WO2013022410A2 - Production method for effervescent formulations comprising dexketoprofen - Google Patents

Production method for effervescent formulations comprising dexketoprofen Download PDF

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Publication number
WO2013022410A2
WO2013022410A2 PCT/TR2012/000130 TR2012000130W WO2013022410A2 WO 2013022410 A2 WO2013022410 A2 WO 2013022410A2 TR 2012000130 W TR2012000130 W TR 2012000130W WO 2013022410 A2 WO2013022410 A2 WO 2013022410A2
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Prior art keywords
effervescent
acid
dexketoprofen
formulation
mixture
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PCT/TR2012/000130
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French (fr)
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WO2013022410A3 (en
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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Publication of WO2013022410A2 publication Critical patent/WO2013022410A2/en
Publication of WO2013022410A3 publication Critical patent/WO2013022410A3/en

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to a method used for production of effervescent formulations comprising dexketoprofen and effervescent formulations obtained by said method.
  • dexketoprofen illustrated in Formula I, which was first disclosed in the European patent numbered EP0668851, is S(+) enantiomer of ketoprofen.
  • Dexketoprofen or its pharmacologically suitable salts are analgesic, anti-inflammatory and antipyretic drugs belonging to the group of non-steroidal anti-inflammatory drugs.
  • Dexketoprofen is produced under the trade name Keral as dexketoprofen tromethamine salt by Menarini on the market.
  • Dexketoprofen trometamol is a white crystalline salt and its melting pointvaries betweenl03-107°C.
  • dexketoprofen has a bitter taste. Therefore, the formulations comprising dexketoprofen leave a bad taste in patient's mouth during use. In order to inhibit this bad taste, this problem is tried to be prevented by formulating dexketoprofen with a flavouring agent.
  • flavouring agents used cause the effervescent formulations comprising dexketoprofen to turn yellow in water and to form an unpleasant layer on the surface during use.
  • the effervescent formulation which is prepared with the production method comprising the steps of granulating the effervescent acid, the effervescent base and at least one excipient; granulating dexketoprofen or a pharmaceutically acceptable salt thereof only with the effervescent base and compressing the two mixtures together obtained in said two steps in tablet form has high stability and pleasant taste and does not cause yellowing or formation of a layer on water surface during use.
  • the first aspect of the present invention is a method for production of the effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that said method is
  • step I obtaining the I st mixture by granulating the effervescent acid, the effervescent base and at least one excipient and optionally by mixing the granules with at least one pharmaceutically acceptable excipient in step I,
  • Dexketoprofen used in the effervescent formulation prepared according to the production method of the present invention can be in the form any salt thereof. Preferably, it is in dexketoprofen trometamol form.
  • Dexketoprofen or a pharmaceutically acceptable salt thereof used in the effervescent formulation prepared according to the production method of the present invention is in the range of 0.1-15%, preferably in the range of 0.5-12%, more preferably in the range of 1-10%) in proportion to total tablet weight.
  • the effervescent formulation prepared according to the production method of the present invention comprises dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 5-100 mg, preferably in the range of 10-80 mg, more preferably in the range of 15-60 mg.
  • the effervescent formulation prepared according to the production method of the present invention can be formulated in form of effervescent granule, effervescent powder or effervescent tablet. Preferably, it is in effervescent tablet form. More preferably the granules obtained in steps I and II are compressed in bilayer tablet form without mixing with each other.
  • the effervescent acid used in the effervescent formulation prepared according to the production method of the present invention can be selected from a group comprising acids such as citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, adipic acid and succinic acid, acetyl salicylic acid; acid salts such as sodium dihydrogen phosphate, sodium acid pyrophosphate, acid citrate salts, amino acid hydrochlorides, sodium acid sulphide, hydrates and anhydrates thereof.
  • citric acid is used.
  • the effervescent base used in the effervescent formulation prepared according to the production method of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen citrate or the combinations thereof.
  • potassium bicarbonate is used.
  • the effervescent formulation prepared according to the production method of the present invention can also comprise the other pharmaceutically acceptable excipients in addition to dexketoprofen or a pharmaceutically acceptable salt thereof, the effervescent acid and the effervescent base.
  • the effervescent formulation prepared according to the production method of the present invention can comprise, but not limited to, binder, sweetener, and/or taste regulating agent, flavouring agent, lubricant or a combination thereof.
  • the binder used in the effervescent formulation prepared according to the production method of the present invention can be selected from, but not limited to, starch, sucrose, glucose, dextrose, lactose, maltodextrin, gelatine; microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone (povidone), polyethylene glycol (PEG), calcium carbonate, calcium phosphate, sorbitol powder, xylitol, mannitol or a combination thereof.
  • the sweetener and/or taste regulating agentused in the effervescent formulation prepared according to the production method of the present invention can be selected from, but not limited to, 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, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
  • the flavouring agent used in the effervescent formulation prepared according to the production method of the present invention can be selected from, but not limited to, natural aroma oils, menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, lemon, orange, blackberry, vanilla or a combination thereof.
  • the method clarified as granulating the effervescent acid, the effervescent base and at least one excipient and optionally mixing the granules with at least one pharmaceutically acceptable excipient in step I can comprise the following steps: la. Preparing the 1 st granulation solution comprising deionized water, the binder and at least one solvent,
  • step Id Sieving the granules obtained in step Ic by adding the sweetener, and then stirring the mixture,
  • the 1 st granulation solution comprising deionized water; 5-50%, preferably 10-45% of total amount of the binder and at least one solvent is prepared.
  • the solvent used while preparing the 1 st granulation solution can be selected from alcohols such as butanone, acetone, isopropyl alcohol, propanol, butanol and ethyl alcohol. Preferably, ethyl alcohol is used.
  • step lb the effervescent acid; 50-95%, preferably 65-85% of the effervescent base; 5-45%, preferably 10-40% of total amount of the binder used are mixed.
  • step Ic the mixture prepared in step lb is granulated with the granulation solution prepared in step la at a temperature in the range of 30-90 °C, preferably at a temperature in the range of 40- 70°C.
  • the obtained granules are dried at 50-98°C, preferably 60-95°C such that the moisture ratio of the product will be maximum 0.05- 1%, preferably 0.1-0.5%.
  • the inventors have observed that when the granules are dried at 50-98°C, preferably 60-95°C at this stage, the obtained effervescent formulations comprising dexketoprofen are stable and have a long shelf life.
  • Another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the granules comprising effervescent acid, the effervescent base and the binder are dried at 50-98°C, preferably 60-95 °C after the granulation.
  • the mixture I is obtained by adding the sweetener and 50-95%, preferably 60- 90% of total amount of the flavouring agent into the granules obtained in step Ic.
  • the inventors have seen the amount of the flavouring agent used in the effervescent formulation comprising dexketoprofen or a pharmaceutically acceptable salt thereof, and how much of this amount is included in which steps of the processare the important parameters fortaste of the formulations obtained and forsolving the problems observed such as yellowing and forming a layer on water surface during use. It has been seen that the effervescent formulations comprising dexketoprofen obtained in the case that the flavouring agent is used less than 3%, preferably in the range of 0.05-3%, more preferably in the range of 0.5- 2% in proportion to total tablet weight leave a pleasant taste in the patient' smouth during use.
  • another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the flavouring agent less than 3%, preferably in the range of 0.05-3%, more preferably in the range of 0.5- 2% is used in said method.
  • flavouring agent used in the case that total amount of the flavouring agent used is formulated with dexketoprofen or a pharmaceutically acceptable salt thereof, it causes yellowing when the formulation is put in water. Therefore, dexketoprofen is treated with less flavouring agent and therefore the problems of yellowing and layering can be prevented by adding 50-95%, preferably 65-80% of the flavouring agent into the I st mixture and the rest of the flavouring agent, which is less than the first part, into the II nd mixture comprising dexketoprofen.
  • another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that 50-95%, preferably 65-80%) of the flavouring agent is added into the I st mixture and the rest of the flavouring agent, which is less than the first part, is added into the II nd mixture comprising dexketoprofen.
  • the method clarified as granulating dexketoprofen or a pharmaceutically acceptable salt thereof only with the effervescent base and optionally adding at least one pharmaceutically acceptable excipient in step II can comprise the following steps:
  • step Illb obtaining the II nd layer mixture by mixing it after adding the flavour and one part of the I st layer mixture obtained in step Va
  • step Ila the 2 nd granulation solution comprising deionized water; 5-40%, preferably 10-35% of total binder amount used and at least one solvent is prepared.
  • step lib dexketoprofen or a pharmaceutically acceptable salt thereof and 5-50%, preferably 15- 35% of the effervescent base are mixed.
  • dexketoprofen or a pharmaceutically acceptable salt thereof is treated only with the effervescent base.
  • the effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof are sufficiently stable and durable.
  • step lib of production method of the present invention the product is heated until the product temperature reaches a temperature in the range of 20-60°C, preferably a temperature in the range of 25-50°C.
  • this mixture comprising dexketoprofen, melting point of which is between 103-107°C, to abovementioned temperature of 20-60°C, preferably of 25-50°C during the process, degradation and stability loss of dexketoprofen are prevented after it is subjected to high temperature.
  • step lie on the other hand, the mixture obtained in step lib is dried and sieved after granulated with the granulation solution obtained in step Ila. Accordingly, the inventors have observed that when the mixture of dexketoprofen and effervescent base is sieved such that the granule particles have d90 value in the range of 300-2000 ⁇ , preferably 500-1750 ⁇ , more preferably 750-1500 ⁇ , the effervescent formulations obtained have high homogeneity and dose uniformity. This provides an effecient treatment of dexketoprofen trometamol.
  • Another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the mixture of dexketoprofen and effervescent base is sieved such that the granule particles having d90 value in the range of 300-2000 ⁇ , preferably 500-1750 ⁇ , ⁇ ⁇ preferably 750-1500 ⁇ .
  • d90 value means that 90% of the said material by volume has particle size below the given value and 10% of the said material by volume has particle size above the given value.
  • the II nd layer mixture is obtained after adding the rest 5-50%, preferably 20-35% of the flavour and 0.5-10%, preferably 1-5% of the I st layer mixture into the granules obtained in step lie.
  • a clear solution can be obtained during use by removing the problem of turning to yellow in water resulting from treating the flavour with dexketoprofen by adding the rest of the flavour, which is less than the first part, into the granules comprising dexketoprofen.
  • step III the last phase of the production method of the present invention ,the I st and II nd layer mixtures obtained in the steps Ie and lid are compressed in bilayer tablet form by being fed to tablet compression machine separately in the case that the final product is prepared in tablet form.
  • the inventors have seen that one of the parameters affecting on the dissolution rates of the tablet forms is tablet hardness and hence tablet compression force applied during compressing the final pharmaceutical composition into tablets. It was observed that when tablet compression force has a value in the range of 50-150 kN, preferably 60-115 kN., the obtained tablet forms have optimum hardness enabling rapid dispersion of tablets and hence for getting them ready for use.
  • Another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the tablet compression force applied during compressing the final mixture into tablet form is in the range of 50-150 kN, preferably 60-120 kN.
  • the effervescent formulations which are highly stable and can form a clear solution without turning yellow in water during use can be provided by mixing dexketoprofen only with the effervescent base and not allowing dexketoprofen to contact with the acid and by minimizing the contact of dexketoprofen with the flavouring agent.
  • the effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof prepared according to production method of the present invention can comprise dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 0.1-15%, the effervescent acid in the range of 10-70%, the effervescent base in the range of 5-65%, the flavouring agent in the range of 0.05-3%, the binder in the range of 0.5-5% and the sweetener and/or taste regulating agent in the range of 0.1-4% in proportion to total tablet weight.
  • the effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof prepared according to production method of the present invention are analgesic, antiinflammatory and antipyretic. They are used in treatment of patients suffering from the diseases of moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • Thel st granulation solution comprising deionized water, one part of the sorbitol powder and ethyl alcohol is prepared.
  • step Ic The mixture obtained in step Ib is dried after granulated with the granulation solution obtained in step la.
  • the sweetener is added into the granules obtained in step Ic and the mixture is sieved and then mixed.
  • flavour is added into the mixture obtained in step Id.
  • II nd mixture in the production method for preparation of the effervescent formulations comprising dexketoprofen trometamol clarified above;
  • the 2 nd granulation solution comprising deionized water, rest of the sorbitol powder and ethyl alcohol is prepared,
  • Dexketoprofentrometamol and the effervescent base are mixed and heated to approximately 40°C.
  • step lib The mixture obtained in step lib is granulated with the granulation solution obtained in step Ila and the mixture is dried,
  • the II nd mixture is obtained bymixing the granules obtained in step lie after adding the flavour and 3% of the I st mixture obtained in step Ie.

Abstract

The present invention relates to aproduction method used for production of effervescent formulations comprising dexketoprofen and the effervescent formulations obtained by this method.

Description

PRODUCTION METHOD FOR EFFERVESCENT FORMULATIONS COMPRISING
DEXKETOPROFEN
The present invention relates to a method used for production of effervescent formulations comprising dexketoprofen and effervescent formulations obtained by said method.
2(+)-(S)-2-(3-benzoylphenyl) propanoic acid or dexketoprofen illustrated in Formula I, which was first disclosed in the European patent numbered EP0668851, is S(+) enantiomer of ketoprofen. Dexketoprofen or its pharmacologically suitable salts are analgesic, anti-inflammatory and antipyretic drugs belonging to the group of non-steroidal anti-inflammatory drugs.
Figure imgf000002_0001
Formula I
Dexketoprofen is produced under the trade name Keral as dexketoprofen tromethamine salt by Menarini on the market. Dexketoprofen trometamol is a white crystalline salt and its melting pointvaries betweenl03-107°C.
In the prior art, patent and patent applications are available wherein topical formulations comprising specifically the active agent dexketoprofen are disclosed. The European patentsor patent applications numbered EP1526849 (Bl), EP1613300 (Bl), EP1488787 (Al) relate to said topical formulations. The patent numbered W098855113 (Al) relates to production method of semi-solid formulations such as gel, cream comprising the active agent dexketoprofen.
Apart from these, patent or patent applications are also available disclosing the formulations comprising the drugs which belong to non-steroidal anti-inflammatory drugs including dexketoprofen. In the patent application numbered WO03043600 (Al), a water soluble but non- effervescent formulation comprising NSAID (non-steroidal anti-inflammatory drug) has been disclosed. In the patent application numbered WO02085414 (A2), an anhydrous formulation comprising phospholipid as a biocompatible carrier along with NSAID has been disclosed. In the European patent numbered EP2034958 (Bl), an aqueous suspension comprising at least one NSAID has been disclosed. In the case that the acidic active agent dexketoprofen is formulated with an effervescent acid in an effervescent formulation,incompatibility problem between them results indecrease in stability of dexketoprofen.In line with this, stability of the formulations comprising dexketoprofen is also decreased. This causesa decrease in shelf life of said drugs; therefore, an efficient treatment cannot be performed.
In another aspect, dexketoprofen has a bitter taste. Therefore, the formulations comprising dexketoprofen leave a bad taste in patient's mouth during use. In order to inhibit this bad taste, this problem is tried to be prevented by formulating dexketoprofen with a flavouring agent. However, flavouring agents used cause the effervescent formulations comprising dexketoprofen to turn yellow in water and to form an unpleasant layer on the surface during use.
In the prior art, various solutions have been developed in order to prevent said problems encountered in production of effervescent formulations. In the patent application numbered US 3.773.922, a production process has been disclosed for the effervescent formulationswhich require granulating the effervescent couple with the active agent. In the patent application numbered WO 1999/059553, a process has been disclosed wherein one of the components comprised in the formulation is melted in order to provide stability of the effervescent formulations comprising the drug. However, the inventors have seen that when the active agent dexketoprofen is treated with high temperature, it degrades and this situation causes stability loss in the end product.
As it is seen, there is still need for new methods that shall be used for production of stable formulations which comprise dexketoprofen or a pharmaceutically acceptable derivative thereof, have a desirable taste, can forma clear solution without turning yellow in water during use.
As a result of the studies they conducted in line with this requirement, the inventors have seen that the formulations developed in order to prepare the drug dosage forms comprising dexketoprofen can solve the problems in the prior art such as stability, bad taste and yellowing during use.
The inventors have surprisingly seen that the effervescent formulation which is prepared with the production method comprising the steps of granulating the effervescent acid, the effervescent base and at least one excipient; granulating dexketoprofen or a pharmaceutically acceptable salt thereof only with the effervescent base and compressing the two mixtures together obtained in said two steps in tablet form has high stability and pleasant taste and does not cause yellowing or formation of a layer on water surface during use. According to this, the first aspect of the present invention is a method for production of the effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that said method is
- obtaining the Ist mixture by granulating the effervescent acid, the effervescent base and at least one excipient and optionally by mixing the granules with at least one pharmaceutically acceptable excipient in step I,
- obtaining the IInd mixture by granulating dexketoprofen or a pharmaceutically acceptable salt thereof only with the effervescent base and optionally by adding at least one pharmaceutically acceptable excipientto the granules in step II,
- combining the two mixtures obtained in steps I and II in a suitable dosage form in step III.
Dexketoprofen used in the effervescent formulation prepared according to the production method of the present invention can be in the form any salt thereof. Preferably, it is in dexketoprofen trometamol form.
Dexketoprofen or a pharmaceutically acceptable salt thereof used in the effervescent formulation prepared according to the production method of the present invention is in the range of 0.1-15%, preferably in the range of 0.5-12%, more preferably in the range of 1-10%) in proportion to total tablet weight.
The effervescent formulation prepared according to the production method of the present invention comprises dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 5-100 mg, preferably in the range of 10-80 mg, more preferably in the range of 15-60 mg.
The effervescent formulation prepared according to the production method of the present invention can be formulated in form of effervescent granule, effervescent powder or effervescent tablet. Preferably, it is in effervescent tablet form. More preferably the granules obtained in steps I and II are compressed in bilayer tablet form without mixing with each other.
The effervescent acid used in the effervescent formulation prepared according to the production method of the present invention can be selected from a group comprising acids such as citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, adipic acid and succinic acid, acetyl salicylic acid; acid salts such as sodium dihydrogen phosphate, sodium acid pyrophosphate, acid citrate salts, amino acid hydrochlorides, sodium acid sulphide, hydrates and anhydrates thereof. Preferably, citric acid is used. The effervescent base used in the effervescent formulation prepared according to the production method of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen citrate or the combinations thereof. Preferably, sodium bicarbonate is used.
The effervescent formulation prepared according to the production method of the present invention can also comprise the other pharmaceutically acceptable excipients in addition to dexketoprofen or a pharmaceutically acceptable salt thereof, the effervescent acid and the effervescent base.
The effervescent formulation prepared according to the production method of the present invention can comprise, but not limited to, binder, sweetener, and/or taste regulating agent, flavouring agent, lubricant or a combination thereof.
The binder used in the effervescent formulation prepared according to the production method of the present invention can be selected from, but not limited to, starch, sucrose, glucose, dextrose, lactose, maltodextrin, gelatine; microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone (povidone), polyethylene glycol (PEG), calcium carbonate, calcium phosphate, sorbitol powder, xylitol, mannitol or a combination thereof.
The sweetener and/or taste regulating agentused in the effervescent formulation prepared according to the production method of the present invention can be selected from, but not limited to, 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, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
The flavouring agent used in the effervescent formulation prepared according to the production method of the present invention can be selected from, but not limited to, natural aroma oils, menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, lemon, orange, blackberry, vanilla or a combination thereof.
Specifically, the method clarified as granulating the effervescent acid, the effervescent base and at least one excipient and optionally mixing the granules with at least one pharmaceutically acceptable excipient in step I can comprise the following steps: la. Preparing the 1st granulation solution comprising deionized water, the binder and at least one solvent,
lb. Mixing the effervescent acid, the effervescent base and the binder
Ic. Granulating the mixture obtained in step lb with the granulation solution obtained in step la and drying the mixture,
Id. Sieving the granules obtained in step Ic by adding the sweetener, and then stirring the mixture,
Ie. Obtaining the Ist mixture after adding the flavour into the mixture obtained in step Id.
In step la, the 1st granulation solution comprising deionized water; 5-50%, preferably 10-45% of total amount of the binder and at least one solvent is prepared. The solvent used while preparing the 1st granulation solution can be selected from alcohols such as butanone, acetone, isopropyl alcohol, propanol, butanol and ethyl alcohol. Preferably, ethyl alcohol is used.
In step lb; the effervescent acid; 50-95%, preferably 65-85% of the effervescent base; 5-45%, preferably 10-40% of total amount of the binder used are mixed.
In step Ic, the mixture prepared in step lb is granulated with the granulation solution prepared in step la at a temperature in the range of 30-90 °C, preferably at a temperature in the range of 40- 70°C. After granulation, the obtained granules are dried at 50-98°C, preferably 60-95°C such that the moisture ratio of the product will be maximum 0.05- 1%, preferably 0.1-0.5%. The inventors have observed that when the granules are dried at 50-98°C, preferably 60-95°C at this stage, the obtained effervescent formulations comprising dexketoprofen are stable and have a long shelf life.
Another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the granules comprising effervescent acid, the effervescent base and the binder are dried at 50-98°C, preferably 60-95 °C after the granulation.
In steps Id and Ie, the mixture I is obtained by adding the sweetener and 50-95%, preferably 60- 90% of total amount of the flavouring agent into the granules obtained in step Ic.
The inventors have seen the amount of the flavouring agent used in the effervescent formulation comprising dexketoprofen or a pharmaceutically acceptable salt thereof, and how much of this amount is included in which steps of the processare the important parameters fortaste of the formulations obtained and forsolving the problems observed such as yellowing and forming a layer on water surface during use. It has been seen that the effervescent formulations comprising dexketoprofen obtained in the case that the flavouring agent is used less than 3%, preferably in the range of 0.05-3%, more preferably in the range of 0.5- 2% in proportion to total tablet weight leave a pleasant taste in the patient' smouth during use.
According to this, another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the flavouring agent less than 3%, preferably in the range of 0.05-3%, more preferably in the range of 0.5- 2% is used in said method.
In another aspect, it has been seen that in the case that total amount of the flavouring agent used is formulated with dexketoprofen or a pharmaceutically acceptable salt thereof, it causes yellowing when the formulation is put in water. Therefore, dexketoprofen is treated with less flavouring agent and therefore the problems of yellowing and layering can be prevented by adding 50-95%, preferably 65-80% of the flavouring agent into the Ist mixture and the rest of the flavouring agent, which is less than the first part, into the IInd mixture comprising dexketoprofen.
According to this, another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that 50-95%, preferably 65-80%) of the flavouring agent is added into the Ist mixture and the rest of the flavouring agent, which is less than the first part, is added into the IInd mixture comprising dexketoprofen.
Specifically, the method clarified as granulating dexketoprofen or a pharmaceutically acceptable salt thereof only with the effervescent base and optionally adding at least one pharmaceutically acceptable excipient in step II can comprise the following steps:
Ila. Preparing the 2nd granulation solution comprising deionized water, the binder and at least one solvent
lib. Mixing dexketoprofen or a pharmaceutically acceptable salt thereof with the effervescent base and heating the mixture to a specific temperature,
He. Drying and sieving the mixture obtained in the step lib after granulated with the granulation solution obtained in step lb,
lid. In step Illb, obtaining the IInd layer mixture by mixing it after adding the flavour and one part of the Ist layer mixture obtained in step Va
In step Ila, the 2nd granulation solution comprising deionized water; 5-40%, preferably 10-35% of total binder amount used and at least one solvent is prepared. In step lib, dexketoprofen or a pharmaceutically acceptable salt thereof and 5-50%, preferably 15- 35% of the effervescent base are mixed. In this step, dexketoprofen or a pharmaceutically acceptable salt thereof is treated only with the effervescent base. In this case, it has been provided that the effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof are sufficiently stable and durable.
In step lib of production method of the present invention, the product is heated until the product temperature reaches a temperature in the range of 20-60°C, preferably a temperature in the range of 25-50°C. By heating this mixture comprising dexketoprofen, melting point of which is between 103-107°C, to abovementioned temperature of 20-60°C, preferably of 25-50°C during the process, degradation and stability loss of dexketoprofen are prevented after it is subjected to high temperature.
In step lie, on the other hand, the mixture obtained in step lib is dried and sieved after granulated with the granulation solution obtained in step Ila. Accordingly, the inventors have observed that when the mixture of dexketoprofen and effervescent base is sieved such that the granule particles have d90 value in the range of 300-2000μηι, preferably 500-1750 μιη, more preferably 750-1500 μπι, the effervescent formulations obtained have high homogeneity and dose uniformity. This provides an effecient treatment of dexketoprofen trometamol.
Another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the mixture of dexketoprofen and effervescent base is sieved such that the granule particles having d90 value in the range of 300-2000μιη, preferably 500-1750 μηι,η θΓε preferably 750-1500 μπι. The expression of d90 value means that 90% of the said material by volume has particle size below the given value and 10% of the said material by volume has particle size above the given value.
In step lid of the production method of the present invention, the IInd layer mixture is obtained after adding the rest 5-50%, preferably 20-35% of the flavour and 0.5-10%, preferably 1-5% of the Ist layer mixture into the granules obtained in step lie. In this step, a clear solution can be obtained during use by removing the problem of turning to yellow in water resulting from treating the flavour with dexketoprofen by adding the rest of the flavour, which is less than the first part, into the granules comprising dexketoprofen.
In step III, the last phase of the production method of the present invention ,the Ist and IIndlayer mixtures obtained in the steps Ie and lid are compressed in bilayer tablet form by being fed to tablet compression machine separately in the case that the final product is prepared in tablet form. The inventors have seen that one of the parameters affecting on the dissolution rates of the tablet forms is tablet hardness and hence tablet compression force applied during compressing the final pharmaceutical composition into tablets. It was observed that when tablet compression force has a value in the range of 50-150 kN, preferably 60-115 kN., the obtained tablet forms have optimum hardness enabling rapid dispersion of tablets and hence for getting them ready for use.
Another aspect of the present invention is the production method of the formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof characterized in that the tablet compression force applied during compressing the final mixture into tablet form is in the range of 50-150 kN, preferably 60-120 kN.
In production method of the present invention, the effervescent formulations which are highly stable and can form a clear solution without turning yellow in water during use can be provided by mixing dexketoprofen only with the effervescent base and not allowing dexketoprofen to contact with the acid and by minimizing the contact of dexketoprofen with the flavouring agent.
The effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof prepared according to production method of the present invention can comprise dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 0.1-15%, the effervescent acid in the range of 10-70%, the effervescent base in the range of 5-65%, the flavouring agent in the range of 0.05-3%, the binder in the range of 0.5-5% and the sweetener and/or taste regulating agent in the range of 0.1-4% in proportion to total tablet weight.
The effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof prepared according to production method of the present invention are analgesic, antiinflammatory and antipyretic. They are used in treatment of patients suffering from the diseases of moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
The present invention is not limited to the example below, yet it is given in order to render the invention more comprehensible. EXAMPLE: Effervescent Tablets Comprising Dexketoprofen
Figure imgf000010_0001
In order to obtain the Ist mixture in the production method for preparation of the effervescent formulations comprising dexketoprofen trometamol clarified above; la. Thelstgranulation solution comprising deionized water, one part of the sorbitol powder and ethyl alcohol is prepared.
Ib. The effervescent acid, approximately 85% of the effervescent base and one part of the sorbitol powder are mixed.
Ic. The mixture obtained in step Ib is dried after granulated with the granulation solution obtained in step la.
Id. The sweetener is added into the granules obtained in step Ic and the mixture is sieved and then mixed.
Ie. The flavour is added into the mixture obtained in step Id. In order to obtain the IInd mixture in the production method for preparation of the effervescent formulations comprising dexketoprofen trometamol clarified above;
Ila. The 2nd granulation solution comprising deionized water, rest of the sorbitol powder and ethyl alcohol is prepared,
lib. Dexketoprofentrometamol and the effervescent base are mixed and heated to approximately 40°C.
lie. The mixture obtained in step lib is granulated with the granulation solution obtained in step Ila and the mixture is dried,
lid. The IInd mixture is obtained bymixing the granules obtained in step lie after adding the flavour and 3% of the Ist mixture obtained in step Ie.
Finally, the mixtures obtained in steps Ie and lid are compressed in bilayer tablet form by being fed to the tablet compression machine separately.

Claims

1. A method for production of effervescent formulations comprising dexketoprofen or a pharmaceutically acceptable salt thereof, characterized in that said method is
- granulating the effervescent acid, the effervescent base and at least one excipient in step I,
- granulatingdexketoprofen or a pharmaceutically acceptable salt thereof only with the effervescent base in step II,
- combining the two mixtures obtained in steps I and II in an appropriate dosage form in step III.
2. The production method according to claim 1, wherein the Istmixture is obtained by mixing at least one pharmaceutically acceptable excipient with the granules obtained by granulating the effervescent acid, the effervescent base and at least one excipient in step I.
3. The production method according to claim 1 and 2, wherein the IIndmixture is obtained by adding at least one pharmaceutically acceptable excipient into the granules obtained by granulating dexketoprofen or a pharmaceutically acceptable salt thereof only with the effervescent base in step II.
4. The production method according to claim 1-3, wherein the mixture obtained in steps I and II is compressed in a single tablet form after loaded to the tablet compression machine separately.
5. The effervescent formulation prepared bythe production method claimedin claim 1-4, wherein said formulation comprises dexketoprofen or a pharmaceutically acceptable salt thereof, effervescent acid, effervescent base, binder, sweetener and/or taste regulating agent, flavouring agent, lubricant or a combination thereof.
6. The formulation according to claim 5, wherein dexketoprofen or a pharmaceutically acceptable salt thereof is dexketoprofentrometamol.
7. The formulation according to claim 5 and 6, wherein said formulation comprises dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 0.1-15% in proportion to total tablet weight.
8. The formulation according to claim 5-7, wherein said formulation comprises 5-100 mg of dexketoprofen or a pharmaceutically acceptable salt thereof.
9. The formulation according to claim 5-8, characterized in that said formulation is formulated in effervescent granule, effervescent powder or effervescent tablet forms.
10. The formulation according to claim 9, wherein said formulation is in effervescent tablet form.
11. The formulation according to claim 5-10, wherein the effervescent acid comprised in said formulation is selected from a group comprising acids such as citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, adipic acid and succinic acid, acetyl salicylic acid; acid salts such as sodium dihydrogen phosphate, sodium acid pyrophosphate, acid citrate salts, amino acid hydrochlorides, sodium acid sulphide.
12. The formulation according to claim 11, wherein citric acid is used as the effervescent acid.
13. The formulation according to claim 5-12, wherein the effervescent base comprised in said formulation is selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen citrate or combinations thereof.
14. The formulation according to claim 13, wherein sodium bicarbonate is used as the effervescent base.
15. The formulation according to claim 5,-14 wherein the binder comprised in said formulation is selected from a group comprising starch, sucrose, glucose, dextrose, lactose, maltodextrin, gelatine; microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone (povidone), polyethylene glycol (PEG), calcium carbonate, calcium phosphate, sorbitol powder, xylitol, mannitol or a combination thereof.
16. The formulation according to claim 5-15, wherein the sweetener and/or taste regulating agent comprised in said formulation is selected from, but not limited to, 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, D-tryptophan, monoammoniumglycyrrhizinate, neohesperidindihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
17. The formulation according to claim 5-16, wherein the flavouring agent comprised in said formulation is selected from, but not limited to, natural aroma oils, menthol, menthane, anethole, methyl salicylate,eucalyptol, cinnamon, lemon, orange, blackberry, vanilla or a combination thereof.
18. The formulation according to claim 17, wherein said formulation comprises the flavouring agent less than 3% in proportion total tablet weight.
19. The formulation according to claim 18, wherein said composition comprises the flavouring agent in the range of 0.05-3% in proportion to total tablet weight.
20. The formulation according to claim 5-19, wherein said formulation comprises dexketoprofen or a pharmaceutically acceptable salt thereof in the range of 0.1-15%, effervescent acid in the range of 10-70%, effervescent base in the range of 5-65%, flavouring agent in the range of 0.05-3%, binder in the range of 0.5-5% and sweetener and/or taste regulating agent in the range of 0.1-4%in proportion to total tablet weight.
21. The production method according to claims 1 and 2, characterized in that said method comprises the following steps:
la. Preparing the lstgranulation solution comprising deionized water, the binder and at least one solvent,
lb. Mixing the effervescent acid, the effervescent base and the binder,
Ic. Drying the mixture obtained in step lb after granulated with the granulation solution obtained in step la,
Id. Sieving the granules obtained in step Ic after adding the sweetener and then stirring the mixture,
Ie. Obtaining the Istmixture by adding the flavour into the mixture obtained in step Id.
22. The production method according to claim 21, characterized in that the granules comprising effervescent acid, the effervescent base and the binder are dried at 60-95°C after the granulation in step Ic.
23. The production method according to claims 1 and 3, characterized in that said method comprises the following steps:
Ila. Preparing the 2nd granulation solution comprising deionized water, the binder and at least one solvent,
lib. Mixing dexketoprofen or a pharmaceutically acceptable salt thereof and the effervescent base and heating the mixture to a specific temperature,
He. Drying and sieving the mixture obtained in step lib after granulated with the granulation solution obtained in step Ila,
lid. Obtaining thellnd mixture by mixing it after adding the flavour and one part of the Istmixture obtained in step Ie into the granules obtained in step lie.
24. The production method according to claims 21-23, wherein 5-50% of total binder amount is included in the 1st granulation solution,5-45% of total binder amount is included in the first granulation process clarified in step lb and finally 5-40% of total binder amount is included in the second granulation solution clarified in step Ila.
25. The production method according to claims 21- 23, wherein 50-95% of the effervescent base is added into the first granulation process in step lb; 5-50% of the effervescent base, on the other hand, is included in the 2nd granulation process comprising dexketoprofen or a pharmaceutically acceptable salt thereof in step lib.
26. The production method according to claims 21- 23 characterized in that the mixture of dexketoprofen and effervescent base is sieved such that the granule particles have d90 value in the range of 750-1500 μπι in step lie.
27. The production method according to claims 21- 23, wherein 60-90% of total flavouring agent is included in thelst mixture in step Ie, the rest 10-30% of total flavouring agent is included in the IInd mixture in step lid.
28. The production method according to claim 23, wherein dexketoprofen or a pharmaceutically acceptable salt thereof and the effervescent base are heated until product temperature reaches at a temperature in the range of 20-60°C before the second granulation process in step lib.
29. The production method according to claim 23, wherein 0.5-10%) of the Istmixture is added into the IIndmixture.
30. The production method according to claims 21-29 characterized in that the tablet compression force applied while compressing the final mixture into tablet form is in the range of 60-120 kN.
PCT/TR2012/000130 2011-08-08 2012-08-08 Production method for effervescent formulations comprising dexketoprofen WO2013022410A2 (en)

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