EP2709587A2 - Water-soluble formulations comprising dexketoprofen - Google Patents

Water-soluble formulations comprising dexketoprofen

Info

Publication number
EP2709587A2
EP2709587A2 EP12730283.4A EP12730283A EP2709587A2 EP 2709587 A2 EP2709587 A2 EP 2709587A2 EP 12730283 A EP12730283 A EP 12730283A EP 2709587 A2 EP2709587 A2 EP 2709587A2
Authority
EP
European Patent Office
Prior art keywords
dexketoprofen
range
formulation according
effervescent
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12730283.4A
Other languages
German (de)
French (fr)
Inventor
Mahmut Bilgic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bilgic Mahmut
Original Assignee
Bilgic Mahmut
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bilgic Mahmut filed Critical Bilgic Mahmut
Publication of EP2709587A2 publication Critical patent/EP2709587A2/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to effervescent formulations which comprise the active substance dexketoprofen and rapidly dissolve in water; and to a process for production of said effervescent formulations.
  • Dexketoprofen named (+)-(S)-2-(3-Benzoylphenyl) propionic acid (Formula I), is the S (+) enantiomer of ketoprofen which is responsible for therapeutic effect. Nonetheless, it was disclosed that S (+) enantiomer of ketoprofen shows a quicker and stronger effect than racemic ketoprofen of the same amount (Sunshine et al., WO89/046558).
  • Dexketoprofen or its pharmaceutically suitable salts are analgesic, anti-inflammatory and antipyretic drugs belonging to the group of non-steroid, anti-inflammatory drugs.
  • Dexketoprofen is produced by Menarini as dexketoprofen tromethamine salt under the tradename Keral on the market.
  • Dexketoprofen tromethamine salt was first disclosed in the European patent numbered EP0668851. In addition, said patent also discloses the production method, suitable dosage forms and indications of dexketoprofen tromethamine salt.
  • Dexketoprofen and its pharmaceutically acceptable salts are drugs used as antipyretic, analgesic and anti-inflammatory in treatment of mild and moderate pains like toothache, menstrual pain, post-operative pains and musculoskeletal pains.
  • dexketoprofen is desired to reach to peak plasma concentration quickly in order to relieve these pains rapidly. It widely depends on absorption of dexketoprofen in the gastrointestinal system in a short time after it is taken into the body.
  • formulations which can allow dissolution of dexketoprofen independent from gastric fluid and pH are needed in order to perform an effective treatment.
  • new formulations which can provide high absorption of dexketoprofen by enabling complete dissolution of the active agent dexketoprofen and therefore can provide high bioavailability; and for dosage forms which include these formulations.
  • the present invention relates to water-soluble formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof and preparation methods of these.
  • the developed water soluble formulation comprising dexketoprofen or a pharmaceutically acceptable salt thereof has enabled dexketoprofen to dissolve in water completely before taken into the body; in line with this, it has been observed that the absorption and bioavailability have increased. Therefore, the water soluble formulation comprising dexketoprofen developed has provided that an effective amount of dexketoprofen is taken by the patient and an effective treatment is carried out.
  • the first aspect of the present invention is water soluble formulations comprising dexketoprofen.
  • water-soluble dexketoprofen formulations When compared to solid oral dosage forms, water-soluble dexketoprofen formulations have been observed to be more advantageous than other oral dosage forms comprising dexketoprofen in terms of enabling an effective amount of the active substance dexketoprofen to dissolve and be absorbed.
  • the developed water-soluble formulations comprising dexketoprofen have provided that problems observed in solid oral dosage forms in the prior art are solved by enabling dexketoprofen to dissolve in water and become ready to be absorbed before taken into the body and an effective treatment is realized when dexketoprofen reaches its peak plasma concentration.
  • Water-soluble formulation of the present invention comprises dexketoprofen as the active substance.
  • dexketoprofen used here includes free acid, pharmaceutically acceptable salts, solvates, hydrates, amorphous and crystalline forms of dexketoprofen.
  • Effervescent formulation of the present invention preferably comprises a pharmaceutically acceptable salt of dexketoprofen, preferably trometamol salt thereof.
  • Another aspect of the invention is water-soluble formulations comprising dexketoprofen trometamol.
  • the amount of the active agent comprised in the water-soluble formulations of the present invention is in the range of 1 mg to 250 mg, preferably in the range of 5 mg to 100 mg.
  • the present invention relates to water soluble formulations comprising dexketoprofen in the range of 1 mg to 250 mg, preferably in the range of 5 mg to 100 mg.
  • Water-soluble formulations can be in water-soluble powder, water-soluble granule, water-soluble tablet, effervescent powder, effervescent granule or effervescent tablet form.
  • the formulation of the present invention is in the form of water soluble tablet or effervescent tablet, hardness and thus disintegration time are important parameters for the bioavailability of the active agent and efficiency of the treatment.
  • the inventors have found that the particle size of dexketoprofen used as active agent in the formulation has a great influence on the disintegration time and the absorption and thus bioavailability of dexketoprofen.
  • the formulation of the present invention comprise dexketoprofen active agent having d90 value in the range of 250-600 ⁇ , preferably 300-500 ⁇ , more preferably 350-450 ⁇
  • said formulation can dissolve in water quickly and effective amount of dexketoprofen can be absorbed easily therefore an efficient treatment can be provided.
  • the present invention relates to water soluble formulations wherein said formulations are in water soluble tablet or effervescent tablet form, said formulations comprise dexketoprofen having d90 value in the range of 250-600 ⁇ , preferably 300-500 ⁇ , more preferably 350-450 ⁇ .
  • d90 value means that 90% of dexketoprofen used as active agent by volume has particle size below this value and 10% of dexketoprofen by volume has particle size above this value.
  • Table 1 indicates data of dissolution time of the effervescent tablet of the present invention so that 98.7% of dexketoprofen active agent can be dissolved in water.
  • the dissolution data have been recorded based on the change in d90 value of dexketoprofen used as active agent.
  • the dissolution time of said effervescent tablets of the present invention should be maximum 5 minutes.
  • the results clearly show that the effervescent tablet can dissolve within this range in the case that the formulation of the present invention comprise dexketoprofen having d90 value in the range of 250-600 ⁇ .
  • the preferable range of the d90 value of dexketoprofen is 300-500 ⁇ and the most preferable one is 350-450 ⁇ for achieving optimum dissolution time of the obtained effervescent tablet.
  • the effervescent tablets of the present invention in which dexketoprofen having d90 value in the range of 250-600 ⁇ , preferably 300-500 ⁇ , more preferably 350-450 ⁇ is used, are much preferred via its optimum dissolution time in water.
  • Vater-soluble formulations of the present invention can also comprise other pharmaceutically acceptable excipients along with dexketoprofen.
  • Water-soluble formulations of the invention can also comprise excipients such as binder, optionally an effervescent couple comprising effervescent acid and effervescent base, carrier, sweetener and/or taste regulating agent, coloring or flavoring agent, filling agents, lubricants, glidants, viscosity enhancers, anti-foaming agents, surfactants along with dexketoprofen.
  • excipients such as binder, optionally an effervescent couple comprising effervescent acid and effervescent base, carrier, sweetener and/or taste regulating agent, coloring or flavoring agent, filling agents, lubricants, glidants, viscosity enhancers, anti-foaming agents, surfactants along with dexketoprofen.
  • Binder which is used in water-soluble formulations of the present invention is selected from, but not limited to, a group comprising povidone, cellulose ester, sucrose, lactose, cellulose derivatives, sorbitol and/or mannitol. Tablet hardness should also be taken into consideration in terms of the bioavailability of active agent and thus the efficiency of the treatment. Because, tablets with high hardness value leads to a slow dispersion and dissolution. Therefore, sufficient active agent can not be dissolved and thus bioavailibility of dexketoprofen decreases. Based on the studies, the inventors have seen that the particle size and the material of the excipient are important parameters on optimizing the tablet hardness and achieving high bioavailibity of dexketoprofen.
  • the inventors have observed that when the formulation of the present invention comprise sorbitol and/or mannitol as binder and the average particle size of the sorbitol and/or mannitol is in the range of 100-450 ⁇ , preferably 150-400 ⁇ , more preferably 200-350 ⁇ , the hardness of the tablets has been found as 8 kP, which is an optimum hardness value within specification limits. Therefore, the water soluble and/or effervescent tablets can disintegrate within 1-2,5 minutes when they contact with water. Accordingly, when the formulation dissolve in water quickly and easily, the absorption and the bioavailability of dexketoprofen used as active agent can increase and hence an effective treatment can be provided.
  • the present invention relates to water soluble formulations wherein - said formulations are in water soluble tablet or effervescent tablet form,
  • said formulations comprise sorbitol and/or mannitol as binder and
  • the average particle size of sorbitol and/or mannitol is in the range of 100-450 ⁇ , preferably 150-400 ⁇ , more preferably 200-350 ⁇ .
  • sorbitol should have an average particle size in an optimum range in order to achieve rapid dissolution and efficient treatment.
  • the dissolution time is tested for achieving dissolution of 98.7% dexketoprofen active agent in water.
  • the hardness value of the tablet should be in the range of 6-9 kP and the optimum range of the dissolution time for said effervescent tablet is maximum 5 minutes.
  • the optimum hardness and dissolution time values which are within the given specification limits can be achieved.
  • the preferable range is obtained as 150-400 ⁇ and the most preferable range is obtained as 200-350 ⁇ . It can be seen that when sorbitol having average particle size in the most preferable range of 200-350 ⁇ , the hardness of the tablet is about 7-8 kP and the dissolution time is about 2 minutes which are the most suitable values for obtaining a high dissolution and bioavailability.
  • the effervescent tablets of the present invention in which sorbitol having average particle size in the range of 100-450 ⁇ , preferably 150-400 ⁇ , more preferably 200-350 ⁇ , are much preferred via its optimum hardness and dissolution time.
  • Carrier which can be used in water-soluble formulations of the present invention can be selected from, but not limited to, a group comprising lactose, saccharose, sorbite, mannitol, starch, pectin and cellulose.
  • Filling agent which can be used in water-soluble formulations of the present invention can be selected from a group comprising cyclodextrin, maltodextrin, ethyl cellulose, lactose, sucrose, glucose, cellulose, microcrystalline cellulose, calcium carbonate, magnesium carbonate, starch and talc.
  • Sweetener and/or taste regulating agent which can be used in water-soluble formulations of the present invention can be selected from a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharin, saccharin salts, acesulfame potassium, aspartame, acesulfame potassium and cyclamates or a combination thereof.
  • Effervescent acid which can be used in water-soluble formulations of the present invention can be selected from a group comprising food acids such as citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, adipic and succinic acid, acetyl salicylic acid; acid salts like sodium dihydrogen phosphate, sodium acid pyrophosphate, acid citrate salts, amino acid hydrochlorides, sodium acid sulphite; their hydrates and anhydrates and combinations thereof.
  • food acids such as citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, adipic and succinic acid, acetyl salicylic acid
  • acid salts like sodium dihydrogen phosphate, sodium acid pyrophosphate, acid citrate salts, amino acid hydrochlorides, sodium acid sulphite; their hydrates and anhydrates and combinations thereof.
  • Effervescent base which can be used in water-soluble formulations of the present invention can be selected from a group comprising carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate, calcium carbonate and combinations thereof.
  • carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate, calcium carbonate and combinations thereof.
  • Diluent which can be used in water-soluble formulations of the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, microcrystalline cellulose, magnesium carbonate, magnesium oxide, sodium chloride, xylitol, lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or combinations thereof.
  • Water soluble formulations of the invention can comprise dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 1-15%, binder in the range of 1-10%, filling agent in the range of 2-25%, sweetener and/or taste regulating agent in the range of 0.1-10%, colouring and/or flavoring agent in the range of 0.5-8%, diluent in the range of 0-65% and effervescent couple in the range of 0-90% when compared to the total weight of unit dose amount.
  • Another aspect of the invention is a process for preparing water-soluble formulations of the present invention comprising dexketoprofen by using wet and/or dry granulation techniques available in the prior art.
  • EXAMPLE 1 Effervescent powder or granule comprising dexketoprofen
  • the process for preparing the effervescent powder or granule dosage forms comprising dexketoprofen trometamol of the present invention comprises the steps of granulating the effervescent couple with a granulation solution comprising binder; drying and sieving the obtained granules; adding dexketoprofen trometamol, filling agent, sweetener and flavouring agent to the mixture.
  • EXAMPLE 2 Effervescent tablet comprising dexketoprofen
  • the process followed for preparing the water-soluble tablet dosage forms comprising dexketoprofen trometamol of the invention comprises the steps of dry mixing dexketoprofen trometamol, binder, filling agent, diluent, sweetener, flavouring agents; and compressing the final mixture obtained in tablet form in tablet compression machine.

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Abstract

The present invention relates to water-soluble formulations comprising the active agent dexketoprofen and to a process for production of said formulations.

Description

WATER-SOLUBLE FORMULATIONS COMPRISING DEXKETOPROFEN
The present invention relates to effervescent formulations which comprise the active substance dexketoprofen and rapidly dissolve in water; and to a process for production of said effervescent formulations.
Dexketoprofen, named (+)-(S)-2-(3-Benzoylphenyl) propionic acid (Formula I), is the S (+) enantiomer of ketoprofen which is responsible for therapeutic effect. Nonetheless, it was disclosed that S (+) enantiomer of ketoprofen shows a quicker and stronger effect than racemic ketoprofen of the same amount (Sunshine et al., WO89/046558). Dexketoprofen or its pharmaceutically suitable salts are analgesic, anti-inflammatory and antipyretic drugs belonging to the group of non-steroid, anti-inflammatory drugs.
Formula I
Dexketoprofen is produced by Menarini as dexketoprofen tromethamine salt under the tradename Keral on the market. Dexketoprofen tromethamine salt was first disclosed in the European patent numbered EP0668851. In addition, said patent also discloses the production method, suitable dosage forms and indications of dexketoprofen tromethamine salt.
Dexketoprofen and its pharmaceutically acceptable salts are drugs used as antipyretic, analgesic and anti-inflammatory in treatment of mild and moderate pains like toothache, menstrual pain, post-operative pains and musculoskeletal pains. In the treatment of the said pains, dexketoprofen is desired to reach to peak plasma concentration quickly in order to relieve these pains rapidly. It widely depends on absorption of dexketoprofen in the gastrointestinal system in a short time after it is taken into the body.
In order for active agents which are taken in solid oral dosage forms such as capsule, conventional tablet or film tablet to be absorbed; firstly, the said substance must completely dissolve in gastric juice. Moreover, the gastric juice amount affects the dissolution rate of the active substance and therefore the absorption rate. In the case that gastric juice amount is low, the dissolution rate of the active substance and also the absorption rate is declined. Dissolution of an organic acid derivative substance such as dexketoprofen in the gastric fluid before being absorbed in the digestive system pulls pH of the stomach down even more and this not only affects the dissolution rate and therefore the absorption of dexketoprofen, but also causes stomach problems because of contact of the active agent with the stomach for too long. Low absorption of dexketoprofen caused by its failure to dissolve in an efficient amount leads to low bioavailability and this results in failure to perform an effective treatment.
As seen, formulations which can allow dissolution of dexketoprofen independent from gastric fluid and pH are needed in order to perform an effective treatment. From another aspect, there is need for new formulations which can provide high absorption of dexketoprofen by enabling complete dissolution of the active agent dexketoprofen and therefore can provide high bioavailability; and for dosage forms which include these formulations.
Surprisingly, the inventors have brought solutions for the problems experienced in solid oral dosage forms in the prior art by developing water-soluble formulations comprising dexketoprofen and dosage forms comprising thereof.
Detailed Explanation of the Invention
The present invention relates to water-soluble formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof and preparation methods of these. Surprisingly, the developed water soluble formulation comprising dexketoprofen or a pharmaceutically acceptable salt thereof has enabled dexketoprofen to dissolve in water completely before taken into the body; in line with this, it has been observed that the absorption and bioavailability have increased. Therefore, the water soluble formulation comprising dexketoprofen developed has provided that an effective amount of dexketoprofen is taken by the patient and an effective treatment is carried out. The first aspect of the present invention is water soluble formulations comprising dexketoprofen.
When compared to solid oral dosage forms, water-soluble dexketoprofen formulations have been observed to be more advantageous than other oral dosage forms comprising dexketoprofen in terms of enabling an effective amount of the active substance dexketoprofen to dissolve and be absorbed. The developed water-soluble formulations comprising dexketoprofen have provided that problems observed in solid oral dosage forms in the prior art are solved by enabling dexketoprofen to dissolve in water and become ready to be absorbed before taken into the body and an effective treatment is realized when dexketoprofen reaches its peak plasma concentration.
Water-soluble formulation of the present invention comprises dexketoprofen as the active substance. The term "dexketoprofen" used here includes free acid, pharmaceutically acceptable salts, solvates, hydrates, amorphous and crystalline forms of dexketoprofen. Effervescent formulation of the present invention preferably comprises a pharmaceutically acceptable salt of dexketoprofen, preferably trometamol salt thereof.
Another aspect of the invention is water-soluble formulations comprising dexketoprofen trometamol. The amount of the active agent comprised in the water-soluble formulations of the present invention is in the range of 1 mg to 250 mg, preferably in the range of 5 mg to 100 mg.
In another aspect, the present invention relates to water soluble formulations comprising dexketoprofen in the range of 1 mg to 250 mg, preferably in the range of 5 mg to 100 mg.
Water-soluble formulations can be in water-soluble powder, water-soluble granule, water-soluble tablet, effervescent powder, effervescent granule or effervescent tablet form. In the case that the formulation of the present invention is in the form of water soluble tablet or effervescent tablet, hardness and thus disintegration time are important parameters for the bioavailability of the active agent and efficiency of the treatment. The inventors have found that the particle size of dexketoprofen used as active agent in the formulation has a great influence on the disintegration time and the absorption and thus bioavailability of dexketoprofen. When the formulation of the present invention comprise dexketoprofen active agent having d90 value in the range of 250-600 μπι, preferably 300-500 μηι, more preferably 350-450 μπι, said formulation can dissolve in water quickly and effective amount of dexketoprofen can be absorbed easily therefore an efficient treatment can be provided. In another aspect, the present invention relates to water soluble formulations wherein said formulations are in water soluble tablet or effervescent tablet form, said formulations comprise dexketoprofen having d90 value in the range of 250-600 μπι, preferably 300-500 μπι, more preferably 350-450 μηι.Τηε expression of "d90 value" means that 90% of dexketoprofen used as active agent by volume has particle size below this value and 10% of dexketoprofen by volume has particle size above this value. Table 1 indicates data of dissolution time of the effervescent tablet of the present invention so that 98.7% of dexketoprofen active agent can be dissolved in water. The dissolution data have been recorded based on the change in d90 value of dexketoprofen used as active agent. According to the specifications, the dissolution time of said effervescent tablets of the present invention should be maximum 5 minutes. The results clearly show that the effervescent tablet can dissolve within this range in the case that the formulation of the present invention comprise dexketoprofen having d90 value in the range of 250-600 μπι. In fact, it can easily be seen that the preferable range of the d90 value of dexketoprofen is 300-500 μηι and the most preferable one is 350-450 μιη for achieving optimum dissolution time of the obtained effervescent tablet. Therefore, it can be concluded that the effervescent tablets of the present invention, in which dexketoprofen having d90 value in the range of 250-600 μιη, preferably 300-500 μηι, more preferably 350-450 μπι is used, are much preferred via its optimum dissolution time in water.
Table 1. The dissolution times varying depending on d90 values of dexketoprofen
Vater-soluble formulations of the present invention can also comprise other pharmaceutically acceptable excipients along with dexketoprofen.
Water-soluble formulations of the invention can also comprise excipients such as binder, optionally an effervescent couple comprising effervescent acid and effervescent base, carrier, sweetener and/or taste regulating agent, coloring or flavoring agent, filling agents, lubricants, glidants, viscosity enhancers, anti-foaming agents, surfactants along with dexketoprofen.
Binder which is used in water-soluble formulations of the present invention is selected from, but not limited to, a group comprising povidone, cellulose ester, sucrose, lactose, cellulose derivatives, sorbitol and/or mannitol. Tablet hardness should also be taken into consideration in terms of the bioavailability of active agent and thus the efficiency of the treatment. Because, tablets with high hardness value leads to a slow dispersion and dissolution. Therefore, sufficient active agent can not be dissolved and thus bioavailibility of dexketoprofen decreases. Based on the studies, the inventors have seen that the particle size and the material of the excipient are important parameters on optimizing the tablet hardness and achieving high bioavailibity of dexketoprofen.
The inventors have observed that when the formulation of the present invention comprise sorbitol and/or mannitol as binder and the average particle size of the sorbitol and/or mannitol is in the range of 100-450 μηι, preferably 150-400 μηι, more preferably 200-350 μηι, the hardness of the tablets has been found as 8 kP, which is an optimum hardness value within specification limits. Therefore, the water soluble and/or effervescent tablets can disintegrate within 1-2,5 minutes when they contact with water. Accordingly, when the formulation dissolve in water quickly and easily, the absorption and the bioavailability of dexketoprofen used as active agent can increase and hence an effective treatment can be provided.
In another aspect, the present invention relates to water soluble formulations wherein - said formulations are in water soluble tablet or effervescent tablet form,
said formulations comprise sorbitol and/or mannitol as binder and
- the average particle size of sorbitol and/or mannitol is in the range of 100-450 μπι, preferably 150-400 μηι, more preferably 200-350 μιη.
Based on the study on the effect of average particle size of sorbitol used as binder on the hardness and dissolution time of the effervescent tablets comprising dexketoprofen, the inventors have observed that sorbitol should have an average particle size in an optimum range in order to achieve rapid dissolution and efficient treatment. The dissolution time is tested for achieving dissolution of 98.7% dexketoprofen active agent in water. According to the specifications, the hardness value of the tablet should be in the range of 6-9 kP and the optimum range of the dissolution time for said effervescent tablet is maximum 5 minutes.
Therefore, it can clearly be seen that when sorbitol having average particle size in the range of 100-450 μιη is used as binder, the optimum hardness and dissolution time values which are within the given specification limits can be achieved. The preferable range is obtained as 150-400 μιη and the most preferable range is obtained as 200-350 μιη. It can be seen that when sorbitol having average particle size in the most preferable range of 200-350 μηι, the hardness of the tablet is about 7-8 kP and the dissolution time is about 2 minutes which are the most suitable values for obtaining a high dissolution and bioavailability. Hence, it can be concluded that the effervescent tablets of the present invention, in which sorbitol having average particle size in the range of 100-450 μη , preferably 150-400 μηι, more preferably 200-350 μπι, are much preferred via its optimum hardness and dissolution time.
Table 2. The hardness and dissolution times varying depending on average particle size values of sortibol
Carrier which can be used in water-soluble formulations of the present invention can be selected from, but not limited to, a group comprising lactose, saccharose, sorbite, mannitol, starch, pectin and cellulose. Filling agent which can be used in water-soluble formulations of the present invention can be selected from a group comprising cyclodextrin, maltodextrin, ethyl cellulose, lactose, sucrose, glucose, cellulose, microcrystalline cellulose, calcium carbonate, magnesium carbonate, starch and talc.
Sweetener and/or taste regulating agent which can be used in water-soluble formulations of the present invention can be selected from a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharin, saccharin salts, acesulfame potassium, aspartame, acesulfame potassium and cyclamates or a combination thereof.
Effervescent acid which can be used in water-soluble formulations of the present invention can be selected from a group comprising food acids such as citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, adipic and succinic acid, acetyl salicylic acid; acid salts like sodium dihydrogen phosphate, sodium acid pyrophosphate, acid citrate salts, amino acid hydrochlorides, sodium acid sulphite; their hydrates and anhydrates and combinations thereof.
Effervescent base which can be used in water-soluble formulations of the present invention can be selected from a group comprising carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate, calcium carbonate and combinations thereof.
Diluent which can be used in water-soluble formulations of the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, microcrystalline cellulose, magnesium carbonate, magnesium oxide, sodium chloride, xylitol, lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or combinations thereof. Water soluble formulations of the invention can comprise dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 1-15%, binder in the range of 1-10%, filling agent in the range of 2-25%, sweetener and/or taste regulating agent in the range of 0.1-10%, colouring and/or flavoring agent in the range of 0.5-8%, diluent in the range of 0-65% and effervescent couple in the range of 0-90% when compared to the total weight of unit dose amount.
Another aspect of the invention is a process for preparing water-soluble formulations of the present invention comprising dexketoprofen by using wet and/or dry granulation techniques available in the prior art.
The examples below are given for a better explanation of the invention, yet the present invention should not be limited to these examples.
EXAMPLE 1: Effervescent powder or granule comprising dexketoprofen
The process for preparing the effervescent powder or granule dosage forms comprising dexketoprofen trometamol of the present invention comprises the steps of granulating the effervescent couple with a granulation solution comprising binder; drying and sieving the obtained granules; adding dexketoprofen trometamol, filling agent, sweetener and flavouring agent to the mixture. EXAMPLE 2: Effervescent tablet comprising dexketoprofen
The process followed for preparing the water-soluble tablet dosage forms comprising dexketoprofen trometamol of the invention comprises the steps of dry mixing dexketoprofen trometamol, binder, filling agent, diluent, sweetener, flavouring agents; and compressing the final mixture obtained in tablet form in tablet compression machine.

Claims

1. A formulation comprising dexketoprofen characterized in that said formulation is in water- soluble form.
2. The formulation according to claim 1, wherein dexketoprofen in said formulation is in the form of pharmaceutically acceptable solvates, hydrates, salts, amorphous and/or crystalline forms thereof.
3. The formulation according to claim 2 characterized in that dexketoprofen is in the form of trometamol salt.
4. The formulation according to claim 1 characterized in that said formulation is in the form of water-soluble powder, water-soluble granule, water-soluble tablet, effervescent powder, effervescent granule or effervescent tablet.
5. The formulation according to claim 1 characterized in that the amount of dexketoprofen is in the range of 1 mg to 250 mg.
6. The formulation according to claim 5 characterized in that the amount of dexketoprofen is in the range of 5 mg to 100 mg.
7. The formulation according to claim 1-6 characterized in that said formulation comprises dexketoprofen having d90 value in the range of 250-600 μηι.
8. The formulation according to claim 7 characterized in that said formulation comprises dexketoprofen having d90 value in the range of 300-500 μηι.
9. The formulation according to claim 7-8 characterized in that said formulation comprises dexketoprofen having d90 value in the range of 350-450 μηι.
10. The formulation according to claim 1-9 characterized in that;
- said formulations are in water soluble tablet or effervescent tablet form,
said formulations comprise dexketoprofen having d90 value in the range of 250-600 μηι.
11. The formulation according to claim 10 characterized in that;
said formulations are in water soluble tablet or effervescent tablet form,
said formulations comprise dexketoprofen having d90 value in the range of 300-500 μιη.
12. The formulation according to claim 10-11 characterized in that;
said formulations are in water soluble tablet or effervescent tablet form,
- said formulations comprise dexketoprofen having d90 value in the range of 350-450 μηι.
13. The formulation according to claim 1-12, wherein said formulation further comprises other pharmaceutically acceptable excipients along with dexketoprofen.
14. The formulation according to claim 13, wherein said formulation comprises excipients such as binder, carrier, sweetener and/or taste regulating agent, colouring agent or flavoring agent, filling agents, lubricants, glidant, viscosity enhancers, anti-foam agents, surfactants, diluents and optionally an effervescent couple comprising one effervescent acid and one effervescent base.
15. The formulation according to claim 14, wherein the binder is selected from a group comprising povidone, cellulose ester, sucrose, lactose, cellulose derivatives, sorbitol and/or mannitol.
16. The formulation according to claim 15, wherein the binder is sorbitol and/or mannitol.
17. The formulation according to claim 15-16, wherein the average particle size of sorbitol and/or mannitol is in the range of 100-450 μηι.
18. The formulation according to claim 17, wherein the average particle size of sorbitol and/or mannitol is in the range of 150-400 μηι.
19. The formulation according to claim 18, wherein the average particle size of sorbitol and/or mannitol is in the range of 200-350 μιη.
20. The formulation according to claim 15-19, wherein
said formulations are in water soluble tablet or effervescent tablet form,
said formulations comprise sorbitol and/or mannitol as binder and
the average particle size of sorbitol and/mannitol is in the range of 100-450 μπι.
21. The formulation according to claim 15-20, wherein
said formulations are in water soluble tablet or effervescent tablet form,
- the water soluble tablet or effervescent tablet form has a hardness value as 8 kP and
- the water soluble tablet or effervescent tablet form disintegrates within 1-2,5 minutes.
22. The formulation according to claim 15-21, wherein
said formulations are in water soluble tablet or effervescent tablet form,
said formulations comprise sorbitol and/or mannitol as binder,
- the average particle size of sorbitol and/mannitol is in the range of 100-450 μιη,
the water soluble tablet or effervescent tablet form has a hardness value as 8 kP and
23. the water soluble tablet or effervescent tablet form disintegrates within 1-2,5 minutes.The formulation according to claim 1-22, wherein said formulation comprises dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 1-15 %, binder in the range of 1- 10%, filling agent in the range of 2-25%, sweetener and/or taste regulating agent in the range of 0.1-10%, colouring and/or flavoring agent in the range of 0.5-8%, diluent in the range of 0-65% and effervescent couple in the range of 0-90% in proportion to the total weight of unit dose amount.
24. A method for preparing water-soluble formulations claimed in claim 1-23, wherein said method uses wet and/or granulation techniques.
EP12730283.4A 2011-05-18 2012-05-08 Water-soluble formulations comprising dexketoprofen Withdrawn EP2709587A2 (en)

Applications Claiming Priority (2)

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TR2011/04864A TR201104864A2 (en) 2011-05-18 2011-05-18 Water-soluble formulations containing dexketoprofen.
PCT/TR2012/000085 WO2012158127A2 (en) 2011-05-18 2012-05-08 Water-soluble formulations comprising dexketoprofen

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Publication number Priority date Publication date Assignee Title
WO2013095315A1 (en) * 2011-12-19 2013-06-27 Mahmut Bilgic Formulations comprising dexketoprofen (particle size 300-2500 micrometer)
TR201723035A2 (en) * 2017-12-29 2019-07-22 Neutec Ar Ge Sanayi Ve Ticaret Anonim Sirketi Dexketoprofen delayed release composition.

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US4868214A (en) 1987-11-17 1989-09-19 Analgesic Associates Onset-hastened/enhanced analgesia
ES2058024B1 (en) * 1992-11-10 1995-05-01 Menarini Lab NEW ARILPROPIONIC DERIVATIVE, MANUFACTURING PROCEDURE OF THE SAME AND ITS USE AS AN ANALGESIC.
GB0113842D0 (en) * 2001-06-07 2001-08-01 Boots Co Plc Therapeutic agents

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Title
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FRANK ETZLER: "Particle Size Analysis: a Comparative Study of Various Methods", PART. PART. SYST . CHARACT., 1 January 1995 (1995-01-01), pages 217 - 224, XP055005762, Retrieved from the Internet <URL:http://onlinelibrary.wiley.com/store/10.1002/ppsc.19950120503/asset/19950120503_ftp.pdf?v=1&t=gryi8s4t&s=a1828a46b030a46279acda03cc453f1439127edf> [retrieved on 20110830], DOI: 10.1002/ppsc.19950120503 *
See also references of WO2012158127A2 *

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