol 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 embodiment, 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 embodiment, 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 embodiment, 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
— 0.1-50% by weight of flurbiprofen
— 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. 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 : Gel formulation of tolperisone hydrochloride and flurbiprofen combination
Figure imgf000010_0001
Example 2: Gel formulation of tolperisone hydrochloride and flurbiprofen combination
Figure imgf000010_0002
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 flurbiprofen 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 glycol 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

Claims

1. A topical pharmaceutical composition comprising tolperisone hydrochloride in combination with flurbiprofen.
2. The topical pharmaceutical composition according to claim 1 , wherein the topical pharmaceutical composition is free of propylene glycol.
3. The topical pharmaceutical composition according to claim 1 or 2, wherein the amount of tolperisone hydrochloride is between 0.1-50%, preferably 0.5-20% and more preferably 1-10% by weight of the total composition.
4. The topical pharmaceutical composition according to claim 1 or 2, wherein the amount of flurbiprofen is between 0.1-50%, preferably 0.5-20% and more preferably 1-10% by weight of the total composition.
5. The topical pharmaceutical composition according to claim 3 or 4, wherein the weight ratio of the flurbiprofen to tolperisone hydrochloride is in the range of 0.002:1 to 500:1 , preferably 0.025:1 to 40:1 , more preferably 0.1 :1 to 10:1.
6. The topical pharmaceutical composition according to any one of the preceding claims, wherein the composition is in a gel dosage form.
7. The topical pharmaceutical composition according to claim 6, wherein 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.
8. The topical pharmaceutical composition according to claim 7, wherein the composition comprises a penetration enhancer which is dimethyl sulfoxide in an amount of lower than %40, preferably lower than %20, more preferably between 5- 15% by weight of the total composition.
9. The topical pharmaceutical composition according to claim 7, wherein the composition comprises a gel forming agent which is hydroxypropyl cellulose.
10. The topical pharmaceutical composition according to claim 9, wherein 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.
11. The topical pharmaceutical composition according to claim 7, wherein the composition comprises two solvents which are polyethylene glycol and ethanol.
12. The topical pharmaceutical composition according to claim 11 , wherein the amount of polyethylene glycol is between 1-50%, preferably 5-40% and more preferably 15-30% by weight of the total composition.
13. The topical pharmaceutical composition according to claim 11 , wherein the amount of ethanol is between 10-60%, preferably 20-50% and more preferably 30-45% by weight of the total composition.
14. The topical pharmaceutical composition according to claim 7, wherein the topical pharmaceutical composition comprises a surfactant which is polysorbate.
15. The topical pharmaceutical composition according to claim 14, wherein the amount of polysorbate is between 0.1-10%, preferably 0.5-4% by weight of the total composition.
16. The topical pharmaceutical composition according to claim 12 or 15, wherein the ratio of polyethylene glycol 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.
17. The topical pharmaceutical composition according to claim 10 or 15, wherein 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
18. The topical pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises
— 0.1-50% by weight tolperisone hydrochloride
— 0.1-50% by weight of flurbiprofen
— 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
19. A process for preparing the topical pharmaceutical composition according to claim 18, comprising the following 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 flurbiprofen and mixing until they are solved
— Adding hydroxypropyl cellulose and mixing until it is swollen
— Adding glycerine, polysorbate and polyethylene glycol respectively and mixing the total mixture until it gets homogeneous
— Resting the total mixture
— Adding 10-30% by weight of ethanol and mixing the final mixture
— Filling the final mixture into tubes.
PCT/TR2019/050902 2018-10-26 2019-10-25 Topical compositions comprising tolperisone and flurbiprofen combination WO2020086046A2 (en)

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MY115126A (en) * 1990-04-27 2003-04-30 Seikisui Chemical Co Ltd Percutaneously absorbable eperisone or tolperisone preparation.
JP2000143510A (en) * 1998-11-16 2000-05-23 Taisho Pharmaceut Co Ltd Preparation for external use
JP5360751B2 (en) * 2007-01-29 2013-12-04 株式会社 メドレックス Salts of non-steroidal anti-inflammatory drugs and organic amine compounds and their uses
HUP0700828A2 (en) * 2007-12-20 2010-01-28 Richter Gedeon Nyrt Transdermal pharmaceutical compositions containing tolperisone alone and in combination
TR201101374A1 (en) * 2011-02-14 2012-09-21 Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ Topical pharmaceutical compositions of flurbiprofen and methylsulfonylmethane.

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