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WO2005092293A1 - Formulations de metformine - Google Patents

Formulations de metformine Download PDF

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Publication number
WO2005092293A1
WO2005092293A1 PCT/IB2005/000750 IB2005000750W WO2005092293A1 WO 2005092293 A1 WO2005092293 A1 WO 2005092293A1 IB 2005000750 W IB2005000750 W IB 2005000750W WO 2005092293 A1 WO2005092293 A1 WO 2005092293A1
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WO
WIPO (PCT)
Prior art keywords
metformin
tablet
polymers
mixtures
blend
Prior art date
Application number
PCT/IB2005/000750
Other languages
English (en)
Inventor
Manish Chawla
Rajeev Singh Raghuvanshi
Ashok Rampal
Original Assignee
Ranbaxy 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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2005092293A1 publication Critical patent/WO2005092293A1/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
    • A61K9/20—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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to extended release unit dosage formulations of metformin or its pharmaceutically acceptable salt thereof, processes for their preparation, and methods of lowering insulin resistance or treating non-insulin dependent diabetes mellitus.
  • Extended release pharmaceutical dosage forms have received much attention in recent years and are highly desirable for providing a constant level of pharmaceutical agent to a patient.
  • the properties and dose of the drug, desired release profile and physiological factors dictate the nature of the delivery system.
  • Extended release dosage forms not only increase patient compliance due to reduction in frequency of dosing, but they also reduce the severity and frequency of side- effects, as they maintain substantially constant blood levels and avoid fluctuations associated with the conventional immediate release formulations.
  • Metformin has been widely prescribed for lowering blood glucose in patients with non-insulin dependent diabetes mellitus (NIDDM).
  • metformin requires twice-a-day (bid) or three times-a-day (tid) dosing.
  • a clear advantage of an extended release dosage form would be a reduction in the frequency of administration.
  • Adverse events associated with metformin use are often gastrointestinal, e.g., anorexia, nausea, vomiting and occasionally diarrhea, etc. Such adverse effects may be partially avoided by reducing the initial and/or maintenance dose or using an extended release dosage form.
  • Metformin has intrinsically poor permeability in the lower portion of the gastrointestinal tract leading to absorption from the upper part of the tract. Metformin has a very high solubility in water (>300 mg/mL at 25 °C).
  • the rate of dissolution of such high solubility drugs may be reduced by embedding the drug in a polymeric matrix or surrounding it with a polymeric barrier membrane through which the drug must diffuse to be released for absorption.
  • the approaches may be beneficial for low dose drugs as large amounts of polymers are required, but not for those drugs that are administered in high daily doses (> 1000 mg/day).
  • Metformin hydrochloride is commercially available under the brand name GLUCOPHAGE (conventional) and GLUCOPHAGE XR (extended release tablets) .
  • GLUCOPHAGE conventional tablets contain 500 mg, 850 mg and 1000 mg of metformin hydrochloride.
  • Extended release metformin hydrochloride tablets have been described as comprising a dual hydropliilic matrix system.
  • a method for preparing a biphasic controlled-release delivery system adapted for delivery of metformin has been previously disclosed, in which a two phase system includes an inner solid particulate phase containing the drug and an extended release material and an outer solid continuous phase containing extended release material.
  • the drug is released from the particles of the inner phase upon contact with the release medium, migrates through the outer solid continuous phase and then released into the upper regions of the gastrointestinal tract.
  • Metformin is a highly water soluble drug exhibiting poor flow and compressibility.
  • controlled-release metformin tablets comprising: (a) metformin and (b) one or more hydrophilic polymers, wherein the one or more hydrophilic polymers comprise one or more anionic polymers and one or more nonionic polymers in a ratio of about 1:5 to about 1:50.
  • the controlled-release metformin tablets can include one or more of the following embodiments.
  • the one or more anionic polymers can be one or more homopolymers or copolymers of polyacrylic acid or polyacrylic acid derivatives, starch derivatives, cellulose derivatives and gums.
  • the one or more anionic polymers can be sodium carboxymethylcellulose.
  • the one or more nonionic polymer can be hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or a mixture thereof.
  • the one or more nonionic polymer can be hydroxypropyl methylcellulose having an average molecular weight of from about 180,000 to about 250,000, a degree of methoxy substitution of from about 19 % to about 24 % and a degree of hydroxypropyl molar substitution of from about 4 % to about 12 %.
  • the tablet can further comprise one or more excipients selected from one or more diluents, binders, lubricants, glidants or mixtures thereof, other embodiments, the diluents can be selected from one or more of lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose, mannitol or mixtures thereof; the binders can be selected from one or more of starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl celluloses, dextrin, carbohydrate gums, alginates, polyacrylic acid, polyvinylalcohol or mixtures thereof; the lubricants can be selected from one or more of talc, Group IA or Group IIA stearates, sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, glyceryl behenate, polyethylene
  • the tablet further comprises one or more sulfonylureas, insulin, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, fibrates, statins, squalene synthesis inhibitors, angiotensin-converting enzyme inhibitors or mixtures thereof.
  • the processes can include one or more of the following embodiments.
  • the metformin can be moisture conditioned prior to blending with one or more hydrophilic polymers and optionally one or more other pharmaceutically acceptable excipients to form a blend.
  • the blend can be moisture conditioned prior to compacting or slugging.
  • the methods can include one or more of the following embodiments.
  • the method further comprises concurrently or sequentially administering one or more sulfonylureas, insulin, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, fibrates, statins, squalene synthesis inhibitors, angiotensin-converting enzyme inhibitors or mixtures thereof.
  • the controlled-release tablet further comprises one or more sulfonylureas, insulin, alpha- glucosidase inhibitors, meglitinides, thiazolidinediones, fibrates, statins, squalene synthesis inhibitors, angiotensin-converting enzyme inhibitors or mixtures thereof.
  • controlled-release tablets of metformin which maintain therapeutic blood level concentrations of the medicament in a patient for sufficiently long time.
  • Such tablets can be formulated as monolithic matrices that slowly release active agents over a prolonged period of time.
  • controlled-release metformin tablets are formulated as monolithic matrices comprising metformin, one or more hydrophilic polymers, wherein the hydrophilic polymers comprise anionic and non-ionic polymers in ratios of about 1 :5 to about 1 :50.
  • the controlled-release metformin tablets can also comprise one or more other pharmaceutically acceptable excipients
  • controlled-release metformin tablets comprise a high dose of metformin and are of acceptable size, making it convenient for oral administration.
  • the controlled-release metformin tablets comprise a monolithic system capable of delivering highly soluble metformin over extended periods of time and is easy to manufacture.
  • monolithic controlled-release tablets comprising not less than 500 mg metformin, wherein the total weight of the tablet does not exceed 1500 mg.
  • processes for preparing controlled- release tablets of metformin or non-toxic acid addition salts thereof comprise the steps of: dry blending metformin with hydrophilic polymers selected from one or more anionic polymers and one or more nonionic polymers in a ratio 1 :5 to 1 :50, and optionally other excipients to form a blend; granulating the blend to form granules; drying, sizing, and lubricating the granules; and compressing the granules into monolithic matrices.
  • processes for preparing controlled- release tablets of metformin or non-toxic acid addition salts thereof comprise the steps of: blending the desired ingredients followed by roller compaction or slugging to form compacts or slugs.
  • the compacts or slugs are suitably sized, lubricated and compressed into tablets.
  • metformin may be moisture conditioned before blending with hydrophilic polymers and other excipients to further improve flow properties.
  • metformin may be blended with the hydrophilic polymers and/or other excipients and then moisture-conditioned.
  • processes for preparing controlled-release metformin tablets comprising the steps of: a. moisture conditioning metformin, b. blending the moisture conditioned metformin with one or more hydrophilic ( polymers and optionally one or more other pharmaceutically acceptable excipients to form a blend, c. compacting slugging the blend into compacts or slugs, d. milling or crushing the compacts/slugs of step (c) into granules, and e. lubricating and compressing the granules to form tablets.
  • Also provided herein are processes for preparing controlled-release metformin tablets comprising the steps of: a. blending metformin, one or more hydrophilic polymers and optionally one or more other pharmaceutically acceptable excipients to form a blend, b. moisture conditioning the blend, c. compacting/slugging the moisture conditioned blend into compacts or slugs, d. milling or crushing the compacts/slugs of step (c) into granules, and e. lubricating and compressing the granules to form tablets.
  • Also provided herein are processes for preparing controlled-release metformin tablets comprising the steps: a. blending metformin, one or more hydrophilic polymers and optionally one or more other pharmaceutically acceptable excipients to form a blend, b. granulating the blend to form granules, c. drying and sizing the granules, and d. lubricating and compressing the granules to form tablets.
  • controlled-release metformin tablets are provided, wherein the tablets provide the following in vitro profile when tested in USP type 2 apparatus at about 50 rpm in about 900 mL of simulated intestinal fluid (pH 6.8 phosphate buffer) at 37 °C ⁇ 0.5 °C: the release of from about 20% to about 50% metformin after 1 hour; the release of from about 50% to about 85% metformin after 4 hours; and the release of not less than 65% metformin after 8 hours.
  • the controlled-release tablets described herein may further include one or more of sulfonylureas, insulin, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, fibrates, statins, squalene synthesis inhibitors, angiotensin-converting enzyme inhibitors or mixtures thereof.
  • metformin includes metformin base or acid addition salts of inorganic or organic acids.
  • acids include, but are not limited to, hydrochloric acid, formic acid, acetic acid, maleic acid, succinic acid, tartaric acid or fumaric acid.
  • Non-ionic hydrophilic polymers can be hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or mixtures thereof. In particular example, hydroxypropyl methylcellulose can have about 19-24% methoxyl substitution and about 4-12% hydroxypropyl substitution.
  • Such polymers include METHOCEL K4M, METHOCEL K15M and METHOCEL K100M (nonnal and premium CR grades, Dow Chemical Co . , Midland Michigan) .
  • Anionic hydrophilic polymers can be, for example, homopolymers and copolymers of polyacrylic acid and polyacrylic acid derivatives, starch derivatives, cellulose derivatives and gums.
  • Homopolymers of polyacrylic acid and their derivatives are available in various grades (e.g., CARBOPOL, BF Goodrich) and such homopolymers are high molecular weight, crosslinked, acrylic acid-based polymers.
  • Copolymers of acrylate or methacrylate monomers can be, for example, polymethacrylates (e.g. , EUDRAGIT).
  • Starch derivatives include, for example, sodium starch glycolate.
  • Gums include, for example, sodium alginate, propylene glycol alginate, Xanthan gum, etc.
  • Anionic cellulose derivatives include, for example, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (e.g., croscarmellose).
  • Preferred anionic cellulose derivatives include sodium carboxymethylcellulose.
  • Metformin is highly soluble in water and therefore the release of the drug from a matrix system can occur by diffusion. Thus, controlled-release of metformin necessarily has high viscosity polymers in the matrix system. Combining hydroxypropyl methylcellulose and sodium carboxymethylcellulose results in rheological synergism whereby the resultant viscosity is considerably higher than the arithmetic mean of the viscosity of the two polymers. This higher viscosity is attributed to strong hydrogen bond- induced crosslinking that takes place between the carboxylic group of sodium carboxymethylcellulose and the hydroxyl group of the hydroxypropyl methylcellulose.
  • Metformin HC1 tablets exhibit excellent compressibility and show lower friability values when prepared with a combination of hydroxypropyl methylcellulose with an average molecular weight in the range of 180,000 to 250,000 with a methoxy degree of substitution ranging from about 19 % to about 24 % and hydroxypropyl molar substitution ranging from about 4 % to about 12 % and sodium carboxymethylcellulose as hydrophilic polymers.
  • Such tablets exhibit extended release times of up to 12 hrs.
  • the formulations of the present invention may contain one or more other excipients, which can act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents. Careful selection of diluents not only improves the flow and compressibility characteristics of the blend, but also aids in avoiding the problem of capping. However, as metformin is a high dosage drug, addition of diluents are not necessary. If required, one or more of lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose, mannitol or mixtures thereof may be used as diluents.
  • Binders may be one or more of starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl celluloses, dextrin, carbohydrate gums, alginates, polyacrylic acid, polyvinylalcohol or mixtures thereof.
  • Lubricants may be one or more of talc, Group IA or Group IIA stearates, including magnesium stearate or other alkali earth metal stearates, for example, zinc stearate, calcium stearate, and the like, or mixtures thereof; sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, glyceryl behenate and polyethylene glycol.
  • Glidants may be one or more of colloidal silicon dioxide, talc, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate or mixtures thereof.
  • Dry blends of metformin can be prepared with one or more hydrophilic polymers, including hydroxypropyl methylcellulose and sodium carboxymethylcellulose, and optionally one or more other excipients to form a powder blend.
  • the powder blend may be sifted through a screen of suitable fineness to remove or break up lumps. Such screening also allows for additional mixing of the powder blend.
  • Twin shell blenders, double cone blenders or planetary mixers may be used for large quantities of powder.
  • the blend could be wet granulated with water or with a solution/dispersion of the binder in a suitable solvent.
  • the powder mass is wetted with water or the binding solution until the mass has the proper consistency.
  • the wet mass is forced through a suitable screen; however for large quantities comminuting mills suitable for wet screening may be used.
  • wet granules can be dried in trays or in fluidized bed dryer.
  • the granulation desirably maintains a residual amount of moisture, which is necessary to facilitate a hydrated state in the various granulation ingredients, such as polymers.
  • the presence of residual moisture content reduces static electric charges on the particles.
  • the stability of products containing moisture sensitive active ingredients may be related to the moisture content of the product.
  • preferred residual moisture contents of the granules can be from about 1.0-6.0% by weight.
  • the dry blend can be moisture conditioned by adding water to the dry blend, exposing the dry blend to higher humidity, or choosing excipients having high water content.
  • the moisture conditioned blend can then be compacted or slugged; the compacted slugged material can be further milled or crushed into granules; and the granules can be lubricated and compressed into tablets.
  • Metformin was blended with sodium carboxymethylcellulose and hydroxypropyl methylcellulose.
  • the blend of step 1 was granulated with a solution of polyvinylpyrrolidone in purified water. 3.
  • the wet mass of step 2 was dried and suitably sized. 4.
  • the dried sized granules were lubricated with magnesium stearate and compressed into tablets.
  • Table 1 provides an in-vitro release profile of the controlled-release tablets of metformin prepared by the composition and process of Example 1 in phosphate buffer pH 6.8 (900 mL), USP 2 at 50 rpm.
  • the methods of dissolution of the tablets include utilizing USP 2 with sinkers. Tablets are kept in the sinkers to prevent floating or sticking to the bottom of the dissolution vessel.
  • the percent drug released was measured by techniques known to those of ordinary skill in the art for quantitative determination of drug present in solution, for example, by spectrophotometry, HPLC or reverse HPLC.
  • Table 1 Release profile of the controlled-release tablets of metformin prepared as per Example 1 in Phosphate buffer pH 6.8 (900 mL), USP 2 at 50 rpm.
  • Process 1. The ingredients were weighed and sifted through suitable sieves. 2. Metfonnin and microcrystalline cellulose were mixed in a blender and sprayed with a sufficient quantity of purified water. The blend of step 2 was mixed with sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, magnesium stearate and colloidal silicon dioxide. The mixture of step 3 was sifted and then compacted using a roller compactor. 5. The compacted material was suitably sized. 6. Sized granules were lubricated and compressed into tablets.
  • Table 2 provides an in-vitro release profile of the controlled-release tablets of metformin prepared by the composition and process of Example 2 in a phosphate buffer pH 6.8 (900 mL), USP 2 at 50 rpm.
  • Table 2 Release profile of controlled-release tablets of metformin prepared as per Example 2 in Phosphate buffer pH 6.8 (900 mL), USP 2 at 50 rpm.
  • Extended release metformin tablets (750 mg) prepared according to Example 1 and Example 2 were subjected to a pharmacokinetic investigation along with 750 mg tablets of GLUCOPHAGE XR, currently marketed by Bristol Myers Squibb, in normal healthy male subjects under fasting/fed conditions.
  • Values for pharmacokinetic parameters including observed C ma ⁇ , AUC 0-t and AUCrj-oc, were calculated using standard non-compartmental methods. The results, as indicated by ratio of test to reference, are shown in Tables 3 and 4.

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Abstract

L'invention concerne des formulations de dosage unitaire à libération prolongée de metformine ou de son sel pharmaceutiquement acceptable, des procédés pour leur préparation et des méthodes permettant d'abaisser la résistance à l'insuline ou de traiter un diabète sucré non insulino-dépendant.
PCT/IB2005/000750 2004-03-22 2005-03-22 Formulations de metformine WO2005092293A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN565DE2004 2004-03-22
IN565/DEL/2004 2004-03-22

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WO2005092293A1 true WO2005092293A1 (fr) 2005-10-06

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006038226A3 (fr) * 2004-10-08 2006-06-22 Rubicon Res Pvt Ltd Compositions de metformine fortement compressibles a liberation controlee
WO2008074108A3 (fr) * 2006-12-20 2008-12-11 Medley S A Ind Farmaceutica Composition pharmaceutique à libération contrôlée, forme pharmaceutique à libération contrôlée et procédé permettant l'obtention de la forme pharmaceutique
EP2099430A2 (fr) * 2006-12-07 2009-09-16 Schering Corporation Formulation de matrice sensible au ph
US20100323011A1 (en) * 2008-03-04 2010-12-23 Nazaneen Pourkavoos Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
CN105878204A (zh) * 2014-12-16 2016-08-24 合肥立方制药股份有限公司 一种盐酸二甲双胍渗透泵控释片及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475521B1 (en) * 1998-03-19 2002-11-05 Bristol-Myers Squibb Co. Biphasic controlled release delivery system for high solubility pharmaceuticals and method
WO2003028704A1 (fr) * 2001-09-28 2003-04-10 Ranbaxy Laboratories Limited Composition pharmaceutique a liberation prolongee contenant de la metformine
US20030104059A1 (en) * 2001-11-06 2003-06-05 Manish Chawla Controlled release tablets of metformin
WO2003105809A1 (fr) * 2002-06-17 2003-12-24 Themis Laboratories Private Limited Comprimes multicouche contenant des thiazolidinediones et des biguanides et procedes de production desdits comprimes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475521B1 (en) * 1998-03-19 2002-11-05 Bristol-Myers Squibb Co. Biphasic controlled release delivery system for high solubility pharmaceuticals and method
WO2003028704A1 (fr) * 2001-09-28 2003-04-10 Ranbaxy Laboratories Limited Composition pharmaceutique a liberation prolongee contenant de la metformine
US20030104059A1 (en) * 2001-11-06 2003-06-05 Manish Chawla Controlled release tablets of metformin
WO2003105809A1 (fr) * 2002-06-17 2003-12-24 Themis Laboratories Private Limited Comprimes multicouche contenant des thiazolidinediones et des biguanides et procedes de production desdits comprimes

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006038226A3 (fr) * 2004-10-08 2006-06-22 Rubicon Res Pvt Ltd Compositions de metformine fortement compressibles a liberation controlee
EP2099430A2 (fr) * 2006-12-07 2009-09-16 Schering Corporation Formulation de matrice sensible au ph
EP2428204A3 (fr) * 2006-12-07 2012-07-04 Schering Corporation Formulation de matrice sensible au pH
WO2008074108A3 (fr) * 2006-12-20 2008-12-11 Medley S A Ind Farmaceutica Composition pharmaceutique à libération contrôlée, forme pharmaceutique à libération contrôlée et procédé permettant l'obtention de la forme pharmaceutique
US20100323011A1 (en) * 2008-03-04 2010-12-23 Nazaneen Pourkavoos Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
CN105878204A (zh) * 2014-12-16 2016-08-24 合肥立方制药股份有限公司 一种盐酸二甲双胍渗透泵控释片及其制备方法

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