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WO2007122474A2 - Formulations à libération prolongée - Google Patents

Formulations à libération prolongée Download PDF

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Publication number
WO2007122474A2
WO2007122474A2 PCT/IB2007/001017 IB2007001017W WO2007122474A2 WO 2007122474 A2 WO2007122474 A2 WO 2007122474A2 IB 2007001017 W IB2007001017 W IB 2007001017W WO 2007122474 A2 WO2007122474 A2 WO 2007122474A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
derivatives
clarithromycin
cellulose
drug
Prior art date
Application number
PCT/IB2007/001017
Other languages
English (en)
Other versions
WO2007122474A3 (fr
Inventor
Girish Kumar Jain
Prashant Manohar Mandaogade
Vinayak Dinkar Kadam
Original Assignee
Wockhardt Ltd
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 Wockhardt Ltd filed Critical Wockhardt Ltd
Publication of WO2007122474A2 publication Critical patent/WO2007122474A2/fr
Publication of WO2007122474A3 publication Critical patent/WO2007122474A3/fr

Links

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
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to an extended release solid pharmaceutical composition of poor to moderately soluble drugs. More preferably the pharmaceutical composition relates to an oral dosage form comprising the drug added in two granule layers, one granule layer comprising of drug and at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 100-100,000 cps; another granule layer comprising of drug with at least one rate controlling hydrophilic polymer having a viscosity in the range of about 50-100,000 cps and higher. These two granule layers are finally compressed together to yield a bilayer tablet.
  • Suitable drugs for incorporation into the said extended release solid pharmaceutical composition include any human or veterinary drug that has poor to moderate solubility.
  • the invention specifically includes erythromycin and/or its salts, solvates and derivatives thereof and more particularly the pharmaceutical composition comprising clarithromycin.
  • Oral solid dosage forms are the preferred route for many drugs and are still the most widely used formulations for new and existing modified release (MR) products.
  • MR modified release
  • approaches and technologies in the area of modified release oral drug delivery have been developed to extend the release of drug over a number of hours, an effect accomplished either by combining the drug with release-retardant materials to form a matrix core, or applying release- modifying film coatings to cores containing the drug.
  • the approach to modified release oral drug delivery systems has changed from a mere line extension to a clinically superior approach for marketed drugs as well as for new chemical entities.
  • the benefits offered by modified release systems include reduced dosing frequency with improved patient compliance, better and more uniform clinical effects with lower incidence of side effects and with possible enhanced bioavailability.
  • the rational design of modified release systems where biological, physicochemical and physicomechanical considerations have been taken into account during formulation of MR dosage form, may eliminate the risk of 'dose dumping' in vivo.
  • US Patent No. 6,010,718 (Abbott Laboratories) describes formulations containing 5%-50% by weight of total polymer. It discloses formulations containing 10%-20% by weight of rate controlling polymer in the formulation in addition to other excipients.
  • the rate-controlling polymer is a hydrophilic water-soluble polymer, preferably cellulose polymers.
  • US Patent No. 5,705,190 (Abbott Laboratories) describes controlled release compositions for poorly soluble basic drugs comprising a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid to facilitate dissolution of the basic drug at a higher pH.
  • the examples disclosed herein describe formulations containing 10-20% w/w of rate controlling polymer.
  • US Patent No. 4,389,393 (Forest Laboratories, Inc.) describes sustained release therapeutic composition using less than about one third of the weight of the solid unit dosage form of a carrier base material constituted of hydroxypropyl methyl cellulose or a mixture of one or more hydroxypropyl methylcelluloses, with up to 30% by weight of certain other rate controlling polymers.
  • the invention as described discloses sustained release solid dosage forms containing as little as 5 to about 30 weight percent of hydroxypropyl methylcellulose delivered desired results.
  • US Patent No. 6,673,369 (Ranbaxy Laboratories Limited) relates to a controlled release pharmaceutical composition comprising a pharmaceutically effective amount of at least one drug having a water solubility of less than one part per 30 parts and from about 0.1 to about 4.5% w/w, of one or more of rate controlling cellulose ether polymers. It describes the formulations comprising clarithromycin tablets containing about 10 % to 90 % of the clarithromycin in the compositions.
  • the key limitation of the invention disclosed in the'369 patent is the use of high viscosity cellulosic ether polymer and these polymers have a viscosity of at least about 4,000 cps.
  • US Application 20050136107 describes an extended release clarithromycin composition comprising clarithromycin along with a polymer component in the concentration of about greater than 50 percent of total composition and the said polymer component comprises at least one hydrophilic polymer and the said polymer component has a viscosity of less than about 50 cps.
  • the examples of the said application illustrate hydroxypropylmethyl cellulose (HPMC) as the preferred hydrophilic polymer.
  • HPMC hydroxypropylmethyl cellulose
  • the viscosity of HPMC described in the examples is about 3 to about 20 cps.
  • US Application 20050064034 describes an extended release clarithromycin composition
  • clarithromycin along with at least one hydrophilic polymer having a viscosity of less than 50 cps and the second polymer having a viscosity of greater than 200 cps and wherein each polymer is independently present in an amount less than 5% or more than 50% by weight of the composition.
  • the present invention provides an extended release solid pharmaceutical composition of poor to moderately soluble drugs.
  • the said extended release solid pharmaceutical composition comprises of clarithromycin as the preferred drug, added in two granule layers, one granule layer comprising of drug and at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 100 -100,000 cps; another granule layer comprising of drag with at least one rate controlling hydrophilic polymer having a viscosity in the range of about 50-100,000 cps, These two granule layers are finally compressed together to yield a bilayer tablet.
  • the present invention therefore also provides a pharmaceutical formulation comprising at least one poorly or moderately soluble pharmaceutically active agent alongwith suitable pharmaceutical excipients, particularly, diluents, binders, lubricants and rate controlling polymers.
  • compositions adapted for oral administration of once a day dosage regimen.
  • This composition comprises of atleast one poorly or moderately soluble pharmaceutically active agent together with suitable pharmaceutically acceptable carriers or excipients thereof.
  • another aspect of the present invention is the use of combination of rate controlling polymers preferably in two layers having specific viscosity in the range of about 50-100,000 cps and higher and the second polymer with a viscosity in the range of about 100-100,000 cps.
  • the invention provides an extended release, solid pharmaceutical composition comprising at least one poorly or moderately soluble pharmaceutically active agent together with rate controlling hydrophilic polymers in combination, added in two layers.
  • the present formulation provides obvious benefits with respect to small tablets, which are easier to administer thus ensuring better patient compliance.
  • Figure 1 illustrates dissolution profile of Clarithromycin from Clarithromycin extended release tablets (Example-1) in 0.3M Phosphate Buffer of pH 6, 900 ml, Apparatus 2, 75 rpm
  • the present invention provides an extended release solid oral pharmaceutical composition suitable for poor to moderately soluble drugs.
  • These drugs can be formulated into an extended release composition by manufacturing the composition in two granule layers, one granule layer comprising of drug and at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 100-100,000 cps; another granule layer comprising of drug with at least one rate controlling hydrophilic polymer and the said polymer having a viscosity in the range of about 50-100,000 cps and higher. These two granule layers are finally compressed together to yield a bilayer tablet.
  • the said medicament according to the present invention comprises a formulation substantially as herein described, and in particular a tablet formulation, typically an extended release tablet formulation substantially as hereinafter further described.
  • a formulation according to the present invention provides an extended release tablet dosage form comprising at least one poorly water-soluble drug together with one or more hydrophilic polymers in suitable amounts within the formulation.
  • the poorly or moderately soluble drug preferably is an erythromycin derivative, most preferably clarithromycin or its salts, solvates or derivatives thereof.
  • the drugs used in accordance with the present invention may be present at a dosage range of about 50-1500 mg.
  • Clarithromycin in particular, is known to be soluble in stomach (pH 1.2) and fairly soluble in the upper region of small intestine (pH 5.0). The solubility of this drug decreases in the lower intestine where the pH is alkaline (pH 6-8), leading to poor absorption in the region.
  • a time-specific controlled release or sustained release formulation comprises of at lease one pharmaceutically active agent having pH-dependent solubility, which may be formulated so that the release of the drug being held significantly pH-independent throughout the environment of the gastro-intestinal tract.
  • a time-specific controlled release or sustained release formulation comprises a pharmaceutically active agents (poorly soluble) alongwith suitable excipients, i.e. one or more hydrophilic polymers, hi particular, the present invention provides extended release tablet formulations comprising an extended release source of at least one poorly soluble active agent.
  • a preferred active for use in tablet according to the present invention is clarithromycin.
  • clarithromycin after oral administration can be released in a sustained manner independent of pH. It has been seen that tablets according to the present invention produce relatively uniform blood levels of clarithromycin over extended periods of therapy, suitably with oral administration at intervals of about 12-18 hours. An extended release is thus achieved by formulation substantially as hereinbefore described.
  • a tablet according to the present invention comprises a combination of materials, including one or more suitable diluents, polymers, binders and lubricants.
  • the above materials are combined with poorly soluble active, such as clarithromycin in the following proportions, to achieve the beneficial steady or extended or sustained release characteristics of the present invention:
  • Binders, lubricants, colorants in specific amounts, manufactured in two layers and compressed as bilayer tablet may include any suitable pharmaceutically acceptable diluents, disintegrants, lubricants and suitable polymers.
  • Pharmaceutically acceptable diluents employed in a pharmaceutical formulation according to the present invention may be, microcrystalline cellulose, powdered cellulose, lactose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, mannitol, kaolin, sucrose derivatives and starch.
  • a preffered diluent employed in pharmaceutical formulation according to the present invention comprises lactose and derivatives thereof.
  • a tablet formulation according to the present invention may include one or more hydrophillic pharmaceutically acceptable polymers, which provide additional support to the composition against any disruptive effect and controls the release of clarithromycin.
  • the pharmaceutically acceptable polymers in addition to their influence in controlling drug release, also provide mechanical support to the solid composition and help to maintain the physical integrity of the composition. The artisan may further select appropriate polymers, which provide the desired effect.
  • Various polymers as appropriate for such formulations include, water soluble or water swellable polymers like polyvinylpyrrolidone, cellulose ethers, vinyl acetate copolymers, polyvinyl alcohol, polysaccharides and carbohydrate gums like xanthan gum, cross-linked polyethylene oxide, maleic anhydride / methyl vinyl ether copolymers and derivatives, solvates and mixtures thereof.
  • the most desired polymers for use according to the present invention include cellulose acetate, cellulose acetate phthalates, methacrylic acids, vinyl ether / maleic anhydride copolymers, polyvinyl acetate phthalates and shellac.
  • the most preferred polymer is hydroxypropyl methylcellulose and derivatives thereof.
  • the present invention further comprises of other pharmaceutically acceptable excipients.
  • suitable excipients for the present invention include talc, polyvinyl pyrrolidone, lactose, silicon dioxide (Aerosil ® ) and the like.
  • a tablet formulation according to the present invention may also include pharmaceutically acceptable lubricants and glidants. The artisan can select appropriate lubricants and glidants to prevent picking and sticking of the tablets to the compression tooling.
  • Suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, calcium silicate, magnesium silicate and colloidal silicone dioxide.
  • the most preferred pharmaceutical lubricant and glidant is magnesium stearate and talc.
  • the present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical formulation, or a medicament substantially as hereinbefore described.
  • Such a process comprises providing at least one poorly soluble drug.
  • This drug may be formulated into an extended release composition by manufacturing the composition in two granule layers, one granule layer comprising of drug and at least one rate controlling hydrophilic polymer in the concentration of preferably about 0.1-20 % by weight of total composition and the said polymer having a viscosity in the range of about 100-100,000 cps; another granule layer comprising of drug with at least one rate controlling hydrophilic polymer in the concentration of preferably about 40-60% by weight of total composition and the said polymer having a viscosity in the range of about 50-150 cps along with other pharmaceutical excipients as hereinbefore described.
  • These two granule layers are finally compressed together to yield a bilayer tablet.
  • Extended release tablets were prepared using the following materials in the stated quantities:
  • Extended release tablets were prepared using the following materials in the stated quantities:
  • step 6 Granulate the blend of step 5 using binder solution in suitable granulator and dry the granules
  • Extended release tablets were prepared using the following materials in the stated quantities:
  • step 6 Granulate the blend of step 5 using binder solution in suitable granulator and dry the granules

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique solide à libération prolongée de médicaments à solubilité faible ou modérée. La composition pharmaceutique est plus préférablement une forme posologique orale comprenant le médicament ajouté dans deux couches granulaires, une couche granulaire comprenant le médicament et au moins un polymère hydrophile régulant la vitesse de libération, ayant de préférence une viscosité comprise entre environ 100 et 100 000 cps; une autre couche granulaire comprenant le médicament et un agent régulant la vitesse de libération présentant une viscosité d'environ 100 cps. Ces deux couches granulaires sont en dernier lieu comprimées ensemble pour former un comprimé bicouche. Cette invention comprend spécifiquement de l'érythromycine et/ou des sels, des solvates et des dérivés de cette dernière et plus particulièrement, la composition pharmaceutique comprend de la clarithromycine.
PCT/IB2007/001017 2006-04-20 2007-04-20 Formulations à libération prolongée WO2007122474A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN623MU2006 2006-04-20
IN623/MUM/2006 2006-04-20

Publications (2)

Publication Number Publication Date
WO2007122474A2 true WO2007122474A2 (fr) 2007-11-01
WO2007122474A3 WO2007122474A3 (fr) 2009-04-16

Family

ID=38625365

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/001017 WO2007122474A2 (fr) 2006-04-20 2007-04-20 Formulations à libération prolongée

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WO (1) WO2007122474A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7943585B2 (en) * 2003-12-22 2011-05-17 Sandoz, Inc. Extended release antibiotic composition

Also Published As

Publication number Publication date
WO2007122474A3 (fr) 2009-04-16

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