WO2005060942A1 - Composition pharmaceutique de metformine a liberation prolongee - Google Patents

Composition pharmaceutique de metformine a liberation prolongee Download PDF

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Publication number
WO2005060942A1
WO2005060942A1 PCT/IB2004/004330 IB2004004330W WO2005060942A1 WO 2005060942 A1 WO2005060942 A1 WO 2005060942A1 IB 2004004330 W IB2004004330 W IB 2004004330W WO 2005060942 A1 WO2005060942 A1 WO 2005060942A1
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WO
WIPO (PCT)
Prior art keywords
dosage form
extended release
cellulose
carbonate
metformin
Prior art date
Application number
PCT/IB2004/004330
Other languages
English (en)
Inventor
Ashish Gogia
Shaik Srinivasa Rao
Saravanan Kannu Samy
Sivakumaran Meenakshisunderam
Original Assignee
Aurobindo Pharma 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 Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of WO2005060942A1 publication Critical patent/WO2005060942A1/fr

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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
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to an extended release dosage form for highly water soluble antidiabetic drug metformin or its pharmaceutically acceptable salts.
  • This invention also relates to methods for preparing the concerned extended release dosage form for metformin or its pharmaceutically acceptable salts systems.
  • Metformin hydrochloride is an oral antidiabetic and is a biguanide derivative (1,1-dimethylbiguanide monohydrochloride).
  • Metformin tablets containing metformin hydrochloride are marketed under the trade name Glucophage and Glucohpage XR (extended release).
  • Metformin hydrochloride has intrinsically poor permeability in the lower portion of the gastrointestinal tract leading to absorption almost exclusively in the upper part of the gastrointestinal tract. Its oral bioavailability is in the range of 40 to 60% decreasing with increasing dosage, which suggests some kind of saturable absorption process, or permeability/transit time limited absorption. It also has a very high water solubility (>300 mg/ml at 25 °C), this can lead to difficulty in providing a slow release rate from a formulation and problems in controlling the initial burst of drug from such a formulation. These two difficulties are further compounded by the high unit dose usually required for metformin hydrochloride.
  • a further problem with highly water-soluble drugs to be formulated into a controlled release dosage form is that a significant and variable burst of the drag can occur from these systems.
  • the burst of a highly water-soluble drug is the initial rapid release of drug that occurs from oral controlled release dosage forms when first contacting fluid, such as gastric fluids, prior to release controlling mechanisms of the dosage form establishing themselves and a stable release rate being provided. Hydration of any polymer matrix used to formulate the dosage form is a prerequirement of establishing a stable release rate. Thus, a readily hydrating polymer is required to establish the desired stable release rate. However, if the polymer used is slow to hydrate, then an undesirable variable burst can occur.
  • Matrix systems may be formulated by homogeneously mixing drug with hydrophilic polymers, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene oxide, carbomer, certain methacrylic acid derived polymers, sodium alginate, or mixtures thereof and compressing the resultant mixture into tablets.
  • hydrophilic polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene oxide, carbomer, certain methacrylic acid derived polymers, sodium alginate, or mixtures thereof and compressing the resultant mixture into tablets.
  • Hydrophobic polymers such as ethyl cellulose, certain polymeric methacrylic acid esters, cellulose acetate butyrate, poly(ethylene-co-vinyl- acetate) may be uniformly incorporated with the above materials to give additional control of release.
  • a further alternative involves embedding drug within a wax-based tablet, by granulation or simply mixing of drug with a wax, such as carnauba wax, microcrystalline wax or commercially available purified fatty acid esters.
  • a wax such as carnauba wax, microcrystalline wax or commercially available purified fatty acid esters.
  • US patent 6,340,475 discloses a controlled release oral dosage form for metformin, where the said dosage form comprises a solid polymeric matrix with metformin dispersed therein.
  • US patent 6,033,685 discloses a tablet for the controlled release of an active agent comprising (a) a matrix layer comprising an active agent embedded in a non-swelling, non-erodible hydrophobic matrix; (b) a first barrier layer applied to a single face of the matrix layer; and (c) an optional second barrier layer laminated to the opposite face of the matrix layer; wherein the matrix layer comprises up to about 80% active agent and from about 5% to about 80% by weight of nonswellable waxes or polymeric material insoluble in aqueous medium, and the first and second barrier layers independently comprise (1) polymeric material exhibiting a high degree of swelling and gelling in aqueous medium or (2) nonswellable wax or polymeric material insoluble in aqueous medium.
  • US 6,475,521 and 6,660,300 discloses a pharmaceutical formulation comprising (1) an inner solid particulate phase, and (2) an outer solid continuous phase in which particles of the inner solid particulate phase are dispersed and embedded, the particles of the inner solid particulate phase comprising (a) a pharmaceutical having a high water solubility selected from metformin or a pharmaceutically acceptable salt thereof; and (b) an extended release material, and the outer solid continuous phase comprising an extended release material, wherein the total extended release material content in both the inner solid particulate phase and the outer solid continuous phase is within the range from about 25 to about 75% by weight of the pharmaceutical formulation.
  • US 6,524,618 describes an extended-release matrix formulation capable of being directly compressed into tablets comprising (a) about 30 to about 60% of metformin hydrochloride having a particle size of about 150 to about 600 microns, (b) one or more pharmaceutically acceptable polymers selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose (c) about 5 to about 40% of a pharmaceutically acceptable insoluble filler; (d) about 0.1 to about 3% by weight a glidant; and (e) about 0.1 to about 3% by weight a acceptable lubricant.
  • US 2004/0161461 and US 20030170302 describes an extended release pharmaceutical tablet comprising: (i) a core comprising by weight, based on the core weight, about 70% to about 99% metformin and pharmaceutically acceptable excipients; and (ii) a coating surrounding said core, wherein said coating is permeable to metformin, said extended release tablet exhibiting a dissolution profile such that after about 2 hours, from about 7% to about 60% of the metformin is released; after about 4 hours, from about 15% to about 90%) of the metformin is released; after about 8 hours, from about 50% to about 100% of the metformin is released; after about 12 hours, more than about 75% of the metformin is released.
  • US 2003/0187074 describes an oral delivery system for the treatment of non-insulin dependent diabetes mellitus in humans for the controlled release of a biguanide or pharmaceutically acceptable salt thereof, comprising: a pharmaceutically effective amount of a biguanide or pharmaceutically acceptable salt of the biguanide; and a water-insoluble polymeric carrier comprising a water-insoluble polymer; wherein the delivery system provides a pH-independent, controlled release of the biguanide or pharmaceutically acceptable salt of the biguanide over an extended period of time.
  • US Patent 5,955,106 discloses a composition comprising metformin as the active substance and a hydrocolloid forming retarding agent, wherein the pharmaceutical composition has a residual moisture content of about 0.5-3% by weight.
  • US patent 6,576,259 discloses a sustained release formulation for tacrolimus or its hydrate in a solid base, where the solid base is selected from a group consisting of water-soluble polymer and a wax.
  • WO 03/011255 discloses a gastric retention controlled drag delivery system comprising : (a) a controlled release core comprising a drag, a highly swellable polymer and a gas generating compound, said core being capable of swelling and achieving floatation rapidly while maintaining its physical integrity in gastrointestinal fluids for prolonged periods, and (b) a rapidly releasing coat composition comprising the same drag as in the core and pharmaceutically acceptable excipients, wherein the coating composition surrounds the core such that the system provides a biphasic release of the drag in gastrointestinal fluids.
  • This publication discloses a biphasic extended release dosage form comprising core and coating the core and provides for immediate release and extended release of the drug, which makes the process costlier and complex.
  • these systems avoided the overdose and the under dose effects.
  • These improvements provided effective medication with reduced side effects, and achieved these results with reduced dosing frequency.
  • Most extended-release forms are designed so that the administration of a single dosage unit provides the immediate release of an amount of drag that promptly produces the desired therapeutic effect and also a gradual and continual release of additional amounts of drug to maintain this level of effect over an extended period of time to overcome frequent or multiple dosing.
  • the design is based on the particular qualities of each individual drug.
  • Floating or buoyant systems are designed to have a low density and thus float on gastric contents after administration until the system either disintegrates (and presumably the resultant particles empty from the stomach) or the device absorbs fluid to the point where its density is such that it loses buoyancy and can pass more easily from the stomach with a wave of motility responsible for gastric emptying.
  • Objective of the invention The object of the present invention is to prepare monophasic extended release pharmaceutical dosage forms of poorly compressible drag, metformin which will have adequate hardness and good reproducibility that releases the drug in a controlled manner over an extended period of time. Yet another objective of the present invention is to provide monophasic extended release dosage form, which is uncoated, simple and economic.
  • the present invention provides an extended release monophasic dosage form of metformin or its pharmaceutically acceptable salts comprising a matrix of polymer and carbonate and one or more pharmaceutically acceptable excipients.
  • the present invention also relates to a process for the preparation of an extended released dosage form of metformin using a matrix of polymer and carbonate which comprises preparing a matrix of polymer and carbonate and mixing metformin or its pharmaceutically acceptable salt, with the matrix and optionally with fillers, disintegrants in rapid mixer granulator and granulating the resulting blend with solution of binder in aqueous or non aqueous solvent, drying the granules, lubricating the dried granules with lubricants compressing the lubricated blend to form extended release tablets.
  • the floating system predominantly depends upon the principle of buoyancy and thus contains one or more of the gas/effervescence generating components like the carbonates, bicarbonates or the acids in the composition.
  • the floating based dosage forms reaches the stomach, water permeates into these dosage forms and triggers the rele ⁇ - ⁇ ⁇ ⁇ — ⁇ * ⁇ — * ⁇ ⁇ e — +1 generating components.
  • the gas generation starts the floating based dosage forms will start experiencing less bulk density than the gastric fluids and so remains buoyant in the stomach for a prolonged period of time. While the system is floating on the gastric contents the drag is released slowly at the desired rate from the system.
  • the extended release dosage forms of the present invention are monophasic and uncoated which releases the drug for prolong period of time.
  • the extended release dosage forms of the present invention comprises drug and a matrix of polymer and carbonate in the ratio of 1 : 0.1 to 1 : 1.2.
  • the extended release dosage forms of the present invention comprises drag and carbonate in the ratio of 1 : 0.01 to 1 : 0.3.
  • the extended release dosage form of the present invention further comprises wax material.
  • the term pharmaceutically acceptable excipients as used in this invention comprise binders, dispersing agents, fillers, lubricants or glidants and the like.
  • the disintegrating agent used in accordance with the present invention is selected from crosscarmellose sodium, crosspovidone, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, xanthan gum, alginic acid, alginates, carbopols and the like or combination thereof.
  • the diluents used according to the present invention are selected from calcium phosphate-dibasic, cellulose-microcrystalline, cellulose powdered, calcium silicate, polyols such as mannitol, sorbitol, xylitol, maltitol, sucrose and combinations thereof.
  • Suitable binders according to the present invention are selected from methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate.
  • Suitable lubricants according to the present invention are selected from talc, magnesium stearate, stearic acid, zinc state, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and suitable glidants include colloidal silicon dioxide or talc, preferably colloidal silicon dioxide.
  • Suitable polymers according to present invention are selected from hydrophilic polymers such as polyvinylpyrrolidone; alginate or its salts; cellulose polymer such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, methylcellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose and the like; polyethylene oxide, carbopol, pectin, cyclodextrins, galactomannan, polyethylene glycol (PEG) and hydrophobic polymers such as ethyl cellulose, methacrylate copolymers (for example, Eudragits such as Eudragit E, R, S, RS, LD, etc.) or amino methacrylate copolymers and combination thereof.
  • hydrophilic polymers such as polyvinylpyrrolidone; alginate or its salts
  • cellulose polymer such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl
  • carbonate in the present invention is playing a pivotal role in controlling the release of metformin hydrochloride to the optimum level by imparting a degree of hydrophobic nature to the dosage form.
  • carbon dioxide liberates from the carbonates on interaction with the gastro intestinal fluids, thereby providing the buoyant nature to the dosage form by reducing the apparent specific gravity of the dosage form, thus resulting in the prolonged gastric retention of the dosage form.
  • the different carbonates that can be used for the carbonate-polymer matrix can be selected from-calcium carbonate, sodium carbonate, magnesium carbonate, barium carbonate and zinc carbonate.
  • Suitable waxes according to the present invention are selected from the following groups without limitations on the usage of other group waxes- glycerin monostearate and sucrose fatty acid esters [for example, mono-, di- or triesters of sucrose with moderate to higher fatty acids, with 8 to 20 carbon atoms, for example caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, oleic acid, linoleic acid, and the like).
  • Additional examples of wax include polyglycerin fatty acid ester; glyceryl behenate, hydrogenated vegetable oil and the like.
  • the present invention provides a simple, non-complex and more economic process for the preparation of an extended release dosage form, which comprises the steps of : i) sifting metformin hydrochloride, polymers and carbonate and other optionally fillers, disintegrants, ii) mixing the sifted material of step (i) in a rapid mixer granulator, iii) granulating the blend of step (ii) with a binder in a solvent, iv) drying the wet mass of step (iii) in a fluid bed drier, v) milling the dried granules using multimill, vi) optionally mixing the dried granules with disintegrants and filler vii) lubricating the blend of step (vi) with lubricants and vi) compressing the lubricated blend of step (vii) to get extended release tablets of metformin.
  • step (i) sifted metformin hydrochloride, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium alginate, ammonio methacrylate copolymer, microcrystalline cellulose, calcium carbonate ii) the sifted material of step (i) are mixed well in rapid mixer granulator iii) the blend of step (ii) was granulated with a solution of polyvinyl pyrrolidone in isopropyl alcohol iv) the wet mass of step (iii) was dried in a fluid bed drier, v) the dried granules are milled using multimill vi) the dried granules are mixed with crosscarmellose sodium, polyethylene oxide and sodium bicarbonate in an octagonal blender, vii) the blend obtained in step (vi) was lubricated with magnesium stearate and vi) the lubricated blend of step (vii) is compressed into metformin hydrochloride extended release tablets. Dissolution data
  • n is the number of dissolution time points
  • R t and T t are the reference and test dissolution values (mean of at least 12 dosage units) at time t.
  • step (i) sifted metformin hydrochloride, hydroxypropylmethyl cellulose, carbomer 941, polyethylene oxide, calcium carbonate, microcrystalline cellulose
  • step (ii) the sifted material of step (i) are mixed well in rapid mixer granulator iii) the blend of step (ii) was granulated with a solution of povidone and copovidone in isopropyl alcohol
  • step (iii) was dried in a fluid bed drier
  • the dried granules are milled using multimill and lubricated with magnesium stearate and vi) the lubricated blend of step (v) is compressed into metformin hydrochloride extended release tablets.

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Engineering & Computer Science (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

La présente invention concerne une forme posologique à libération prolongée du médicament antidiabétique à solubilité élevée dans l'eau, la metformine, ou de ses sels pharmaceutiquement acceptables. L'invention concerne également des procédés de préparation de cette forme posologique à libération prolongée de metformine ou de ses systèmes de sels pharmaceutiquement acceptables.
PCT/IB2004/004330 2003-12-19 2004-12-20 Composition pharmaceutique de metformine a liberation prolongee WO2005060942A1 (fr)

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IN1038CH2003 2003-12-19
IN1038/CHE/2003 2003-12-19

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WO2006038226A2 (fr) * 2004-10-08 2006-04-13 Rubicon Research Pvt. Ltd. Compositions de metformine fortement compressibles a liberation controlee
EP1755568A1 (fr) * 2004-04-01 2007-02-28 Hanmi Pharm. Co., Ltd. Formulation a liberation lente pour l'administration orale de metformine
WO2007048223A2 (fr) * 2005-10-25 2007-05-03 Pharmascience Inc. Systeme d'administration de medicaments a retention gastrique
EP1959923A2 (fr) * 2005-08-30 2008-08-27 Nicholas Piramal India Limited Composition pharmaceutique de metformine a liberation lente et procede de production correspondant
US20080220060A1 (en) * 2005-07-19 2008-09-11 Ethypharm Gastroretentive Formulations and Manufacturing Process Thereof
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US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
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US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
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US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
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GB2599950A (en) * 2020-10-16 2022-04-20 Zentiva Ks Pharmaceutical compositions with low amounts of nitrosamine impurities and methods for producing the same
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US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
EP1755568A4 (fr) * 2004-04-01 2010-03-03 Hanmi Pharm Ind Co Ltd Formulation a liberation lente pour l'administration orale de metformine
EP1755568A1 (fr) * 2004-04-01 2007-02-28 Hanmi Pharm. Co., Ltd. Formulation a liberation lente pour l'administration orale de metformine
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
WO2006038226A2 (fr) * 2004-10-08 2006-04-13 Rubicon Research Pvt. Ltd. Compositions de metformine fortement compressibles a liberation controlee
WO2006038226A3 (fr) * 2004-10-08 2006-06-22 Rubicon Res Pvt Ltd Compositions de metformine fortement compressibles a liberation controlee
US10675278B2 (en) 2005-02-04 2020-06-09 Grünenthal GmbH Crush resistant delayed-release dosage forms
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US20080220060A1 (en) * 2005-07-19 2008-09-11 Ethypharm Gastroretentive Formulations and Manufacturing Process Thereof
US9629800B2 (en) * 2005-07-19 2017-04-25 Ethypharm Gastroretentive formulations and manufacturing process thereof
EP1959923A2 (fr) * 2005-08-30 2008-08-27 Nicholas Piramal India Limited Composition pharmaceutique de metformine a liberation lente et procede de production correspondant
AU2006290352B2 (en) * 2005-08-30 2012-06-07 Abbott Healthcare Private Limited Extended release pharmaceutical composition of metformin and a process for producing it
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