EP2001302A2 - Compositions pharmaceutiques contenant de la metformine - Google Patents

Compositions pharmaceutiques contenant de la metformine

Info

Publication number
EP2001302A2
EP2001302A2 EP07752735A EP07752735A EP2001302A2 EP 2001302 A2 EP2001302 A2 EP 2001302A2 EP 07752735 A EP07752735 A EP 07752735A EP 07752735 A EP07752735 A EP 07752735A EP 2001302 A2 EP2001302 A2 EP 2001302A2
Authority
EP
European Patent Office
Prior art keywords
metformin
glimepiride
patient
hydrochloride
formulation
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.)
Withdrawn
Application number
EP07752735A
Other languages
German (de)
English (en)
Inventor
Krishna Vishnupad
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.)
Neurosci Inc
Original Assignee
Neurosci Inc
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 Neurosci Inc filed Critical Neurosci Inc
Publication of EP2001302A2 publication Critical patent/EP2001302A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide

Definitions

  • the present invention relates to combination compositions of pharmaceutical therapeutics and the process of making the same.
  • the present invention relates to metformin and salts thereof essentially combined with other commonly known oral antidiabetic compounds.
  • This combination composition can be formulated in an instant release formulation or granulated and combined with an extended release polymer and further dispersed in a rate-controlling matrix.
  • Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, insulin resistance, and is often associated with other disorders such as obesity, hypertension, hyperlipidemia, as well as complications such as cardiovascular disease, retinopathy, neuropathy, and nephropathy.
  • the disease is progressive in nature, and can often be controlled initially by diet alone, but generally requires treatment with drugs such as sulfonylureas and as the disorder progresses injections of exogenous insulin.
  • Another agent known as a biguan ⁇ de also is used to decrease hepatic glucose production as well as intestinal absorption of glucose.
  • combination therapy with a biguanide and a sulfonylreas results in dramatic improvement in glycemic control, and that even better control and patient compliance can be achieved by using a combination comprised of a biguanide, and a sulfonylurea. Accordingly, such combinations are especially useful in treating diabetes and associated complications.
  • This invention provides a method of treating diabetes by administering to a subject in need of treatment a single dosage form having a combination of a sulfonylurea together with a biguanide anti-diabetic agent such as metformin.
  • the sulfonylureas are a class of compounds that have been widely employed to treat diabetes. Such compounds are well known, for example as described in U.S. Pat. Nos. 3.454.635. 3.669.966. 2.968.158. 3.501.495. 3.708.486. 3.668,215, 3.654.357. and 3.097.242, all of which are incorporated in their entirety by reference.
  • Preferred sulfonylureas to be employed in the combinations of this invention are glyburide, gliquidone, glipizide, tolbutamide, tolazamide, glisoxepid, chlorpropamide, glibornuride, gliclazide, glimepiride, phenbutamide, and tolcyclamide.
  • the foregoing sulfonylureas are used in combination with a biguanide to treat diabetes with improved patient compliance thereby improving glycemic control.
  • Metformin Hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C4H11N5 ⁇ CI and a molecular weight of 165.63. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. Metformin is a biguanide that is not chemically or pharmacologically related to any other classes of oral anti-hyperglycemic agents. It is absorbed mainly from the small intestine. Metformin is stable in vivo and it does not bind to plasma proteins and is therefore excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours.
  • metformin The maximum recommended daily dose of metformin is about 4 gms.
  • Metformin is anti-hypererglycemic and it improves glucose tolerance in patients with type II diabetes, lowering both basal and postprandial plasma glucose. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type II diabetes or normal subjects. Hence it is a drug of choice in controlling type II diabetes and is widely prescribed by physicians all over the world. It is presented in both instant release and extended release formulations. The extended release formulations have been developed to increase patient compliance.
  • the present invention addresses the problems with patient compliance with biguamide, such as metformin in combination with other orally active hypoglycemic agents used in combination therapy and provides a single formulation composition of metformin and in combination with a sulphonylurea, eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepiride or glicazide, which improves patient compliance with the convenience of a single formulation.
  • a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepiride or glicazide
  • metformin in combination with glimepiride is formulated in an extended release formulation.
  • Glimepiride is an oral blood-glucose lowering drug of the sulfonylureas class.
  • Glimepiride is a white to yellowish-white crystalline, odorless to practically odorless powder that can be incorporated into combination tablets in doses of 1 mg, 2mg and 4mg strengths for oral administration. Glimepiride can be administered up to 8mg per day in divided doses or up to 8mg in an extended release formulation. Chemically, glimepiride is identified as l ⁇ ⁇ p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-l-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-
  • glimepiride 4-methylcyclohexyurea.
  • the primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells.
  • extrapancreatic effects may also pay a role in the activity of sulfonylureas such as glimepiride.
  • a method of treatment of hyperglycemic patients comprising administering the tablets having a combination of orally active hypoglycemic agents of varied doses made according to the invention in divided doses or in an extended release formulation once daily to patients in need thereof.
  • a further object of the present invention is to provide controlled or instant release compositions of metformin and other orally active hypoglycemic agents that are simple to manufacture without involving cost intensive methods of preparation.
  • Another object of the present invention is to provide controlled or instant release compositions of metformin in combination with other orally active hypoglycemic agents that are simple to manufacture and have good compressibility that results in good hardness tablets that can withstand the rigors of coating.
  • biguanides such as phenformin or buformin or pharmaceutically acceptable salts thereof
  • the preferred drug, having high water solubility for use herein is metformin or pharmaceutically acceptable salts such as metformin hydrochloride, metformin fumarate, and metformin succinate.
  • metformin can be used in varying doses such as 500 mg, 750 mg, 850 mg, and 1000 mg in instant release formulations and up to 4000mg per day in extended release formulations. It is contemplated within the scope of the invention that where desired, metformin or a salt thereof may be used in combination with another antihyperglycemic agent, which may be administered orally in the same dosage form in accordance with the present invention.
  • the present composition according to the invention can be either an instant release formulation or a controlled release formulation which is essentially comprised of one or more binders in an amount within the range of from with about 0.1% to about 10% binder , preferably about 0.2% to about 5 % 2-4% binder and most preferably about 0.25% to about 4.5% binder by weight of the composition.
  • Binders usually are low viscosity polymers or non-polymeric materials and therefore they do not extend the release of a drug. Although binders improve appearance, hardness & friability of the preparation they are usually not intended to influence the disintegration or dissolution roles of active substance.
  • Binders which are suitable for use herein include but are not limited to copovidone or polyvinyl pyrrolidone (PVP).
  • Copovidone is a white or yellowish- white spray-dried powder that has a relatively fine particle size and good flow properties. It has a typical slight odor and a faint taste in aqueous solutions. Because of the ratio of vinylpyrrolidone to vinyl acetate in copovidone, it is almost as universally soluble as polyvinyl pyrrolidone. It dissolves in extremely hydrophilic liquids such as water as well as in more hydrophobic solvents such as butanol. Copovidone has a molecular weight ranging from about 45000 to about 70000 and is available commercially in different grades and trade names such as Kollidon VA 64.
  • binders such as polyvinyl pyrrolidone (PVP) with a molecular weight ranging from about 4000 to about 1500000 and preferably about 30,000-1500000 can be used as a binder.
  • PVP polyvinyl pyrrolidone
  • Polyvinylpyrrolidone is available in different grades based on K-value and molecular weights such as polyvinyl pyrrolidone with K value of 24-26, 29-32 or 85-95.
  • polyvinyl pyrrolidone with K value 85-95 Plasdone K-90/D®, Kollidon 90F®
  • K value 85-95 Plasdone K-90/D®, Kollidon 90F®
  • binders can be used such as but not limited to hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, sodium carboxy methyl cellulose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like.
  • Metformin hydrochloride granules prepared with copovidone (copolyvidone, Kollidon VA 64) have been found to have a good compressibility.
  • Metformin is essentially granulated with suitable binders, the binder concentration ranging from h about 0.1% to about 10% binder , preferably about 0.2% to about 5 % 2-4% binder and most preferably about 0.25% to about 4.5% binder. Although concentrations above 4% can give also give binding effect, there appears to be no substantial increase in binding. It is contemplated within the scope of the disclosure that multiple granulation steps can be preformed to improve compressibility.
  • the solvent used with the binder for granulation is preferably water. It is contemplated that other solvents such as isopropyl alcohol or the like can also be employed. Metformin granules so formed are uniformly dispersed in a controlled release matrix comprising of rate controlling polymers. In a further illustrative embodiment according to the disclosure Metformin granules so formed are uniformly dispersed in a controlled release matrix comprising of rate controlling polymers along with free metformin.
  • Controlled-release as used herein to describe a method and composition for making an active ingredient available to the biological system of a host.
  • a controlled release preparation according to the present invention is one that achieves slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery.
  • This admixture is typically compressed under pressure to produce a tablet. Drug is released from this tablet by diffusion and erosion.
  • the preferred polymeric matrices are those with a relatively high molecular weight.
  • release of the drug is achieved by allowing the gastric fluid to diffuse into the matrix where fluid dissolves the matrix-held drug and then diffuses outward while the matrix retains its integrity, or disintegrates at a rate that is considerably slower than the rate at which the drug is dissolved from matrix. Controlled release is thus achieved by the integrity of the matrix and the need for the gastric fluid to diffuse into the matrix to reach the drug.
  • the controlled release gastro-retentive swelling system of the present invention employs a combination of rate controlling polymers, which swell voluminously in presence of gastric contents to increase the dosage form size such that it precludes its passage through the pylorus.
  • rate controlling polymer includes hydrophilic polymers that are capable of retarding the release of metformin hydrochloride in combination with other anti-diabetic agents in vivo when metformin hydrochloride and other anti-diabetic agents are dispersed in a polymeric matrix formed from the rate controlling polymers.
  • Preferred polymers for the controlled release system of high solubility drug of the 5 present invention are those which ensure rapid hydration of the polymer matrix to minimize variable and undesirable burst of combination drugs, yet effectively control the release of drugs within a combination being liberated from the discrete particles or drug granules.
  • the hydrophilic water-soluble polymers may be used individually or in combination. Examples of polymers suitable for this invention include the polymers well known in the
  • acrylic polymers such as available as Eudragit RS, Eudragit RL, natural gums as xanthan gum, karaya gum, locust bean gum, guar gum, gelan gum, gum arabic, tragacanth, carrageenan, pectin, carboxymethyl cellulose (CMC) agar, alginic acid, sodium alginate polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl
  • Preferred polymers with appropriate hydration characteristics include hydroxypropylmethylcellulose 2208 USP (hydroxypropylmethylcellulose with a methoxyl content of 19-24% and a hydroxypropyl content of 7-12%), viscosity grades ranging from
  • hydroxypropylmethylcellulose 2910 USP hydroxypropylmethylcellulose with a methoxyl content of 28-30% and a hydroxypropyl content of 7-12%)
  • viscosity grades ranging from about 3 to about 150 cps.
  • Another preferred polymer is sodium carboxy methylcellulose having viscosity of about 2000-50000 cps.
  • the amount of polymer relative to the drug may vary depending on the release rate desired, nature of the polymers and their physicochemical characteristics.
  • the amount of the polymer in the dosage form generally varies from about 10% to about 50% by weight of the composition.
  • the amount of polymers varies from about 15% to about 45% by weight of the dosage form.
  • the amount of polymer is about 20% to about
  • the dosage form 30 24% by weight of the dosage form.
  • the polymer concentration can be reduced as they are utilized optimally due to their incorporation in dry form.
  • Additional excipients that are although not essential for the present invention, are required for the tableting process as known to those skilled in art, and may be suitably included.
  • composition of the invention therefore typically includes pharmaceutically acceptable excipients.
  • pharmaceutical excipients are routinely incorporated into solid dosage forms. This is done to ease the manufacturing process as well as to improve the performance of the dosage form.
  • Common excipients include diluents, lubricants, granulating aids, colorants, flavorants, surfactants, pH adjusters, anti-adherents and gildants etc. Such excipients are routinely used in the dosage forms of this invention.
  • the present invention may additionally include one or more fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
  • fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
  • composition in the form of a tablet, it may include one or more tableting lubricants in an amount within the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and mixtures thereof.
  • Other conventional pharmaceutical ingredients which may optionally be present, include preservatives, stabilizers, and FD &C colors etc.
  • composition made according to the present invention may be formulated as tablets within a capsule or a tablet. Most preferably, the composition is a tablet.
  • the tablet may optionally be coated with a thin layer of a film forming polymer or a pharmaceutical excipient.
  • the controlled release preparation according to the invention may conveniently be film coated using any film coating material conventional in the pharmaceutical art. It is contemplated that the film coating can be formulated to delay the release of any drug for a selected period of time that is desirable for therapeutic reasons. Preferably an aqueous film coating is used.
  • the dosage form of present invention is a solid dosage form, preferably a tablet, which may vary in shape such as oval, triangle, almond, peanut, parallelogram, pentagonal, hexagonal, and trapezoidal.
  • the preferred shapes are oval and parallelogram forms.
  • a controlled release preparation according to the present invention is one that achieves slow release of a drug or drugs in combination over an extended period of time, thereby extending the duration of drug or drugs action over that achieved by conventional delivery.
  • such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more.
  • Tablets formulated according to the invention allow for controlled release metformin hydrochloride in combination with other anti-diabetic agents over at least a twelve-hour period following oral administration.
  • Another preferred dissolution rate in vitro upon release of the controlled release preparation for administration twice daily according to the invention is between 5 and 50% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 1 hour, between 10 and 75% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 2 hours, between 20 and 95% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 4 hours, between 40 and 100% (by weight) metformin hydrochloride and another antidiabetic agent such as glimepiride released after 8 hours, more than 50% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) metformin hydrochloride and another anti-diabetic agent such as glimepiride released after
  • Tablets formulated according to the invention allow for controlled release metformin hydrochloride over at least a twelve-hour period following oral administration, the in vitro release rate preferably corresponds to the following % rate of metformin hydrochloride released as shown in Table 1 :
  • Yet another preferred preparation particularly suited for once-a-day dosing has an in- vitro release rate corresponding to the following % rate of metformin hydrochloride released as shown in Table 2:
  • a still farther preferred preparation in accordance with the invention is also particularly suited for once-a-day dosing has an in vitro release rate corresponding to the following % rate of metformin hydrochloride released as shown in Table 3:
  • Another preferred dissolution rate in vitro upon release of the controlled release preparation for administration twice daily according to the invention is between 5 and 50% (by weight) metformin hydrochloride released after 1 hour, between 10 and 75% (by weight) metformin hydrochloride released after 2 hours, between 20 and 95% (by weight) metformin hydrochloride released after 4 hours, between 40 and 100% (by weight) metformin hydrochloride released after 8 hours, more than 50% (by weight) metformin hydrochloride released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) metformin hydrochloride released after 24 hours.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa.,1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 3000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is a base addition salt of a compound having the utility of a free acid.
  • a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
  • solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in- water or water-in-oil liquid emulsion.
  • the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.
  • a typical tablet that may be prepared by conventional tableting techniques may contain:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions combinées à libération instantanée et à administration contrôlée de metformine ou de sels de celle-ci et de glimépiride et son procédé de fabrication. La metformine et le glimépiride sont granulés avec un liant et en outre dispersés dans une matrice de contrôle de vitesse ce qui résulte en une composition à libération contrôlée augmentant le respect de la prescription par le patient. Dans un autre mode de réalisation donné à titre d'exemple, la metformine et le glimépiride sont formulés sous la forme d'une présentation à libération instantanée utilisant des excipients pharmaceutiques connus dans la technique.
EP07752735A 2006-03-09 2007-03-09 Compositions pharmaceutiques contenant de la metformine Withdrawn EP2001302A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78094406P 2006-03-09 2006-03-09
PCT/US2007/006055 WO2007103563A2 (fr) 2006-03-09 2007-03-09 Compositions pharmaceutiques contenant de la metformine

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EP2001302A2 true EP2001302A2 (fr) 2008-12-17

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CN110801443A (zh) * 2019-12-03 2020-02-18 仁和堂药业有限公司 一种盐酸二甲双胍缓释制剂及其质量检测方法

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WO2004045622A1 (fr) * 2002-11-15 2004-06-03 Ranbaxy Laboratories Limited Formes galeniques pharmaceutiques de combinaisons de biguanide-sulfonyluree

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See references of WO2007103563A3 *

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