WO2004069234A1 - Compositions pharmaceutiques et procede de production - Google Patents

Compositions pharmaceutiques et procede de production Download PDF

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Publication number
WO2004069234A1
WO2004069234A1 PCT/IN2003/000312 IN0300312W WO2004069234A1 WO 2004069234 A1 WO2004069234 A1 WO 2004069234A1 IN 0300312 W IN0300312 W IN 0300312W WO 2004069234 A1 WO2004069234 A1 WO 2004069234A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
metoprolol
composition according
cellulose
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2003/000312
Other languages
English (en)
Inventor
Ramachandran Thembalath
Yatish Kumar Bansal
Subhrangshu Sengupta
Nivedita Singh
Original Assignee
Ipca Laboratories Limited
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 Ipca Laboratories Limited filed Critical Ipca Laboratories Limited
Priority to EP03773988A priority Critical patent/EP1589957A1/fr
Priority to AU2003282375A priority patent/AU2003282375A1/en
Priority to NO20042890A priority patent/NO20042890L/no
Publication of WO2004069234A1 publication Critical patent/WO2004069234A1/fr

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to the field of medicine and pharmacology. More specifically, the invention relates to an extended release oral dosage pharmaceutical composition comprising metoprolol or a pharmaceutically acceptable succinate salt thereof provided with an extended release polymer base retardant coating, and to a process for its production.
  • Metoprolol succinate is a beta-selective (cardioselective) adrenoreceptor blocking agent, for oral administration, available as extended release tablets to treat the heart condition angina.
  • the drug reduces the oxygen demand to the heart, slowing the heart rate, reducing cardiac output when at rest and on exercise and reduces systolic blood pressure among other things.
  • metoprolol formulations already known, which usually comprise controlled release pellets, wherein each pellet acts as a separate drug delivery unit. But in order to obtain a desirable release of a drug, a considerable amount of experimentation needs to be performed. So, in accordance with the present investigation, an extended release pharmaceutical formulation has been devised which releases the drug for up to 24 hours in a suitably controlled manner.
  • U.S. Patent 4792452 to Howard et al. describes a controlled release pharmaceutical formulation which releases the drug at a controlled rate regardless of the pH of the environment. Its formulation includes up to about 45% by weight of a pH dependent polymer, which is a salt of alginic acid in addition to a pH independent hydrocarbon gelling agent, such as hydroxypropylmethyl cellulose.
  • EP 0293347 to Henry A.C. and Christina E.E. describes metoprolol succinate as a new therapeutically active compound, and pharmaceutical preparations comprising it.
  • This invention discusses a new oral, therapeutically active compound, which is soluble in the pH range 1 to 8, which therefore can be released in the gastrointestinal tract below the upper part of the small intestine.
  • the sustained release excipient is prepared by dry blending the requisite amounts of xanthan gum, dextrose and calcium sulfate.
  • U.S. Patent 4871549 to Yoshio U. et al describes a time controlled explosion system comprising metoprolol, a swelling agent such as a low substituted hydroxypropylcellulose, sodium starch glycolate or carboxymethylcellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period.
  • a swelling agent such as a low substituted hydroxypropylcellulose, sodium starch glycolate or carboxymethylcellulose sodium
  • U.S. Patent 4927640 to Dahlinder L-ED et al also describes controlled release beads having a glass or silicon dioxide core. Metoprolol succinate was sprayed onto the cores of silicon dioxide, glass and sodium chloride from a solution of ethanol 95% and methylene chloride. Then the coated beads were filled into hard gelatin capsules.
  • U.S. Patent 5081154 to Henry A.C. and Christina E.E. which is a continuation of EP 0293346 also relates to metoprolol succinate wherein an oral pharmaceutical composition comprising a core containing a therapeutically active compound is disclosed.
  • the core has been coated with a layer comprising an anionic polymer and a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers.
  • the investigators suggest that in order to achieve a steady blood plasma level of the therapeutically active compound, a split dose unit of the therapeutically active compound provided with a coating according to the present invention can be administered together with some particles/granules which are not coated.
  • U.S. Patent 5399358 to Stanoforth George N and Baichwal Anand R is directed to sustained release formulations which provide a 24 hour release of metoprolol using a combination of xanthan gum with locust bean gum as the preferred gum combination.
  • EP Application 110542 by McCall Troy W and Baichwal Anand R describes once-a- day oral dosage form of metoprolol to be released over a period of 24 hours in the gastrointestinal tract.
  • the sustained release matrix comprises heterosaccharide derivatives of xanthan gum.
  • a number of patents in the prior art deal with sustained or controlled release formulations of metoprolol. These include water insoluble glass, silicon dioxide or plastic resin beads, which are sprayed with metoprolol salt and then coated with controlled release polymeric membrane.
  • Another sustained release excipient commonly used is a heteropolysaccharide e.g., xanthan gum or a gum combination of xanthan and locust bean gum for delaying the drug release.
  • xanthan gum or a gum combination of xanthan and locust bean gum for delaying the drug release.
  • a pharmaceutical composition comprising a matrix material having metoprolol, or a pharmaceutically acceptable salt thereof, dispersed therein, the dispersion of the metoprolol or pharmaceutically acceptable salt thereof within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition, the tablet being provided with a substantially water-insoluble polymeric coating effective further to delay the release profile on administration of the pharmaceutical composition.
  • pharmaceutically acceptable salt is a succinate.
  • the matrix material may be capable of forming a swelling gel when in contact with water and may comprise a cellulosic polymer and a carbomer.
  • the cellulosic polymer is preferably hydroxypropyl methyl cellulose.
  • the polymeric coating may comprises cellulose derivatives without protolysable groups, for example ethyl cellulose.
  • the metoprolol, or pharmaceutically acceptable salt thereof is preferably provided in the form of a granulated active ingredient. It may be present in an amount of from 12.5mg to 200mg in the composition, for example in an amount of 12.5mg, 25mg, 50mg, lOOmg or 200mg in the composition.
  • the pharmaceutical composition according to the invention may further comprise a binder, for example a povidone.
  • the hardness of the tablet may vary from 35 Nortons to 160 Nortons for tablets of different strengths.
  • One preferred pharmaceutical composition according to the invention comprises: metoprolol succinate 27 to 30% microcrystalline cellulose 17 to 30% carbomer 1 to 6% hydroxypropyl methyl cellulose 14 to 56%
  • the weight ratio of metoprolol, or pharmaceutically active salt thereof, to carbomer is in the range of 10: 1 to 1 : 12.
  • Also provided in accordance with the invention is a process for the production of a pharmaceutical composition according to the invention, comprising blending metoprolol, or a pharmaceutically acceptable salt thereof, with a matrix material, granulating the blended mixture and compressing to form a tablet, and spray coating the tablet with a polymeric coating.
  • At least one carbomer is preferably introduced into the composition during the blending and granulation steps.
  • the tablet is prepared by a wet granulation process, preferably a non-aqueous process, for example a process using a hydroalcoholic wetting material
  • the invention provides a process for preparing a pharmaceutical composition
  • a process for preparing a pharmaceutical composition comprising: a) introduction of metoprolol succinate, carbomer and hydroxy polymethyl cellulose by blending, milling and sieving prior to granulation b) introduction of a solution of polymer in non-aqueous / hydroalcoholic solvent during granulation of the blended material as in (a) c) spray coating of the compressed tablets as in (c), with a water-insoluble polymeric membrane containing derivatives of cellulose without protolyasable groups d) thereby incorporating the tablet and the coating into a matrix forming a swelling gel in contact with water.
  • a process for producing pharmaceutically extended-release preparations of metoprolol succinate is provided.
  • the object of this invention is to obtain a solid preparation with high bioavailability of the drug in combination with an extended absorption in the gastrointestinal tract thus achieving an even effect of up to 24 hours after one (or twice in case of a lower dosage such as 12.5mg) daily administration.
  • the present invention further provides a process for producing oral solid extended release pharmaceutical formulations, which releases metoprolol succinate over a time period of up to 24 hours.
  • the carbomer is included in an amount from about 4.54% to about 11.5%, by weight of the final product.
  • the drug to carbomer ratio may be, from about 10:1 to about 1:12 for example.
  • the drug to carbomer ratio is from about 10:1.25 to about 1:12 by weight of formulation.
  • the preparation of the said tablet is by compression and mixing of polymers.
  • the carbomers are used in both granulation as well as mixing stages.
  • extended release it is meant for purposes of the present invention that the therapeutically active medicament is released from the formulation at an extended rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 24 hour dosage form.
  • the term "environment" is meant for purposes of the present invention to encompass a mammalian body, an organ of such a body or area of such a body, for example, the gastro-intestinal area. Such an environment can be tested by means of in-vitro dissolution testing, as is standard practice for testing of therapeutically active substances prior to use in mammalian bodies.
  • the preparation may be manufactured into a commercially acceptable form, e.g. a tablet that shows unexpectedly good bioavailability of both active compounds as well as a prolonged duration of action.
  • the active ingredient, MCC, carbopol and HPMC were blended together, and then the blend milled through a screen with appropriately size mesh.
  • the blended material was then granulated with a solution of polymer in non-aqueous/ hydroalcoholic solvent.
  • the granules were then dried at a suitable temperature and screened through a mesh of appropriate size.
  • the blend was lubricated with a soluble or insoluble lubricant.
  • the tablets were then formed by compression.
  • composition of the tablets containing lOOmg metoprolol succinate without carbomer had the following composition:
  • the coating solution to be applied to the tablets had the following composition:
  • Titanium dioxide 3.8 %
  • Tablets containing 12.5mg, 25 mg, 50 mg, and 200 mg were similarly prepared.
  • a retarding coating solution with the following composition was used to further coat the tablets from Examples 1 and 3.
  • Opadry OY-C-7000A (M/S coloreon) 4.5 % Ethyl cellulose 1.0 % Iso propyl alcohol qs Methylene chloride qs
  • Dissolution tests were then carried out for the tablets produced in Examples 1-4.
  • the dissolution tests were conducted in an automated USP dissolution apparatus (Paddle type II, pH 6.8 buffer, 50 rpm). The results are given in Table 5 & 6.
  • Beta-blockers in chronic heart failure considerations for selecting an agent. Mayo Clin Proc 2002 Nov;77(l 1):1199-206.
  • Metoprolol CR XL in female patients with heart failure analysis of the experience in

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention se rapporte à une nouvelle formulation posologique orale solide à libération prolongée de succinate de métoprolol qui comprend un enrobage d'un retardateur à base polymère à libération prolongée, et à un procédé de production de cette dernière. Selon l'invention, les comprimés de succinate de métoprolol contenant des dosages de 12,5 à 200 mg sont préparés selon un procédé de granulation par voie humide afin d'obtenir une formulation permettant de libérer du métoprolol pendant une période allant jusqu'à 24 heures.
PCT/IN2003/000312 2003-02-05 2003-09-17 Compositions pharmaceutiques et procede de production WO2004069234A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP03773988A EP1589957A1 (fr) 2003-02-05 2003-09-17 Compositions pharmaceutiques et procede de production
AU2003282375A AU2003282375A1 (en) 2003-02-05 2003-09-17 Pharmaceutical compositions and process of production thereof
NO20042890A NO20042890L (no) 2003-02-05 2004-07-07 Farmasoytiske preparater og fremgangsmate for fremstilling derav

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN151/MUM/2003 2003-02-05
IN151MU2003 2003-02-05

Publications (1)

Publication Number Publication Date
WO2004069234A1 true WO2004069234A1 (fr) 2004-08-19

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ID=32843822

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Application Number Title Priority Date Filing Date
PCT/IN2003/000312 WO2004069234A1 (fr) 2003-02-05 2003-09-17 Compositions pharmaceutiques et procede de production

Country Status (4)

Country Link
EP (1) EP1589957A1 (fr)
AU (1) AU2003282375A1 (fr)
NO (1) NO20042890L (fr)
WO (1) WO2004069234A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007048233A1 (fr) * 2005-10-24 2007-05-03 Orbus Pharma Inc. Compositions pharmaceutiques stabilisées et à libération retardée qui comprennent un antagoniste de bêta-adrénorécepteur
WO2007142546A2 (fr) * 2006-06-02 2007-12-13 Zaklady Farmaceutyczne Polpharma S.A. Comprimé enrobé à libération prolongée ayant un profil de libération précisement régulé
EP2255791A1 (fr) * 2009-04-03 2010-12-01 Farmaprojects, S.A. Composition pharmaceutique à libération prolongée comprenant du succinate de métoprolol
CN102085195A (zh) * 2011-01-10 2011-06-08 中国药科大学 琥珀酸美托洛尔缓释片及其制备方法
EP2361616A1 (fr) 2009-12-25 2011-08-31 Dexcel Pharma Technologies Ltd. Compositions à libération étendue pour ingrédients pharmaceutiques actifs à haute solubilité et haute perméabilité
CN102008456B (zh) * 2009-09-04 2015-01-14 鲁南制药集团股份有限公司 含有美托洛尔琥珀酸盐的新型骨架缓释片
WO2016138908A1 (fr) 2015-03-03 2016-09-09 Saniona A/S Formulation à base de combinaison de tésofensine et de bêta-bloquant
WO2018204317A1 (fr) * 2017-05-02 2018-11-08 Lubrizol Advanced Materials, Inc. Compositions de médicament hautement chargées à libération prolongée améliorées
WO2020144146A1 (fr) 2019-01-07 2020-07-16 Saniona A/S Tesofensine pour la réduction du poids corporel chez des patients prader-willi
WO2021214233A1 (fr) 2020-04-22 2021-10-28 Saniona A/S Traitement de l'obésité hypothalamique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0148811A1 (fr) * 1984-01-10 1985-07-17 Lejus Medical Aktiebolag Composition pharmaceutique
EP0210540A1 (fr) * 1985-07-19 1987-02-04 Fujisawa Pharmaceutical Co., Ltd. Systèmes d'explosion à retardement et procédé pour leur préparation
EP0237345A2 (fr) * 1986-03-12 1987-09-16 Washington University Technology Associates, Inc. Méthode et appareil de granulation et produit granulé
WO2002058677A1 (fr) * 2001-01-24 2002-08-01 Astrazeneca Ab Nouveau pelliculage

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0148811A1 (fr) * 1984-01-10 1985-07-17 Lejus Medical Aktiebolag Composition pharmaceutique
EP0293347A1 (fr) * 1984-01-10 1988-11-30 Aktiebolaget Hässle Succinate de métoprolol et composition pharmaceutique le contenant
EP0210540A1 (fr) * 1985-07-19 1987-02-04 Fujisawa Pharmaceutical Co., Ltd. Systèmes d'explosion à retardement et procédé pour leur préparation
EP0237345A2 (fr) * 1986-03-12 1987-09-16 Washington University Technology Associates, Inc. Méthode et appareil de granulation et produit granulé
WO2002058677A1 (fr) * 2001-01-24 2002-08-01 Astrazeneca Ab Nouveau pelliculage

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007048233A1 (fr) * 2005-10-24 2007-05-03 Orbus Pharma Inc. Compositions pharmaceutiques stabilisées et à libération retardée qui comprennent un antagoniste de bêta-adrénorécepteur
WO2007142546A2 (fr) * 2006-06-02 2007-12-13 Zaklady Farmaceutyczne Polpharma S.A. Comprimé enrobé à libération prolongée ayant un profil de libération précisement régulé
WO2007142546A3 (fr) * 2006-06-02 2008-02-21 Zaklady Farm Polpharma Sa Comprimé enrobé à libération prolongée ayant un profil de libération précisement régulé
EP2255791A1 (fr) * 2009-04-03 2010-12-01 Farmaprojects, S.A. Composition pharmaceutique à libération prolongée comprenant du succinate de métoprolol
CN102008456B (zh) * 2009-09-04 2015-01-14 鲁南制药集团股份有限公司 含有美托洛尔琥珀酸盐的新型骨架缓释片
EP2361616A1 (fr) 2009-12-25 2011-08-31 Dexcel Pharma Technologies Ltd. Compositions à libération étendue pour ingrédients pharmaceutiques actifs à haute solubilité et haute perméabilité
CN102085195A (zh) * 2011-01-10 2011-06-08 中国药科大学 琥珀酸美托洛尔缓释片及其制备方法
US9579288B2 (en) 2015-03-03 2017-02-28 Saniona A/S Tesofensine and beta blocker combination formulations
WO2016138908A1 (fr) 2015-03-03 2016-09-09 Saniona A/S Formulation à base de combinaison de tésofensine et de bêta-bloquant
US10231951B2 (en) 2015-03-03 2019-03-19 Saniona A/S Tesofensine, beta blocker combination formulation
US10537551B2 (en) 2015-03-03 2020-01-21 Saniona A/S Tesofensine and beta blocker combination formulations
US10828278B2 (en) 2015-03-03 2020-11-10 Saniona A/S Tesofensine and beta blocker combination formulations
US11426383B2 (en) 2015-03-03 2022-08-30 Saniona A/S Tesofensine and beta blocker combination formulations
WO2018204317A1 (fr) * 2017-05-02 2018-11-08 Lubrizol Advanced Materials, Inc. Compositions de médicament hautement chargées à libération prolongée améliorées
CN110709068A (zh) * 2017-05-02 2020-01-17 路博润先进材料公司 改进的缓释高负荷药物组合物
CN110709068B (zh) * 2017-05-02 2022-11-08 路博润先进材料公司 改进的缓释高负荷药物组合物
WO2020144146A1 (fr) 2019-01-07 2020-07-16 Saniona A/S Tesofensine pour la réduction du poids corporel chez des patients prader-willi
WO2021214233A1 (fr) 2020-04-22 2021-10-28 Saniona A/S Traitement de l'obésité hypothalamique

Also Published As

Publication number Publication date
NO20042890L (no) 2004-07-07
AU2003282375A1 (en) 2004-08-30
EP1589957A1 (fr) 2005-11-02

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