WO2005092293A1

WO2005092293A1 - Formulations of metformin

Info

Publication number: WO2005092293A1
Application number: PCT/IB2005/000750
Authority: WO
Inventors: Manish Chawla; Rajeev Singh Raghuvanshi; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-03-22
Filing date: 2005-03-22
Publication date: 2005-10-06

Abstract

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.

Description

FORMULATIONS OF METFORMIN

Technical Field of the Invention 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.

Background of the Invention

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. For example, it would prove challenging to develop an extended release system for a high dose, water-soluble drug with a narrow absorption window limited to either stomach and/or the upper intestine. 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). However, being a short acting drug, 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). These parameters can lead to difficulty in providing a sustained release of the drug and the concomitant problems associated with controlling the initial burst from such a formulation. 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. In such a two phase system, 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. This could lead to the tendency of the tablets to "cap," thus making the production of such a formulation commercially unviable. Moreover, the high drug content leaves little flexibility in varying the excipients. Attempts have been made to obtain directly compressed tablets by compressing drug and suitable excipients, which aid in processing and improve the properties of the product. However, direct compression is usually limited to those situations where the drug has a crystalline structure and physical characteristics required to form pharmaceutically acceptable tablets. In cases where the active ingredient is not directly compressible, one or more excipients must be added. Since each excipient added to the formulation necessarily increases the tablet size, direct compression methods are limited to formulations containing a low dose active ingredient. Moreover, the tendency for capping is particularly high in the case of directly compressed tablets containing high doses of active ingredient. The use of specific excipients of particular size and density range to improve the flow and compressibility of metformin hydrochloride has been disclosed. Such excipients are blended with metformin and the blend is then directly compressed. PCT Patent Application No. WO 03/39527 discloses controlled-release tablets of metformin and processes for their preparation, using a combination of non-ionic and anionic hydrophilic polymers, wherein the total hydrophilic polymer concentration is at least about 16% by weight of the composition. The anionic and non-ionic polymers are disclosed as being present in a ratio of about 1 : 1 to about 1:5. It has now surprisingly been found that controlled-release tablets could satisfactorily be prepared with anionic and non-ionic polymers present in a ratio of about 1:5 to about 1:50. Summary of the Invention

Generally provided are 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. For example in one embodiment, 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. In another embodiment, the one or more anionic polymers can be sodium carboxymethylcellulose. i another embodiment, the one or more nonionic polymer can be hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or a mixture thereof. In yet another embodiment, 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 %. In one embodiment, 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 glycol or mixtures thereof; and the glidants can be selected from one or more of colloidal silicon dioxide, talc, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate or mixtures thereof. i one embodiment, 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.

Also provided are processes for preparing controlled-release tablets of metformin, comprising the steps of: blending metformin with one or more hydrophilic polymers comprising one or more anionic polymers and one or more nonionic polymers in a ratio of about 1 :5 to about 1 :50 and optionally one or more other pharmaceutically acceptable excipients to form a blend; granulating the blend to form granules; drying, sizing and lubricating the granules to form lubricated granules; and compressing the lubricated granules to form a tablet.

Also provided are processes for the preparation of controlled-release tablets of metformin, comprising the steps of: ι blending metformin with one or more hydrophilic polymers comprising one or more anionic polymers and one or more nonionic polymers in a ratio of about 1 :5 to about 1:50 and optionally one or more other pharmaceutically acceptable excipients to form a blend; compacting or slugging the blend to form compacted or slugged material; milling or crushing the compacted or slugged material to form granules; and lubricating and compressing the granules to form tablets. The processes can include one or more of the following embodiments. For example in one embodiment, 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. In another embodiment, the blend can be moisture conditioned prior to compacting or slugging.

Also provided herein are methods for lowering insulin resistance or treating non- insulin dependent diabetes mellitus in a patient, comprising administering to a patient in need thereof a controlled-release tablet comprising metformin, one or more hydrophilic polymers and optionally one or more pharmaceutically acceptable excipients, 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 methods can include one or more of the following embodiments. For example in one embodiment, 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. In another embodiment, 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.

Detailed Description of the Invention Generally provided herein are 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.

Thus according to one aspect, 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

In another aspect, the controlled-release metformin tablets comprise a high dose of metformin and are of acceptable size, making it convenient for oral administration. In another aspect, 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.

In one general aspect, provided herein are monolithic controlled-release tablets comprising not less than 500 mg metformin, wherein the total weight of the tablet does not exceed 1500 mg.

In another general aspect, provided herein are processes for preparing controlled- release tablets of metformin or non-toxic acid addition salts thereof, which 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.

In another general aspect, provided herein are processes for preparing controlled- release tablets of metformin or non-toxic acid addition salts thereof, which 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.

According to copending patent application WO 03028704, which is incorporated herein by reference, metformin may be moisture conditioned before blending with hydrophilic polymers and other excipients to further improve flow properties. Alternatively, metformin may be blended with the hydrophilic polymers and/or other excipients and then moisture-conditioned.

Accordingly, provided herein are 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.

In other embodiments, 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.

Also provided herein are methods for lowering insulin resistance or treating non- insulin dependent diabetes mellitus in a patient in need thereof, comprising administering a controlled-release tablet comprising metformin and one or more hydrophilic polymers, wherein the one or more hydrophilic polymers comprise one or more anionic polymers and one or more non-ionic polymers in a ratio of about 1:5 to about 1:50.

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.

Unless otherwise defined, all technical and scientific terms used herein have the same ordinary meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control, h addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

The term metformin, as used herein, includes metformin base or acid addition salts of inorganic or organic acids. Examples of such 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.

In addition to the active and hydrophilic polymers, 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.

Other conventional ingredients, which may optionally be present, include one or more stabilizers, anti-adherents, colorants 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. When drying, 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. Also, 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. For example, preferred residual moisture contents of the granules can be from about 1.0-6.0% by weight.

After drying, the granules are reduced in size by passing through a small mesh screen. After sizing, the granules are lubricated and compressed to form tablets. Alternatively 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. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples

EXAMPLE 1

Process: 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.

EXAMPLE 2

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.

Pharmacokinetic evaluation

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_maχ, 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. Test (A): Metformin hydrochloride Extended Release tablets 750 mg (Example 1) Test (B): Metformin hydrochloride Extended Release tablets 750 mg (Example 2) Reference (R): GLUCOPHAGE XR (750 mg) tablets

Table 3: Summary of pharmacokinetic parameters (Fasting)

Claims

We Claim:

1. A controlled-release metformin tablet 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.

2. The tablet of claim 1, wherein the one or more anionic polymers comprise one or more homopolymers or copolymers of polyacrylic acid or polyacrylic acid derivatives, starch derivatives, cellulose derivatives and gums.

3. The tablet of claim 2, wherein the cellulose derivative comprises sodium carboxymethylcellulose.

4. The tablet of claim 1, wherein the one or more nonionic polymers comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or a mixture thereof.

5. The tablet of claim 4, wherein the one or more nonionic polymer comprises 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 %.

6. The tablet of claim 1, further comprising one or more excipients selected from one or more diluents, binders, lubricants, glidants or mixtures thereof.

7. The tablet of claim 6, wherein the diluents are selected from one or more of lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose, mannitol or mixtures thereof

8. The tablet of claim 6, wherein the binders are 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.

9. The tablet of claim 6, wherein the lubricants are selected from one or more of talc, Group LA or Group IIA stearates, sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, glyceryl behenate, polyethylene glycol or mixtures thereof.

10. The tablet of claim 6, wherein the glidants are selected from one or more of colloidal silicon dioxide, talc, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate or mixtures thereof.

11. The tablet of claim 1 further comprising one or more sulfonylureas, insulin, alpha- glucosidase inhibitors, meglitinides, thiazolidinediones, fibrates, statins, squalene synthesis inhibitors, angiotensin-converting enzyme inhibitors or mixtures thereof.

12. A process for preparing controlled-release tablets of metformin, comprising the steps of: a. blending metformin with one or more hydrophilic polymers comprising one or more anionic polymers and one or more nonionic polymers in a ratio of about 1 :5 to about 1 :50 and optionally one or more other pharmaceutically acceptable excipients to form a blend; b. granulating the blend to form granules; c. drying, sizing and lubricating the granules to form lubricated granules; and d. compressing the lubricated granules to form a tablet.

13. A process for the preparation of controlled-release tablets of metformin, comprising the steps of: a. blending metformin with one or more hydrophilic polymers comprising one or more anionic polymers and one or more nonionic polymers in a ratio of about 1 :5 to about 1 :50 and optionally one or more other phannaceutically acceptable excipients to form a blend; b. compacting or slugging the blend to form compacted or slugged material; c. milling or crushing the compacted or slugged material to form granules; and d. lubricating and compressing the granules to form tablets.

14. The process of claim 13, wherein the metformin is moisture conditioned prior to blending with one or more hydrophilic polymers and optionally one or more other pharmaceutically acceptable excipients to form a blend.

15. The process of claim 13, wherein the blend is moisture conditioned prior to compacting .or slugging.

16. A method for lowering insulin resistance or treating non-insulin dependent diabetes mellitus in a patient, comprising administering to a patient in need thereof a controlled-release tablet comprising metformin, one or more hydrophilic polymers and optionally one or more pharmaceutically acceptable excipients, 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.

17. The method of claim 16, further comprising 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.

18. The method of claim 16, wherein 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.