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WO2008114276A1 - Nouvelle composition orale de carvédilol à libération contrôlée - Google Patents

Nouvelle composition orale de carvédilol à libération contrôlée Download PDF

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Publication number
WO2008114276A1
WO2008114276A1 PCT/IN2008/000148 IN2008000148W WO2008114276A1 WO 2008114276 A1 WO2008114276 A1 WO 2008114276A1 IN 2008000148 W IN2008000148 W IN 2008000148W WO 2008114276 A1 WO2008114276 A1 WO 2008114276A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
controlled release
carvedilol
pharmaceutical composition
oil
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2008/000148
Other languages
English (en)
Inventor
Ashish Sharadchandra Guha
Bharat Raghunath Metkar
Makrand Krishnakumar Avachat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lupin Ltd
Original Assignee
Lupin 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 Lupin Ltd filed Critical Lupin Ltd
Publication of WO2008114276A1 publication Critical patent/WO2008114276A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the present invention relates to a novel oral controlled release composition
  • a novel oral controlled release composition comprising therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt thereof, one or more controlled release agent(s) and other pharmaceutically acceptable excipients.
  • U.S. Pat. No. 4,503,067 describes a compound, which is known as carvedilol.
  • This compound is a novel multiple action drug useful in the treatment of mild to moderate hypertension.
  • Carvedilol is known to be both a competitive non-selective ⁇ -adrenoceptor antagonist and a vasodilator.
  • the vasodilatory actions of carvedilol result primarily from (X 1 - adrenoceptor blockade, whereas the ⁇ -adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension.
  • These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug.
  • carvedilol as a consequence of its antioxidant action in attenuating oxygen free radical-initiated lipid peroxidation, is useful in organ protection, in particular, cardioprotection. Additionally, carvedilol is useful in the treatment of congestive heart failure.
  • a controlled release profile from a drug dosage form is desirable in clinical use to reduce side effects and improve patient compliance.
  • the technology used to formulate sustained release dosage forms is well documented.
  • the entrapment of a drug in a polymer based matrix is a common approach to formulate sustained release tablets with a desirable release profiles.
  • depot drug formulations for controlled release of pharmaceutical drugs may be prepared using alginates alone (see U.S. Pat. No. 5,132,295), using combinations of alginates and polyacrylates (see U.S. Pat. No. 5,230,901) and using combinations of alginates and a pH independent gelling agent, such as, for example, hydroxypropyl methylcellulose (see U.S. Pat. No. 4,792,452). It is also known that the use of alginates alone for this purpose often presents difficulties in tableting, film coating and storage.
  • a sustained release dosage form useful in providing once-a-day medication consists of the admixture of hydroxypropyl methylcellulose (viscosity of 80 to 120 cps in a 2% aqueous solution) and ethylcelluose with etodolac (see U.S. Pat. No. 4,966,768).
  • Matrix drug delivery system has been described in U. S. Patent No. 6,150,410.
  • This patent discloses extended release pharmaceutical compositions of acidic pharmacological agents that have reduced dependence of the release rate upon pH and gastric residence time.
  • the extended release compositions comprise a combination of water-swellable, hydrophilic polymer and acid soluble polymer, which is swellable above pH 5. These compositions provide an enhanced rate of release of the acidic pharmacological agent in the stomach where the pH of the gastric juices is low and diminished release rate at neutral or slightly alkaline pH of the intestines.
  • U. S. Patent Nos. 5,695,781 and 6,083,532 disclose a three component, release rate controlling matrix composition that includes a pH dependent gelling polymer such as an alginate component, an enteric polymer and a pH independent gelling polymer.
  • U. S. Patent No. 6,251,430 describes the use of ethyl cellulose or Eudragit RS or RL in combination with hydroxypropyl methylcellulose and sodium alginate to provide for a controlled release of the drug.
  • an object of the invention is to provide novel controlled release pharmaceutical compositions for oral administration comprising carvedilol SUMMARY OF THE INVENTION
  • a novel oral controlled release composition comprising a therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt thereof, one or more controlled release agent(s) selected from pH independent polymers, water insoluble substances and combinations thereof, and other pharmaceutically acceptable excipients.
  • the present invention provides a novel oral controlled release composition
  • a novel oral controlled release composition comprising a therapeutically effective amount of carvedilol or a pharmaceutically acceptable salt thereof, one or more controlling release agent(s) selected from the group comprising pH independent polymers or water insoluble substances or combinations thereof, and other pharmaceutically acceptable excipients.
  • Carvedilol or pharmaceutically acceptable salts thereof can be used in the present invention, the preferred salt being carvedilol phosphate.
  • Carvedilol or a pharmaceutically acceptable salt thereof used in the present invention may be in crystalline or amorphous or anhydrous or hydrate form thereof. These forms include but not limited to carvedilol phosphate hemihydrate (Form I) or Form A or Form B or anhydrous form or amorphous form.
  • controlled release it is meant as any formulation that achieves slow release of drug over an extended period of time. It is taken to encompass sustained release, prolonged release, timed release, retarded release and extended release.
  • An example of a controlled release system is a matrix formulation.
  • the formulations of the present invention allow for once-a- day dosing containing 10, 20, 40, or 80 mg carvedilol phosphate.
  • the novel oral controlled release formulation comprises matrix controlled release agents that retards the rate of release of drug from the dosage form which include pH independent polymers or water insoluble substances or combinations thereof.
  • pH independent polymers includes but not limited to acrylic or methacrylic polymers or co-polymers of acrylate or methacrylate monomers for example polymethacrylates marketed under the brand names of Eudragit®. These polymers include Eudragit® RS, Eudragit® RL, Eudragit® L 5 Eudragit® E, Eudragit® S, Eudragit® RD, particularly Eudragit® NE 30 D, Eudragit® NE 40 D and the like.
  • Eudragit® NE 30 D is an aqueous dispersion of a neutral co-polymer consisting of polymethacrylic acid esters. These dispersions are milky-white liquids of low viscosity and have a weak aromatic odor. Films prepared from the lacquer swell in water, to which they become permeable. Thus, films produced are insoluble in water, but give pH independent drug release.
  • pH independent polymers include a mixture of polyvinyl acetate and polyvinylpyrrolidone. This is commercially available as Kollidone® SR by BASF Aktiengesellschaft. Kollidone® SR is a spray formulated, free flowing, non-hygroscopic powder consisting of 8 parts (w/w) polyvinyl acetate and 2 parts (w/w) polyvinylpyrrolidone. Kollidone® SR has excellent flow and compression properties. Matrix formulation using Kollidone® SR show only slight swelling behaviour and the drug release was according to Higuchi's law showing a quicker release at the beginning and slower at the end, which is characteristic for an inert matrix with pores. Povidone and the active are dissolved creating pores through which further active can diffuse.
  • compositions used in the oral controlled release formulations of carvedilol include those known to a person ordinarily skilled in the art such as diluents, binders, and lubricants.
  • Diluents may include but not limited to lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol, cellulose and the like.
  • Binders may include but not limited to starches, alginates, gums, celluloses, vinyl polymers, sugars and the like.
  • Lubricants may include but not limited to stearates such as magnesium stearate, talc, colloidal silicon dioxide and the like.
  • Oral controlled release compositions of carvedilol or a pharmaceutically acceptable salt thereof of the present invention may be prepared by processes like direct compression, wet granulation and dry granulation methods.
  • the active, controlled release agent(s) together with other diluents and lubricants are blended and are either directly compressed into tablets or mini tablets or filled directly into capsules.
  • the active, controlled release agent(s) together with other diluents and lubricants may be dry granulated or granulated with water or controlled release agent and are either directly compressed into tablets or mini tablets or filled directly into pharmaceutically acceptable hard gelatin capsules.
  • the size of the mini tablet varies from 1-4 mm in diameter.
  • mini tablets are further filled into pharmaceutically acceptable hard gelatin capsules using techniques well known to those ordinarily skilled in the art.
  • One or more mini tablets are loaded into a single hard gelatin capsule to provide a unit dose.
  • Most preferably the mini tablets provide additive amount of carvedilol without modifying the release profile. For example, by making a mini tablet containing 2.5 mg of carvedilol, capsules containing 10, 20, 40 or 80 mg of carvedilol can be formed by standard filing of capsule with 4, 8, 16 and 32 mini tablets respectively.
  • Carvedilol phosphate is blended with diluent, lactose or dibasic calcium phosphate and granulated with controlled release agent, Eudragit NE 40 D or Hydrogenated Vegetable Oil or granulated by dissolving Kollidone SR in purified water.
  • the granules are dried and lubricated with magnesium stearate and compressed into mini tablets. These mini tablets are then filled into pharmaceutically acceptable hard gelatin capsules.

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

Abstract

La présente invention concerne une composition pharmaceutique orale à libération contrôlée qui comprend une quantité thérapeutiquement efficace de carvédilol ou d'un sel pharmaceutiquement acceptable de ce dernier, un ou plusieurs agents de libération contrôlée sélectionnés parmi des polymères indépendants du pH, des substances insolubles dans l'eau et des combinaisons de ces derniers ainsi qu'au moins un excipient pharmaceutiquement acceptable. Un procédé de préparation d'une composition orale à libération contrôlée de carvédilol ou d'un sel pharmaceutiquement acceptable de ce dernier consiste à mélanger une quantité thérapeutiquement efficace de l'ingrédient actif avec au moins un autre excipient pharmaceutiquement acceptable et à former des granulés avec un agent de libération contrôlée comprenant des polymères indépendants du pH ou des substances insolubles dans l'eau ou des combinaisons de ces derniers ou bien consiste à dissoudre le ou les agents de libération contrôlée dans de l'eau purifiée et à comprimer le mélange sous forme de comprimés ou de mini-comprimés.
PCT/IN2008/000148 2007-03-16 2008-03-14 Nouvelle composition orale de carvédilol à libération contrôlée Ceased WO2008114276A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN501MU2007 2007-03-16
IN501/MUM/2007 2007-03-16

Publications (1)

Publication Number Publication Date
WO2008114276A1 true WO2008114276A1 (fr) 2008-09-25

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000148 Ceased WO2008114276A1 (fr) 2007-03-16 2008-03-14 Nouvelle composition orale de carvédilol à libération contrôlée

Country Status (1)

Country Link
WO (1) WO2008114276A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011154012A1 (fr) * 2010-06-10 2011-12-15 Lifecycle Pharma A/S Mini-comprimés comprenant un matériau adsorbant poreux
US9056054B2 (en) 2009-06-25 2015-06-16 Elite Laboratories, Inc. Abuse resistant oral dosage forms

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032174A2 (fr) * 1998-11-27 2000-06-08 F. Hoffmann-La Roche Ag Specialite pharmaceutique combinee
WO2002065834A2 (fr) * 2000-10-24 2002-08-29 Smithkline Beecham Corporation Nouvelles formulations de carvedilol
WO2002092078A1 (fr) * 2001-05-17 2002-11-21 Sun Pharamceutical Industries Limited Composition pharmaceutique a liberation controlee administree par voie orale pour therapie a dose quotidienne unique en traitement et prevention de troubles cardiaques et circulatoires
WO2004016249A1 (fr) * 2002-08-14 2004-02-26 Ranbaxy Laboratories Limited Comprimes matriciels a liberation prolongee
WO2005051322A2 (fr) * 2003-11-25 2005-06-09 Sb Pharmco Puerto Rico Inc. Base libre de carvedilol, ses sels, formes anhydres ou solvates, compositions pharmaceutiques correspondantes, formulations a liberation controlee, et procedes de traitement ou d'administration
US20060182804A1 (en) * 2003-11-25 2006-08-17 Burke Matthew D Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods
WO2008070072A2 (fr) * 2006-12-01 2008-06-12 Mutual Pharmaceutical Company, Inc. Formes, compositions de carvédilol, et leurs procédés de préparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032174A2 (fr) * 1998-11-27 2000-06-08 F. Hoffmann-La Roche Ag Specialite pharmaceutique combinee
WO2002065834A2 (fr) * 2000-10-24 2002-08-29 Smithkline Beecham Corporation Nouvelles formulations de carvedilol
WO2002092078A1 (fr) * 2001-05-17 2002-11-21 Sun Pharamceutical Industries Limited Composition pharmaceutique a liberation controlee administree par voie orale pour therapie a dose quotidienne unique en traitement et prevention de troubles cardiaques et circulatoires
WO2004016249A1 (fr) * 2002-08-14 2004-02-26 Ranbaxy Laboratories Limited Comprimes matriciels a liberation prolongee
WO2005051322A2 (fr) * 2003-11-25 2005-06-09 Sb Pharmco Puerto Rico Inc. Base libre de carvedilol, ses sels, formes anhydres ou solvates, compositions pharmaceutiques correspondantes, formulations a liberation controlee, et procedes de traitement ou d'administration
US20060182804A1 (en) * 2003-11-25 2006-08-17 Burke Matthew D Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods
WO2008070072A2 (fr) * 2006-12-01 2008-06-12 Mutual Pharmaceutical Company, Inc. Formes, compositions de carvédilol, et leurs procédés de préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI Y-H ET AL: "Modulation of combined-release behaviors from a novel ''tablets-in-capsule system''", JOURNAL OF CONTROLLED RELEASE, ELSEVIER, AMSTERDAM, NL, vol. 95, no. 3, 24 March 2004 (2004-03-24), pages 381 - 389, XP004496378, ISSN: 0168-3659 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9056054B2 (en) 2009-06-25 2015-06-16 Elite Laboratories, Inc. Abuse resistant oral dosage forms
US10213388B2 (en) 2009-06-25 2019-02-26 Elite Laboratories, Inc. Abuse resistant oral dosage forms
WO2011154012A1 (fr) * 2010-06-10 2011-12-15 Lifecycle Pharma A/S Mini-comprimés comprenant un matériau adsorbant poreux

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