WO2013109224A1 - Compositions pharmaceutiques contenant du diclofénac - Google Patents

Compositions pharmaceutiques contenant du diclofénac Download PDF

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Publication number
WO2013109224A1
WO2013109224A1 PCT/TR2013/000037 TR2013000037W WO2013109224A1 WO 2013109224 A1 WO2013109224 A1 WO 2013109224A1 TR 2013000037 W TR2013000037 W TR 2013000037W WO 2013109224 A1 WO2013109224 A1 WO 2013109224A1
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WO
WIPO (PCT)
Prior art keywords
formulation
effervescent
diclofenac
agents
comprised
Prior art date
Application number
PCT/TR2013/000037
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English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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 Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013109224A1 publication Critical patent/WO2013109224A1/fr

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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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil

Definitions

  • the present invention relates to analgesic, anti-inflammatory and antipyretic pharmaceutical formulations comprising diclofenac that shall be used in the treatment of diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • Said formulations are characterized by being in effervescent form.
  • Diclofenac was first disclosed in the application numbered US3558690. In said document, it has been indicated that diclofenac has analgesic, anti-inflammatory and antipyretic impact and it is effective in the treatment of diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • Diclofenac is available in the forms of 25 mg and 50 mg dragee; 75 mg/3ml ampoule; 1%, 2% and 3% gel; 100 mg capsule; 0.1% eye drop; 50 mg and 100 mg suppository; 75 mg and 100 mg sustained release tablet; 25 mg, 50 mg and 100 mg enteric-coated tablet and 100 mg retard tablet on the market.
  • these dosage forms comprised in the prior art are disadvantageous for pediatric and geriatric patients and people who have swallowing difficulties. In addition, they are not preferred by most patients.
  • suspension forms are not mostly preferred due to the reasons that they carry the possibility of uncontrolled dose intake, their production costs are high, they have physical and chemical instability problems, they pose problems during use and carrying phases.
  • suspension forms have higher bioavailability values as compared to solid dosage forms, it is seen that they are more inconvenient than solid dosage forms when evaluated in terms of stability and shelf-life.
  • the pharmaceutical compositions comprising diclofenac have been prepared in tablet and suspension forms.
  • use of tablet dosage form cause problems for those who have swallowing difficulties such as children, elderly and disabled people or for those who do not want to swallow tablets or capsules.
  • Solution dosage forms are not preferred since they complicate compliance of the patients with the treatment as they carry the possibility of uncontrolled dose intake, have bad taste and are not user-friendly and since they have shorter shelf life than solid dosage forms due to their low stability.
  • the inventors have surprisingly found that the problems in the prior art can be solved by the effervescent formulations prepared according to the subject of the present invention.
  • the present invention relates to analgesic, anti-inflammatory and antipyretic pharmaceutical formulations comprising diclofenac and characterized by being in effervescent form that shall be used in the treatment of the diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • the formulations of the present invention are characterized in that they are in the form of effervescent powder, tablet and granule which have the advantages of both tablet and suspension forms together and they remove the problems encountered in said dosage forms. Effervescent dosage forms are useful especially for patients who have swallowing difficulties.
  • the pharmaceutical formulations of the present invention comprise effervescent oral dosage forms comprising at least one pharmaceutically acceptable excipient in addition to diclofenac and effervescent couple or comprising only diclofenac and effervescent couple.
  • the present invention relates to effervescent oral dosage forms comprising diclofenac as the active agent, effervescent couple and at least one pharmaceutically acceptable excipient.
  • Diclofenac comprised in the formulations of the present invention is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in amorphous form or crystalline form or a combination thereof in terms of polymorphic structure.
  • the amount of diclofenac comprised in the formulations is in the range of 1% to 90% by weight, preferably in the range of 1% to 85% by weight, more preferably in the range of 1% to 80% by weight.
  • Another characteristic feature of the effervescent formulations of the present invention is that the formulations are in effervescent powder, tablet and granule forms.
  • the characteristic feature of the effervescent formulations of the present invention is that they are in effervescent powder, tablet and granule forms and the amount of diclofenac comprised in the formulations is in the range of 1% to 90% by weight, preferably in the range of 1% to 85% by weight, more preferably in the range of 1% to 80% by weight.
  • the effervescent formulations of the present invention are used as dissolved in a glass of water or in another suitable liquid. At this point, it is clear that water solubility of the formulation is a very important parameter in order to provide an effective treatment and therefore bioavailability.
  • the inventors have found that the highest solubility in the effervescent formulations comprising diclofenac is obtained with the formulations wherein the average particle size of diclofenac is less than 50 ⁇ in the effervescent formulations comprising diclofenac as the active agent.
  • one characteristic feature of the effervescent formulations of the present invention is that the formulations comprise diclofenac having an average particle size less than 50 ⁇ as the active agent.
  • another characteristic feature of the effervescent formulations of the present invention is to comprise diclofenac having an average particle size in the range of 1 ⁇ to 50 ⁇ as the active agent.
  • another characteristic feature of the effervescent formulations of the present invention is to comprise diclofenac having an average particle size in the range of 1 ⁇ to 45 ⁇ as the active agent.
  • effervescent formulations of the present invention comprising diclofenac is that - they are in effervescent powder, tablet and granule forms
  • the amount of diclofenac comprised in said formulations is in the range of 1% to 90% by weight, preferably in the range of 1% to 85% by weight, more preferably in the range of 1% to 80% by weight and - the average particle size of diclofenac comprised in the formulations is less than 50 ⁇ , preferably in the range of 1 ⁇ to 50 ⁇ and more preferably in the range of 1 ⁇ to 45 ⁇ .
  • average particle size refers to average particle size by volume and is also shown with d 50 in short.
  • d 50 signifies that one half of the said substance by volume has a particle size over the value stated with d 50 and the other half of the substance by volume has a particle size below the value stated with d 50.
  • D 50 value can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
  • a device which measures particle distribution by laser diffraction for instance, Malvern Mastersizer etc.
  • Another characteristic feature of the effervescent formulations of the present invention is that the formulations comprise at least one pharmaceutically acceptable excipient along with diclofenac and effervescent couple.
  • excipients that can be comprised in the effervescent formulations of the present invention can be selected from a group comprising binders, disintegrants, viscosity enhancing compounds, filling agents, drying agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, oiling agents, pH regulators, effervescent acids, effervescent bases, gelling agents, flavouring agent, sweeteners, taste regulating agents, emulsifying agents, antifoaming agents, antioxidants, preservative agents, solvent or solvent mixtures, colouring agents and complexing agents or combinations thereof.
  • the disintegrant that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
  • the diluent that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
  • the oiling agent that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
  • the binder that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
  • effervescent acids that can be used in the effervescent formulations of the present invention comprising diclofenac are selected from a group comprising organic acids such as citric acid and acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid or pharmaceutically acceptable hydrates, anhydrates and similar forms or combinations thereof.
  • the effervescent bases that can be comprised in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising alkaline or alkaline earth metal carbonates or bicarbonates or combinations thereof.
  • the effervescent formulations of the present invention comprising diclofenac comprise an effervescent couple composed of at least one pharmaceutically acceptable effervescent acid and effervescent base in the range of 10% to 95%, preferably in the range of 15% to 95%, more preferably in the range of 20% to 95% in proportion to total weight of formulation.
  • the term "effervescent couple” refers to mixture of at least one effervescent acid and at least one effervescent base. Both or either of these agents can be in combination form of different types in the mixture of effervescent couple. For instance, an effervescent couple comprising two different effervescent acids and one effervescent base or two different effervescent acids and two different effervescent bases can be used.
  • the ratio of at least one pharmaceutically acceptable effervescent acid to the effervescent base comprised in the effervescent formulations of the present invention comprising diclofenac is in the range of 0.1 to 10 by weight.
  • the pH regulating agent that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from citrate, phosphate, carbonate tartrate, fumarate, acetate and amino acid salts.
  • the surfactant that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from the agents comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and so forth.
  • the stabilizing agents that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
  • the sweetener and/or taste regulating agent that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
  • the flavouring agent that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from flavours comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and so forth.
  • the lubricants that can be used in the effervescent formulations of the present invention comprising diclofenac can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.
  • excipients that can be used in the effervescent formulations of the present invention comprising diclofenac are preferably selected from a group comprising binders, disintegrants, filling agents, surfactants, stabilizing agents, oiling agents, lubricants, diluents, glidants, effervescent acids, effervescent bases, flavouring agents, sweeteners, solvent or solvent mixtures or combinations thereof.
  • the effervescent formulations of the present invention comprising diclofenac can optionally comprise a second active agent in addition to diclofenac.
  • the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosup
  • the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to diclofenac can be prepared in any dosage forms such as effervescent tablet, effervescent granule, effervescent dry powder; in the case that the two active agents are comprised in different formulations but in the same dosage form, the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to diclofenac can be prepared in the dosage forms such as layered tablet, capsule; in the case that the two active agents are comprised in different formulations and in different dosage forms, the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to diclofenac can be prepared in a treatment package form wherein diclofenac is in any dosage forms of effervescent tablet, effervescent granule, effervescent dry powder; the second active agent, on the other hand, is in any solid
  • any production method in the prior art can be used to formulate the formulations of the present invention; wet granulation, dry granulation and dry blending methods can be listed among these production methods.
  • formulations of the present invention can be produced according to any production methods given below;
  • formulations of the present invention can be any formulations of the present invention.
  • the effervescent formulations of the present invention are preferably in tablet form.
  • compressing the formulations produced according to any abovementioned methods in the prior art in tablet form under a tablet compression force in the range of 3 kN to 50 kN, preferably in the range of 4 kN to 45 kN, more preferably in the range of 4 kN to 40 kN cause a positive improvement in solubility of the end product.
  • the characteristic feature of the effervescent formulations of the present invention comprising diclofenac is that the said formulations are in effervescent form and tablet compression force implemented during compressing said formulations into tablet form is in the range of 3 kN to 50 kN, preferably in the range of 4 kN to 45 kN, more preferably in the range of 4 kN to 40 kN.
  • the pharmaceutical formulations of the present invention have analgesic, anti-inflammatory and antipyretic effects and they can be used in the treatment of diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • diseases such as mild, moderate and severe pain, arthralgia, fever, toothache, dysmenorrhea, toothache, myalgia, osteoarthritis, rheumatoid arthritis, backache.
  • effervescent formulation given above is produced according to any methods in the prior art explained in detail in the description; and the formulation is presented for use in the desired dosage form.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des formulations pharmaceutiques analgésiques, anti-inflammatoires et antipyrétiques comprenant du diclofénac, utilisables dans le traitement de maladies telles que la douleur légère, modérée ou intense, l'arthralgie, la fièvre, l'odontalgie, la dysménorrhée, la myalgie, l'arthrose, la polyarthrite rhumatoïde, la dorso-lombalgie. Ces formulations se caractérisent en ce qu'elles se présentent sous une forme effervescente.
PCT/TR2013/000037 2012-01-18 2013-01-18 Compositions pharmaceutiques contenant du diclofénac WO2013109224A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201200602 2012-01-18
TR2012/00602 2012-01-18

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WO2013109224A1 true WO2013109224A1 (fr) 2013-07-25

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3558690A (en) 1965-04-08 1971-01-26 Gelgy Chemical Corp Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation
GB2217598A (en) * 1988-03-25 1989-11-01 Ciba Geigy Effervescent tablet containing diclofenac
US5211957A (en) * 1988-03-25 1993-05-18 Ciba-Geigy Corporation Solid rapidly disintegrating dosage form
DE4403943A1 (de) * 1994-02-08 1995-08-10 Hexal Pharma Gmbh Orale Azrneimittelzubereitung mit Diclofenac-Natrium
US20040258740A1 (en) * 2003-04-10 2004-12-23 Nene Labs Transdermal delivery composition
WO2005063199A1 (fr) * 2003-12-19 2005-07-14 Bayer Healthcare Ag Preparation effervescente d'une substance basique a action pharmaceutique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3558690A (en) 1965-04-08 1971-01-26 Gelgy Chemical Corp Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation
GB2217598A (en) * 1988-03-25 1989-11-01 Ciba Geigy Effervescent tablet containing diclofenac
US5211957A (en) * 1988-03-25 1993-05-18 Ciba-Geigy Corporation Solid rapidly disintegrating dosage form
DE4403943A1 (de) * 1994-02-08 1995-08-10 Hexal Pharma Gmbh Orale Azrneimittelzubereitung mit Diclofenac-Natrium
US20040258740A1 (en) * 2003-04-10 2004-12-23 Nene Labs Transdermal delivery composition
WO2005063199A1 (fr) * 2003-12-19 2005-07-14 Bayer Healthcare Ag Preparation effervescente d'une substance basique a action pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOWEN P: "Particle Size Distribution Measurement from Millimeters to Nanometers and from Rods to Platelets", JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY, TAYLOR AND FRANCIS GROUP, NEW YORK, NY, US, vol. 23, no. 5, 1 January 2002 (2002-01-01), pages 631 - 662, XP009102859, ISSN: 0193-2691, DOI: 10.1081/DIS-120015368 *

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