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Title:
DELAYED RELEASE DEXKETOPROFEN COMPOSITION
Document Type and Number:
WIPO Patent Application WO/2019/212426
Kind Code:
A2
Abstract:
The present invention is related to pharmaceutical compositions comprising dexketoprofen free base and and dexketoprofen trometamol to be used to treat fever, mild and moderate pain, headache, toothache, migrane prophylaxis and mialgia diseases.

Inventors:
BILGIÇ, Mahmut (Yiidız Teknik Üniversitesi Davutpaşa Kampüsü Teknoloji, Geliştirme Bölgesi D1 Blok K.3, Esenler/İstanbul, TR)
Application Number:
TR2018/000129
Publication Date:
November 07, 2019
Filing Date:
December 28, 2018
Export Citation:
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Assignee:
NEUTEC AR-GE SANAYI VE TICARET ANONIM ŞIRKETI (Yiidız Teknik Üniversitesi Davutpaşa Kampüsü Teknoloji, Geliştirme Bölgesi D1 Blok K.3, Esenler/İstanbul, TR)
Attorney, Agent or Firm:
GÖKDEMIR, Burcu (Yiidız Teknik Üniversitesi Davutpaşa Kampüsü Teknoloji, Geliştirme Bölgesi D1 Blok K.3, Esenler/İstanbul, TR)
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Claims:
CLAIMS

1. A pharmaceutical delayed release composition comprising dexketoprofen free base and together with this a pharmaceutically acceptable salt of dexketoprofen as the active agent in order to treat fever, mild and moderate pain, headache, toothache, migrane prophylaxis mialgia diseases, characterized in that the ratio of dexketoprofen salt to the dexketoprofen free base by weight is in the range of 1 : 1 to 1 :4 respectively.

2. A pharmaceutical composition according to claim 1, characterized in that the ratio of dexketoprofen salt to dexketoprofen free base by weight is respectively in the range of 1 :1 to 1:3.5 and preferably in the range of 1 : 1 to 1 :3.

3. A pharmaceutical compositions according to claims 1 to 2, characterized in that the pharmaceutically acceptable salt of dexketoprofen is dexketoprofen trometamol.

4. A pharmaceutical composition which comprises dexketoprofen free base and dexketoprofen trometamol salt according to claim 3, characterized in that it is provided in forms such as tablets, effervescent tablets, effervescent granules, effervescent dry powder, film coated tablets, enteric coated tablets, dry powder, granules, capsules, prolonged release tablets, modified release tablets, delayed release tablets, orodispersible tablets, chewing tablets and bilayer (two layered) tablets and a combination thereof.

5. A pharmaceutical composition according to claim 4, characterized in that said composition is in the form of tablets or bilayer (two layered) tablets.

6. A pharmaceutical composition comprising dexketoprofen free base and dexketoprofen trometamol according to claims 3 to 5, characterized in that it comprises at least a pharmaceutically acceptable excipient in addition dexketoprofen free base and dexketoprofen trometamol.

7. A pharmaceutical composition which comprises dexketoprofen free base and dexketoprofen trometamol salt according to claim 6, characterized in that it comprises a disintegrant, a diluent, a glidant, a lubricant, a binder, an effervescent pair comprising at least an acidic agent, and at least a basic agent, or an excipient that is pharmaceutically acceptable selected from the group comprising a colorant, a pH adjusting agent, a surfactant, a stabilizing agent, a sweetener and/or flavor adjusting agent, an aroma agent in addition to the active agents.

8. A pharmaceutical composition according to any of the preceding claims characterized in that in addition to the active agents it comprises at least a third active agent selected from antiacids, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiaknantibacterial, antimicotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti parkison, antiprotozoal, anthelmintic, antiinflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tthiozolidindion, biguanide, immunostimulant, immunusuppresant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitorls, ACE inhibitors;; multivitamin and minerals, vitamin A, vitamin D and analogues, vitamin Bi, vitamin C, vitamin E, vitamin Be, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.

9. A pharmaceutical composition which comprises a combination of lOmg to l lOmg dexketoprofen free base and lOmg to 110 mg of dexketoprofen trometamol as the active agent per unit dosage form.

10. A pharmaceutical composition according to claim 9, characterized in that it comprises;

• 50 mg dexketoprofen free base,

• 25 mg dexketoprofen trometamol salt and,

• At least an excipient.

Description:
DELAYED RELEASE DEXKETOPROFEN COMPOSITION

Prior Art

The present invention is related to pharmaceutical compositions having delayed release features comprising dexketoprofen free base as an active agent and pharmaceutically acceptable salts thereof in order to be used in pain treatment.

Dexketoprofen is an analgesic, anti-inflammatory and antipyretic drug which is included in an antiinflammatory drug group which is not a steroid. It is used in treating light and moderate pains such as musculoskeletal system pains, dysmenorrhea, and postoperative pain. Ketoprofen is a racemic mixture formed of equal amounts of ketoprofen S(+) and (R-) enantiomers. Dexketoprofen is a ketoprofen S(+) enantiomer.

Dexketoprofen shows the anti inflammatory effects by inhibiting prostaglandin synthesis. The chemical name of Dexketoprofen; is (S)-2-(3-Benzoilphenyl) propionic acid, wherein it has been described for the first time with the patent application numbered W09411332. In said document it has been described that dexketoprofen was effective in preventing pain and inflammation.

Figure 1. Dexketoprofen

Dexketoprofen is available in the market as preparate dosages of 25.50 and 75mg tablet, powder or injectable forms.

Detailed Description of the Invention

As described herein the expression“pharmaceutically acceptable” means compounds, materials, compositions and/or unit doses that are suitable to be given to patients in compliance with a modest benefit/risk ratio without causing unacceptable toxicity irritation allergic responses or other problems or complications according to correct medical foresight. As used herein, the expression “pharmaceuitcal composition” means a drug which comprises dexketoprofen to be used in treating a mammal such as a human. The pharmaceutical composition of the invention may contain one or more carriers.

As used herein,“delayed release” enables the active agent to reach its target with delay or in a long term via a matrix agent that is used.

Subject of the Invention

The compositions subject to the present invention may comprise dexketoprofen free base as the active agent or pharmaceutically acceptable salts thereof or a combination thereof.

Therefore according to one aspect, the invention is a pharmaceutical delayed release compoistion comprising dexketoprofen free base and together with this a pharmaceutically acceptable salt thereof as the active agent in order to treat fever, mild and moderate pain, headache, toothache, migrane prophylaxis mialgia diseases, wherein the dexketoprofen salt ratio to the dexketoprofen free base by weight is in the range of 1 : 1 to 1 :4 respectively.

Therefore according to another aspect, the present invention is related to compositions in which the ratio of the dexketoprofen salt to dexketoprofen free base is preferably in the range of 1 :1 to 1 :3.5, and more preferably in the range of 1 :1 to 1 :3 in order for the desired release features to be obtained.

As a result of the development studies they have carried out, the inventors, have determined that the usage of dexketoprofen free base together with dexketoprofen trometamol salt as the active agent in the dexketoprofen compositions was suitable to provide the release feature to create the desired treatment effect.

Accordingly 25mg dexketoprofen trometamol salt and 50mg dexketoprofen free base has been used to form 75mg of active agent in total inside the composition.

According to another aspect, by means of the subject matter of the invention, the effect and efficiency of the treatment has been increased by using dexketoprofen free base and trometamol salt together as active agents. Another benefit is that the toxic effect on the patient has been reduced by means of the increased treatment effect.

The pharmaceutical compositions which comprise dexketoprofen free base together with dexketoprofen trometamol salt according to the invention, may be prepared in any form such as tablets, effervescent tablets, effervescent granules, effervescent dry powder, film coated tablets, enteric coated tablets, dry powder, granules, capsules, prolonged release tablets, modified release tablets, delayed release tablets, orodispersible tablets, chewing tablets and bilayer (two layered) tablets. The pharmaceutical compositions according to the invention are in tablet form or bilayer (two layered) tablet form.

According to another aspect, compositions according to the invention may comprise at least one pharmaceutically acceptable excipient in addition to active agents.

The pharmaceutical compositions according to the invention comprises a disintegrant, a diluent, a glidant, a lubricant, a binder, an effervescent pair comprising at least an acidic agent, and at least a basic agent, or an excipient that is pharmaceutically acceptable selected from the group comprising a colorant, a pH adjusting agent, a surfactant, a stabilizing agent, a sweetener and/or flavor adjusting agent, an aroma agent.

The disintegrant that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidon, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.

The diluent that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrine, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or a combination thereof.

The glidant that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising calcium stearate, magnesiym stearate, polyethylene glycol, sodium benzoate, potassium benzoate, lauril sulphate, stearic acid, zinc stearate or a combination thereof.

The lubricant that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc or a combination thereof.

The binder that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hipermellose, magnesium aluminium silicate, maltodextrine, methyl cellulose povidone, starch or a combination thereof.

The acidic agent which forms the effervescent pair formed of at least an acidicagent and at least a basic agent which can be used inside the pharmaceutical compositions suitable to the invention can be selected from group comprising organic acids such as maleic acid, cytric acid, tartaric acid, fumaric acid or a combination thereof and the basic agent can be selected from the group comrising sodium carbonate, pottasium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or a combination thereof.

The pH adjusting agent that can be used inside the pharmaceutical compositions suitable for the invention can be selected from the group comprising citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts or a combination thereof.

The surfactant that can be used inside the pharmaceutical compositions suitable for the invention can be selected from the group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, poloxypropylene glycol and other similar agents.

The stabilizing agent that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising tocopherole, tetrasodium edetate, nicotinamide, cyclodextrin or a combination thereof.

The sweetener and/or flavouring agent that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising acesulfame, aspartam, dextrose, fructose, maltitol, maltose, mannitol, sacchharine, sacchharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride or a combination thereof.

The aroma agent that can be used among the pharmaceutical compositions suitable for the invention can be selected from the group comprising mentholi lemon, orange, vanilla, strawberry, raspberry, caramel or other similar aromas or a combination thereof.

In the case that the tablets compositions subject to the invention are desired to be coated to provide rapid, slow or controlled release features, the coating composition or polymers which determine release speed that may be contained in the pharmaceutical tablet composition can be selected from polymers depending on pH, polymers independent from pH, swellable polymers, non swelling polymers, hydrophillic polymers, hydrophobic polymers and/or one or more hydrophobic agents, sodium alginate, polylactide-co-glycolides, polylactic acids, polyglycholic acids, polyactic acid co glycolic acids, polyaprolacton, polycarbonates, polesteramides, polyanhydrides, polyamino acids, polyorthoesters, polyacetyls, polycyanoacrylates, polyesters, polydioxanones, polyalkylene alchilates, polyethylene glycol and polyorthoester copolymers, biologically separable polyurethanes, hydrogels and mixtures thereof and copolymers thereof, polymers that are soluble in high molecular weight water such as polyethylene oxide, carbomer, ionic polymers such as calcium carboxymethyl cellulose or carboxy methyl cellulose, non ionic polymers such as hydroxy propyl methyl cellulose; alkyl celluloses, hydroxy alkyl cellulose, cellulose ethers, nitro cellulose, dextrin, agar, karagenan, pectin, starch and starch derivatives, or natural/synthetic polysacharides such as mixtures of these, xanthan gum, hydrophilic polysacchharide polymers such as chitosan, cellulosic polymers, methacrylate polymers, methacrylate copolymers, polyvinyl pyrrolidone, polyvinyl pyrrolidone-polyvinyl acetate copolymers, polyvinyls such as polyvinyl alcohol, polyacrylic acids, alginates, gelatin, natural resins such as guar gum, ethyl cellulose, cellulose acetate, cellulose propionate (with high, medium or low molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polyvinyl acetate, polyvinyl chloride, sodium bicarbonate or a combination thereof.

Pharmaceutical compositions according to the invention, comprises dexketoprofen free base by weight in the range of 0,1 to 99% preferably 1 to 98%, most preferably 5 to 95% in ratio

Pharmaceutical compositions according to the invention, comprises dexketoprofen trometamol salt by weight in the range of 0,1 to 99%, preferably 1 to 98%, most preferably 5 to 95% in ratio.

Pharmaceutical compositions according to the invention comprises dexketoprofen free base in the range of lOmg to 1 lOmg preferably in the range of 15mg to 100 mg and most preferably in the range of 20mg to 90mg per unit dosage form.

Pharmaceutical compositions according to the invention comprises dexketoprofen trometamol salt in the range of lOmg to l lOmg preferably in the range of 15mg to 100 mg and most preferably in the range of 20mg to 90mg per unit dosage form.

According to another aspect, die present invention is a delayed release pharmaceutical composition, characterized in that it comprises, per unit dosage form;

• 50 mg dexketoprofen free base,

• 25 mg dexketoprofen trometamol salt and,

• at least a pharmaceutically acceptable excipient.

The delayed release pharmaceutical compositions according to the invention are preferably in double layered tablet form.

Said double layered tablet form, comprises dexketoprofen and at least an excipient in one of the layers and dexketoprofen trometamol and at least an excipient in the other layer.

The layers can have the same release features with each other or they can be prepared to have different release features from each other.

According to another preferred embodiment of the invention, the delayed release tablet form contains a rapid release layer comprising dexketoprofen trometamol and at least an excipient and a second delayed release layer comprising dexketoprofen and at least an excipient.

The matrix agents that can be used to provide delated release can be selected from the group comprising hydrophilic polymers such as methyl cellulose, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ehtylhydroxyethyl cellulose (E-HEC), sodium-carboxymethyl cellulose (Na-CMC) or hydrophobic polymers such as ethyl cellulose, cellulose acetate, cellulose acetate propionate, hypromellose acetate succinate or from non cellulose groups such as sodium alginate, chitosan, guar gum, pectin, poliethyleneoxide or a combination thereof.

Inside the pharmaceutical compositions comprising dexketoprofen free base and dexketoprofen trometamol salt according to the invention a third active agent can be present according to preference in addition these active agents. The third active agent can be selected from antiacids, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiaknantibacterial, antimicotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti parkison, antiprotozoal, anthelmintic, antiinflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tthiozolidindion, biguanide, immunostimulant, immunusuppresant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitorls, ACE inhibitors;; multivitamin and minerals, vitamin A, vitamin D and analogues, vitamin Bl, vitamin C, vitamin E, vitamin B6, vitamin B, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride and selenium.

The pharmaceutical compositions according to the invention can be provided in various dosage forms as mentioned above.

In the case that the dosage form is in tablet form, the obtained tablets can be coated optionally with film coating agents, such as sugar based coating agents, water soluble film coating agents, enteric coating agents, delayed release coating agents or coating compositions comprising a combination thereof.

The sugar based coating agent can be used only with sacchharose, or optionally together with agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvnylpirrolidon, and pullulan or a combination thereof.

The water soluble film coating agent can be selected from cellulose derivatives such as, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose, synthetic polymers such as polyvinyl acetate, diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinyl pirrolidon and polysaccharides such as pullulan or a combination thereof.

Enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acrylic acid derivatives such as methacrylic acid copolymer S and methacyrlic acid copolymer L, methacrylic acid copolymer LD and natural agents such as shellac or a combination thereof.

Delayed release coating agents are selected from cellulose derivatives such as ethyl cellulose, acrylic acid derivatives such as amino alkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylic copolymer emulsion or a combination thereof.

According to another aspect if the composition according to the invention is in capsule form, the capsule to be used can be made of a material selected from the group consisting of gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and from top and bottom sections that fit into each other.

The pharmaceutical composition according to the invention is used to prevent and treat fever, mild and moderate pain, headache, toothache, migrane prophylaxis and mialgia diseases.

The composition according to the invention can be produced with any of the methods of dry mixing, wet granulation or direct compression.

The example given below has been given only to further describe the pharmaceutical compositions subject to the invention and the subject matter of the invention cannot be limited with this example.

EXAMPLE: Drug composition which comprises 50 mg dexketoprofen free base and 25 mg dexketoprofen trometamol

The rapid release layer of the composition that has been produced with two layers by means of dry powder mixing comprises trometamol salt and is obtained by mixing the active agent with suitable excipients. The delayed release layer comprises dexketoprofen free base.

Rapid release layer;

Delayed release layer: