WO2020022976A2 - A formulation comprising dexketoprofen - Google Patents

A formulation comprising dexketoprofen Download PDF

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Publication number
WO2020022976A2
WO2020022976A2 PCT/TR2018/000136 TR2018000136W WO2020022976A2 WO 2020022976 A2 WO2020022976 A2 WO 2020022976A2 TR 2018000136 W TR2018000136 W TR 2018000136W WO 2020022976 A2 WO2020022976 A2 WO 2020022976A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
tablet form
continuous release
agent
performing continuous
Prior art date
Application number
PCT/TR2018/000136
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French (fr)
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WO2020022976A3 (en
Inventor
Mahmut Bi̇lgi̇ç
Original Assignee
NEUTEC AR-GE SANAYİ VE TĺCARET ANONİM ŞİRKETİ
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Publication of WO2020022976A2 publication Critical patent/WO2020022976A2/en
Publication of WO2020022976A3 publication Critical patent/WO2020022976A3/en

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    • 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]
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention is related to a pharmaceutical composition in tablet form which provides continuous release comprising a dexketoprofen free base and pharmaceutically acceptable salt thereof as an active agent used in prolonged pain treatment, particularly musculoskeletal system pains.
  • Dexketoprofen is an analgesic, anti-inflammatory and antipyretic drug which is included in an anti-inflammatory drug group which is not a steroid. It is used in beating light and moderate pains such as musculoskeletai system pains, dysmenorrhea, and postoperative pain.
  • Dexketoprofen is a ketoprofen S(+) enantiomer.
  • the pharmaceutically acceptable salt of Dexketoprofen is a white crystallized powder of dexketoprofen trometamol which is a trometamin salt, where the melting temperature is between 103-107oC. Dexketoprofen shows the anti inflammatory effects by inhibiting prostaglandin synthesis.
  • Dexketoprofen is (S)-2-(3-Benzoilphenyl) propionic acid, wherein it has been described for the first time with the patent application numbered W09411332. In said document it has been described that dexketoprofen was effective in preventing pain and inflammation.
  • Topical formulations which particularly comprise the active agent of dexketoprofen have been described in the European patent documents numbered EP1526849, EP1613300 and EP1488787 of the known state of the art.
  • the patent numbered WO98855113 is related to the production method of semi-solid formulations such as gel, cream which comprises foe active agent of dexketoprofen.
  • Patent documents where the formulations comprising drugs within the scope of non-steroid anti-inflammatory drug groups in which dexketoprofen is also present have been explained are present in the known state of the art.
  • a water soluble formulation which comprises NSAID non steroid antiinflammatory drug
  • a non aqueous formulation which comprises phospholipids as a biocompatible carrier together with NSAID is described.
  • EP2034958 an aqueous suspension which comprises at least a NSAID is described.
  • Pharmaceutical compositions comprising dexketoprofen in the market are available in tablet, powder and injectable preparate forms of 12.5, 25 and 50mgs.
  • the aim of this invention is to provide a pharmaceutical composition in tablet form which provides continuous release, where the adverse effects are minimized by using the lowest possible dose that is effective for a short period of time, which is necessary to control the symptoms.
  • the aim of this invention is to enable dexketoprofen which is an active agent to reach its target for a continuous period of time using a matrix agent that is used for heating prolonged pain.
  • Another aim of this invention is to provide a pharmaceutical composition in a film coated tablet form which carries out continuous release and comprises dexketoprofen in order to provide a stable and effective treatment and has a long shelf life.
  • Another aim of this invention is to provide a pharmaceutical composition in a film coated tablet form which carries out continuous release comprising dexketoprofen as the active agent which reaches its target with a prolonged release or delayed release via a matrix agent.
  • the invention comprises a pharmaceutical composition in tablet form which catties out continuous release, at least a dexketoprofen free base or pharmaceutically acceptable salt therefore as an active agent.
  • dexketoprofen trometamol salt is used as the active agent.
  • the pharmaceutical composition subject to this invention comprises around 40% to 60%, preferably 45% to 55% by weight of dexketoprofen trometamol salt.
  • the dexketoprofen free salt inside the pharmaceutical compositions in tablet form which carries out continuous retease and comprises dexketoprofen is around 20mg to 100mg per dosage form.
  • the pharmaceutical composition in tablet form which carries out continuous release and enables to provide prolonged efficiency using the most effective and lowest dose comprises 110,64mg of dexketoprofen trometamoi which is equivalent to 75mg dexketoprofen such that the dexketoprofen free salt is preferably 75mg per unit dosage form.
  • the pharmaceutical composition comprises a matrix agent for said pharmaceutical composition comprising dexketoprofen used in pain treatment subject to the Invention to be able to perform continuous release, to the Studies carried out, it has been determined that It was suitable for the pharmaceutical composition in tablet form which carries out continuous release and comprises dexketoprofen subject to the invention to comprise, a matrix agent around 5% to 20%, preferably 8% to 15% by weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises at least a matrix agent selected from the group comprising hydrophilic polymers such as methyl cellulose, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydraxyethy! cellulose (HEC), ehtylhydroxyethy! cellulose (E-HEC), sodium-carboxymetoyl cellulose (Na-CMC) or hydrophobic polymem such as ethyl cellulose, cellulose acetate, cellulose acetate propionate, hyproroe!tese acetate succinate or from non cellulose groups such as sodium alginate, chitosan, guar gum, pectin, poliethyleneoxide or a combination thereof.
  • hydroxypropylmethyl cellulose HPMC
  • HPMC hydroxypropylmethyl cellulose
  • the weight ratio of the matrix agent to dexketoprofen trometamol salt which is the active agent needs to be around 1:12 to 1:2.
  • the weight ratio of the matrix agent to the dexketoprofen trometamoi salt which is the active agent is around 1:7 to 1:3. According to the studies carried out In relation to the ratio of the matrix agent to the active agent, it has been determined that the pharmaceutical composition in tabiet form which performs continuous release having the ratios described above provides longer effect.
  • the pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention also comprises an auxiliary agent selected from the group comprising a fitting agent, diluting agent, lubricating agent, a glidant, binding agent, colorant, pH adjuster, surfactant, stabilizing agent, sweetener and a coating agent.
  • an auxiliary agent selected from the group comprising a fitting agent, diluting agent, lubricating agent, a glidant, binding agent, colorant, pH adjuster, surfactant, stabilizing agent, sweetener and a coating agent.
  • the pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention comprises a filling agent around 25% to 45%, preferably 30% to 40% by weight of the composition.
  • Said pharmaceutical composition comprises at least a fitting agent selected from the group comprising calcium carbonate, dibasic calcium phosphate, tribasic caltium phosphate, calcium sulphate, miaocrystalne cellulose, dextrose, fructose, lactitol, lactose, lactose anhydrous, magnesium carbonate, magnesium oxide, mattitoi, maitodextrine, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or a combination thereof.
  • lactose anhydrous DC is used as the fitting agent.
  • the pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention comprises a lubricating agent around 0,1% to 5%, preferably 0,1% to 1% by weight of the composition.
  • Said pharmaceutical composition comprises at least a lubricating agent selected from the group comprising tribasic caidum phosphate, colloidal silicon dioxide, magnesium stticate, magnesium trisilicate, talc or a combination thereof,
  • colloidal silicon dioxide (Aerosil 200 ⁇ is used as the lubricating agent.
  • the pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention comprises a glldant around 0,1% to 10%, preferably 0,1% to 5% by weight of the composition.
  • Said pharmaceutical competition comprises at least a glldant selected from a group comprising talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, stearic add, sodium stearil fumarate or a combination thereof,
  • a glldant selected from a group comprising talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, stearic add, sodium stearil fumarate or a combination thereof.
  • magnesium stearate is used as a glldant
  • Saccharose can be used on its own or together with agents such as tale, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum Arabic, polyvinyl pirrolidon and pullulan or a combination thereof as a sugar based coating agent.
  • agents such as tale, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum Arabic, polyvinyl pirrolidon and pullulan or a combination thereof as a sugar based coating agent.
  • the water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and synthetic polymers such as sodium carboxymethyl cellulose, polyvinyl acetate diethyl am inoaoetete, amino alkyl methacrylate copolymers and polyvinyl pirroltdon and polysaccharides such as perpetratlulan and a combination thereof.
  • cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and synthetic polymers such as sodium carboxymethyl cellulose, polyvinyl acetate diethyl am inoaoetete, amino alkyl methacrylate copolymers and polyvinyl pirroltdon and polysaccharides such as131ulan and a combination thereof.
  • Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phihaiate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthaiate, acrylic add derivatives such as methacryfic add copolymer S and methacyrlic add copolymer t, methacrylic add copolymer ID and natural agents such as shellac or a combination thereof.
  • cellulose derivatives such as hydroxypropyl methyl cellulose phihaiate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthaiate
  • acrylic add derivatives such as methacryfic add copolymer S and methacyrlic add copolymer t, methacrylic add copolymer ID and natural agents such as shellac or a combination thereof.
  • Delayed release coating agents are selected from cellulose derivatives such as ethyl cellulose, acrylic add derivatives such as amino alkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylic copolymer emulsion or a combination thereof.
  • the coating agent comprises talc, polyvinyl alcohol, titanium dioxide (E171) ledihin (soya (E322)), polyethylene and glycol/macrogol [Opadry® II 85G18490 White].
  • the tablets are coated with a film coating solution that has been prepared by dissolving 5mg coating agent per unit dosage form inside sufficient purified water.
  • the solvents that can be used in pharmaceutical formulations of the invention can be selected from the group consisting of ethyl alcohol, methyl alcohol, propyl alcohol, benzene, toluene, acetone, deionized water or a combination thereof.
  • the pharmaceutical composition in tablet form which performs continuous release subject to the invention can be used in treating the symptoms and findings of a continuous disease (rheumatoid arthritis) which leads to osteoarthritis, joint pains and distortions, and a rheumatism disease that is progressive and seen with pain and stiffness in the spine (ankylosing arthritis), in inflammatory joints observed in gout disease (acute gout arthritis), acute musculoskeletal system pains, postoperative pain, and in painful menstrual periods (diysmenorrhea).
  • a continuous disease rheumatoid arthritis
  • a rheumatoid arthritis which leads to osteoarthritis, joint pains and distortions
  • a rheumatism disease that is progressive and seen with pain and stiffness in the spine
  • gout disease acute gout arthritis
  • acute musculoskeletal system pains postoperative pain
  • painful menstrual periods diysmenorrhea
  • Example 1 SR film tablet comprising Dexketoprofen tromatemol and preparation method thereof.
  • the pharmaceutical composition in tablet form, performing continuous release comprising dexketoprofen subject to the invention is prepared by means of a dry mixing method.
  • a matrix agent filling agent and lubricant is mixed in a mixer, the prepared mixture is sieved through a sieve and a glidant is added and mixed, final mixture obtained is compressed
  • the film coating agent is dissolved in a solvent for film coating following the tablet compressing step, the compressed tablets are loaded into a film coating machine and the prepared tablets are coated with the prepared coating solution.
  • Example 2 SR film tablet content comprising dexketoprofen tromatemol according to a preferred embodiment

Abstract

This Invention is related to a pharmaceutical composition in tablet form which provides continuous release comprising a dexketeprofen free base and pharmaceutically acceptable salt thereof as an active agent used In prolonged pain treatment, particularly musculoskeletal system pains.

Description

A FORMULATION COMPRISING DEXKETOPROFEN
Technical Field
This invention is related to a pharmaceutical composition in tablet form which provides continuous release comprising a dexketoprofen free base and pharmaceutically acceptable salt thereof as an active agent used in prolonged pain treatment, particularly musculoskeletal system pains.
Prior Art
Dexketoprofen is an analgesic, anti-inflammatory and antipyretic drug which is included in an anti-inflammatory drug group which is not a steroid. It is used in beating light and moderate pains such as musculoskeletai system pains, dysmenorrhea, and postoperative pain. Dexketoprofen is a ketoprofen S(+) enantiomer. The pharmaceutically acceptable salt of Dexketoprofen is a white crystallized powder of dexketoprofen trometamol which is a trometamin salt, where the melting temperature is between 103-107ºC. Dexketoprofen shows the anti inflammatory effects by inhibiting prostaglandin synthesis. The chemical name of Dexketoprofen; is (S)-2-(3-Benzoilphenyl) propionic acid, wherein it has been described for the first time with the patent application numbered W09411332. In said document it has been described that dexketoprofen was effective in preventing pain and inflammation.
Figure imgf000002_0001
Topical formulations which particularly comprise the active agent of dexketoprofen have been described in the European patent documents numbered EP1526849, EP1613300 and EP1488787 of the known state of the art. The patent numbered WO98855113 is related to the production method of semi-solid formulations such as gel, cream which comprises foe active agent of dexketoprofen.
Patent documents where the formulations comprising drugs within the scope of non-steroid anti-inflammatory drug groups in which dexketoprofen is also present have been explained are present in the known state of the art. In the WO03043600 numbered international patent document a water soluble formulation which comprises NSAID (non steroid antiinflammatory drug) is described. In the WO02085414 numbered international document a non aqueous formulation which comprises phospholipids as a biocompatible carrier together with NSAID is described. In the European patent document numbered EP2034958 an aqueous suspension which comprises at least a NSAID is described. Pharmaceutical compositions comprising dexketoprofen in the market are available in tablet, powder and injectable preparate forms of 12.5, 25 and 50mgs.
However it is significantly important for the active agent inside a system to be continuously released in a period of time rather than instantly when treating prolonged pain. An application of this type not only provides maximum efficiency from a drug but it also makes it easier for the patient to use and the excessive drug intake of the patient is prevented.
Brief Description of the Invention
The aim of this invention is to provide a pharmaceutical composition in tablet form which provides continuous release, where the adverse effects are minimized by using the lowest possible dose that is effective for a short period of time, which is necessary to control the symptoms.
The aim of this invention is to enable dexketoprofen which is an active agent to reach its target for a continuous period of time using a matrix agent that is used for heating prolonged pain.
Another aim of this invention is to provide a pharmaceutical composition in a film coated tablet form which carries out continuous release and comprises dexketoprofen in order to provide a stable and effective treatment and has a long shelf life.
Another aim of this invention is to provide a pharmaceutical composition in a film coated tablet form which carries out continuous release comprising dexketoprofen as the active agent which reaches its target with a prolonged release or delayed release via a matrix agent. Detailed Description of the Invention
The invention comprises a pharmaceutical composition in tablet form which catties out continuous release, at least a dexketoprofen free base or pharmaceutically acceptable salt therefore as an active agent. In a preferred embodiment of the pharmaceutical composition in tablet form which carries out continuous release subject to the invention dexketoprofen trometamol salt is used as the active agent. The pharmaceutical composition subject to this invention comprises around 40% to 60%, preferably 45% to 55% by weight of dexketoprofen trometamol salt.
The dexketoprofen free salt inside the pharmaceutical compositions in tablet form which carries out continuous retease and comprises dexketoprofen, is around 20mg to 100mg per dosage form.
In a preferred embodiment of the invention, the pharmaceutical composition in tablet form which carries out continuous release and enables to provide prolonged efficiency using the most effective and lowest dose comprises 110,64mg of dexketoprofen trometamoi which is equivalent to 75mg dexketoprofen such that the dexketoprofen free salt is preferably 75mg per unit dosage form.
The pharmaceutical composition comprises a matrix agent for said pharmaceutical composition comprising dexketoprofen used in pain treatment subject to the Invention to be able to perform continuous release, to the Studies carried out, it has been determined that It was suitable for the pharmaceutical composition in tablet form which carries out continuous release and comprises dexketoprofen subject to the invention to comprise, a matrix agent around 5% to 20%, preferably 8% to 15% by weight of the pharmaceutical composition.
The pharmaceutical composition, comprises at least a matrix agent selected from the group comprising hydrophilic polymers such as methyl cellulose, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydraxyethy! cellulose (HEC), ehtylhydroxyethy! cellulose (E-HEC), sodium-carboxymetoyl cellulose (Na-CMC) or hydrophobic polymem such as ethyl cellulose, cellulose acetate, cellulose acetate propionate, hyproroe!tese acetate succinate or from non cellulose groups such as sodium alginate, chitosan, guar gum, pectin, poliethyleneoxide or a combination thereof. In a preferred embodiment of the invention hydroxypropylmethyl cellulose (HPMC) is used as the matrix agent.
According to the studies carried out, in order tor the pharmaceutical composition in tablet form performing continuous release comprising dexketoprofen subject to the invention to perform continuous release, the weight ratio of the matrix agent to dexketoprofen trometamol salt which is the active agent needs to be around 1:12 to 1:2.
According to a preferred embodiment of the invention, the weight ratio of the matrix agent to the dexketoprofen trometamoi salt which is the active agent is around 1:7 to 1:3. According to the studies carried out In relation to the ratio of the matrix agent to the active agent, it has been determined that the pharmaceutical composition in tabiet form which performs continuous release having the ratios described above provides longer effect.
The pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention also comprises an auxiliary agent selected from the group comprising a fitting agent, diluting agent, lubricating agent, a glidant, binding agent, colorant, pH adjuster, surfactant, stabilizing agent, sweetener and a coating agent.
The pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention comprises a filling agent around 25% to 45%, preferably 30% to 40% by weight of the composition.
Said pharmaceutical composition comprises at least a fitting agent selected from the group comprising calcium carbonate, dibasic calcium phosphate, tribasic caltium phosphate, calcium sulphate, miaocrystalne cellulose, dextrose, fructose, lactitol, lactose, lactose anhydrous, magnesium carbonate, magnesium oxide, mattitoi, maitodextrine, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or a combination thereof. In a preferred embodiment of the invention lactose anhydrous DC is used as the fitting agent.
The pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention comprises a lubricating agent around 0,1% to 5%, preferably 0,1% to 1% by weight of the composition.
Said pharmaceutical composition comprises at least a lubricating agent selected from the group comprising tribasic caidum phosphate, colloidal silicon dioxide, magnesium stticate, magnesium trisilicate, talc or a combination thereof, In a preferred embodiment of the invention colloidal silicon dioxide (Aerosil 200} is used as the lubricating agent. The pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention comprises a glldant around 0,1% to 10%, preferably 0,1% to 5% by weight of the composition.
Said pharmaceutical competition comprises at least a glldant selected from a group comprising talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, stearic add, sodium stearil fumarate or a combination thereof, In a preferred embodiment of the invention magnesium stearate is used as a glldant
The pharmaceutical composition in tablet form which performs continuous release comprising dexketoprofen subject to the invention comprises; at least a dexketoprofen base as the active agent or pharmaceutically acceptable salt thereof, at least a matrix agent selected from the group comprising hydrophilic polymers such as methyl cellulose, hydroxypropylmethyl cellulose (HPMC), hydraxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ehtylhydroxyethyl cellulose (E-HEC), sodium- carboxymethyl cellulose (Na-CMC) or hydrophobic polymers such as ethyl cellulose, cellulose acetate, cellulose acetate propionate, hypromellose acetate succinate or from non cellulose groups such as sodium alginate, chitosan, guar gum, pectin, poliethyleneoxide or a combination thereof, at least a filling agent selected from the group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, lactose anhydrous, magnesium carbonate, magnesium oxide, maftitol, maltodexbine, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or a combination thereof, at least a lubricating agent selected from the group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium tristete, talc or a combination thereof at least a glldant selected from a group comprising talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, stearic add, sodium stearil fumarate or a combination thereof, The pharmaceutical composition in tablet form which performs continuous release subject to the invention can also be treated with coating compositions which comprise film coating agents, for example sugar based coating agents, water soluble film mating agents, enteric coating agents, delayed release coating agents or a combination thereof. Saccharose, can be used on its own or together with agents such as tale, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum Arabic, polyvinyl pirrolidon and pullulan or a combination thereof as a sugar based coating agent.
The water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and synthetic polymers such as sodium carboxymethyl cellulose, polyvinyl acetate diethyl am inoaoetete, amino alkyl methacrylate copolymers and polyvinyl pirroltdon and polysaccharides such as puilulan and a combination thereof.
Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phihaiate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthaiate, acrylic add derivatives such as methacryfic add copolymer S and methacyrlic add copolymer t, methacrylic add copolymer ID and natural agents such as shellac or a combination thereof.
Delayed release coating agents are selected from cellulose derivatives such as ethyl cellulose, acrylic add derivatives such as amino alkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylic copolymer emulsion or a combination thereof.
In a preferred embodiment of the invention the coating agent comprises talc, polyvinyl alcohol, titanium dioxide (E171) ledihin (soya (E322)), polyethylene and glycol/macrogol [Opadry® II 85G18490 White].
In a preferred embodiment, the tablets are coated with a film coating solution that has been prepared by dissolving 5mg coating agent per unit dosage form inside sufficient purified water.
The solvents that can be used in pharmaceutical formulations of the invention can be selected from the group consisting of ethyl alcohol, methyl alcohol, propyl alcohol, benzene, toluene, acetone, deionized water or a combination thereof. The pharmaceutical composition in tablet form which performs continuous release subject to the invention can be used in treating the symptoms and findings of a continuous disease (rheumatoid arthritis) which leads to osteoarthritis, joint pains and distortions, and a rheumatism disease that is progressive and seen with pain and stiffness in the spine (ankylosing arthritis), in inflammatory joints observed in gout disease (acute gout arthritis), acute musculoskeletal system pains, postoperative pain, and in painful menstrual periods (diysmenorrhea).
Example 1: SR film tablet comprising Dexketoprofen tromatemol and preparation method thereof.
Figure imgf000008_0001
The pharmaceutical composition in tablet form, performing continuous release comprising dexketoprofen subject to the invention is prepared by means of a dry mixing method. In order for said formulations to be prepared, first of all dexketoprofen trometamol, a matrix agent filling agent and lubricant is mixed in a mixer, the prepared mixture is sieved through a sieve and a glidant is added and mixed, final mixture obtained is compressed Into tablet form, the film coating agent is dissolved in a solvent for film coating following the tablet compressing step, the compressed tablets are loaded into a film coating machine and the prepared tablets are coated with the prepared coating solution.
Example 2: SR film tablet content comprising dexketoprofen tromatemol according to a preferred embodiment
Figure imgf000009_0001
It is possible for several various embodiments to be developed in relation to the Formulation Comprising Dexketoprofen subject to the invention without deviating from the scope of the invention and the invention cannot be limited to the examples provided herein, and it is essentially as described in the claims.

Claims

1. Pharmaceutical composition in tablet form, performing continuous release characterized in that it comprises at least a dexketoprofen free base or pharmaceutically acceptable salt thereof as an active agent and at least a matrix agent as an auxiliary agent.
2. Pharmaceutical composition in tablet form, performing continuous release according to claim 1, characterized in that it comprises around 40% to 60% by weight of dexketoprofen trometamol.
3. Pharmaceutical composition in tablet form, performing continuous release according to claim 1 or 2, characterized in that it emprises around 45% to 55% by weight of dexketoprofen trometamol.
4. Pharmaceutical composition in tablet form, performing continuous release according to any of the preceding claims, characterised in that it comprises around 5% to 20% by weight of a matrix agent.
5. Pharmaceutical composition in tablet form, performing continuous release according to claim 4, characterized in that it comprises around 8% to 15% by weight of a matrix agent.
6. Pharmaceutical composition in tablet form, performing continuous release according to any of the preceding claims characterized in that the matrix agent is selected from the group comprising hydrophilic polymers such as methyl cellulose, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ehtylhydroxyethyl cellulose (E-HEC), sodium-carboxymethyl cellulose (Na-CMC) or hydrophobic polymers such as ethyl cellulose, cellulose acetate, cellulose acetate propionate, hypromellose acetate succinate or from non cellulose groups such as sodium alginate, chitosan, guar gum, pectin, poliethyleneoxide or a combination thereof.
7. Pharmaceutical composition in tablet form, performing continuous release according to claim 6, characterized in that it comprises hydroxypropylmethyl cellulose (HPMC).
8. Pharmaceutical composition in tablet form, performing continuous release according to any of the preceding claims characterized in that the weight ratio of the matrix agent to dexketoprofen trometamoi salt which is the active agent is around 1; 12 to 1:2.
9. Pharmaceutical composition in tablet form, performing continuous release according to claim 8, characterized in that the weight ratio of the matrix agent to dexketoprofen trometamol salt which is the active agent is around 1:7 to 1:3.
10. Pharmaceutical composition in tablet form, performing continuous release according to any of the preceding claims characterized in that it (comprises an auxiliary agent selected from the group comprising a filling agents diluting agent, lubricating agent, a glidant, binding agent, colorant, pH adjuster, surfactant, stabilizing agent, sweetener and a coating agent.
11. Pharmaceutical composition in tablet form, performing continuous release according to claim 18, characterized in that it comprises a filling agent around 25% to 45% by weight.
12. Pharmaceutical composition in tablet form, performing continuous retease according to claim 11, characterized in that it comprises a filling agent around 30% to 40% by weight.
13. Pharmaceutical composition in tablet form, performing continuous release according to claim 10 to 12 characterized in that it comprises at least a filling agent selected from the group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, caldum sulphate, microcrystafline cellulose, dextrose, fructose, lactitol, lactose, lactose anhydrous, magnesium carbonate, magnesium oxide, maltitol, maltodextrine, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or a combination thereof.
14. Pharmaceutical composition in tablet form, performing continuous release according to claim 13, characterized in that It comprises lactose anhydrous.
15. Pharmaceutical composition In tablet form, performing continuous release according to claim 10, characterized in that it comprises a lubricating agent around 0,1% to 5% by weight
16. Pharmaceutical composition in tablet form, performing continuous release according to claim 15, characterized in that it comprises a lubricating agent around 0,1% to 1% by weight.
17. Pharmaceutical composition in tablet form, performing continuous release according to claim 15 or 16 characterized in that it comprises at least a lubricating agent selected from the group comprising dibasic caltium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc or a combination thereof.
18. Pharmaceutical composition in tablet form, performing continuous release according to claim 17, characterized in that it comprises colloidal silicon dioxide.
19.Pharmaceutical composition in tablet form, performing continuous release according to claim 10, characterized in that it comprises a glidant around 0.1% to 10% by weight
20.Pharmaceutical composition in tablet form, performing continuous release according to claim 19, characterized in that it comprises a glidant around 0.1% to 5% by weight.
21. Pharmaceutical composition in tablet form, performing continuous release according to claim 19 or 21 characterized in that it comprises at least a glidant selected from a group comprising talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, stearic acid, sodium stearii fumarate or a combination thereof.
22. Pharmaceutical composition in tablet form, performing continuous release according to claim 21, characterized in that it comprises magnesium stearate as a glidant.
23. Pharmaceutical composition in tablet form, performing continuous release according to any of the preceding claims characterized in that it is a film tablet costed with a coating agent comprising talc, polyvinyl alcohol, titanium dioxide (E171) lecithin (soya (E322)), polyethylene and glycol/macrogol.
24. Pharmaceutical composition in tablet form, performing continuous release according to any of the preceding claims characterized in that it is used in treating the symptoms and findings of a continuous disease (rheumatoid arthritis) which leads to osteoarthritis, joint pains and distortions, and a rheumatism disease that is progressive and seen with pain and stiffness in the spine (ankylosing arthritis), in inflammatory joints observed in gout disease (acute gout arthritis), acute musculoskeletal system pains, postoperative pain, and in painful menstrual periods (diysmenorrhea).
25. A pharmaceutical composition in tablet form, performing continuous release according to any of the preceding claims, characterized in that it is prepared by the follows steps;
. mixing dexketoprofen trometamol, the matrix agent, filling agent and lubricant in a mixer,
- sieving the prepared mixture through a sieve and adding a glidant and mixing,
- compressing the final mixture obtained into tablet form,
- dissolving the film coating agent in a solvent for film coating following the tablet compressing step,
- loading the compressed tablets into a film coating machine and coating the prepared tablets with the prepared coating solution.
PCT/TR2018/000136 2017-12-29 2018-12-28 A formulation comprising dexketoprofen WO2020022976A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR2017/23035A TR201723035A2 (en) 2017-12-29 2017-12-29 Dexketoprofen delayed release composition.
TR2017/23035 2017-12-29
TR2018/15617 2018-10-19
TR2018/15617A TR201815617A2 (en) 2017-12-29 2018-10-19 A formulation containing dexketoprofen.

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WO2020022976A3 WO2020022976A3 (en) 2020-03-12

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CN115607509B (en) * 2022-10-11 2024-01-30 南京正科医药股份有限公司 Dexketoprofen tromethamine injection and preparation process thereof

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CN101623280A (en) * 2008-07-10 2010-01-13 广东肇庆星湖生物科技股份有限公司 Compound sustained release preparation for easing pain and preparation method thereof
TR201104864A2 (en) * 2011-05-18 2012-12-21 Bi̇lgi̇ç Mahmut Water-soluble formulations containing dexketoprofen.
CN102813638A (en) * 2011-06-07 2012-12-12 贵阳医学院 Preparation method of dexketoprofen trometamol double-layer sustained-release tablets
ES2394888B1 (en) * 2011-06-15 2013-09-23 Farmalider, S.A. PHARMACEUTICAL FORM OF MODIFIED RELEASE OF DEXKETOPROPHENE AND INHIBITOR OF THE PUMP OF PROTONS AND USE OF THE SAME.
WO2013022410A2 (en) * 2011-08-08 2013-02-14 Mahmut Bilgic Production method for effervescent formulations comprising dexketoprofen
WO2013095315A1 (en) * 2011-12-19 2013-06-27 Mahmut Bilgic Formulations comprising dexketoprofen (particle size 300-2500 micrometer)

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TR201723035A2 (en) 2019-07-22
WO2019212426A3 (en) 2019-11-28
WO2020022976A3 (en) 2020-03-12
WO2019212426A2 (en) 2019-11-07

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