The present invention relates to extended release unit dosage formulations of metformin or its pharmaceutically acceptable salt thereof and the process for their preparation.
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 (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 diarrhoea, etc. These 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 (>300mg/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), currently marketed by Bristol Myers Squibb. Glucophage conventional tablets contain 500 mg, 850 mg and 1000 mg of metformin hydrochloride. Glucophage XR tablets (500 mg and 750 mg metformin hydrochloride; extended release) comprise a dual hydrophilic matrix system which is covered by US patent 6,475,521, which describes a method for preparing a biphasic controlled release delivery system adapted for delivery of metformin. It describes a two phase system which includes an inner solid particulate phase containing the drug and an extended release material and an outer solid continuous phase containing extended release material. On coming in contact with the release medium, the drug released from the particles of the inner phase, migrates through the outer solid continuous phase and is 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 scope to play with 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. But, in cases where the active ingredient is not compressible directly, one or more excipients must be added. Since each excipient added to the formulation necessarily increases the tablet size, direct compression method is limited to formulations containing a low dose active ingredient. Moreover, the tendency for capping is particularly high in case of directly compressed tablets containing high doses of active ingredient.

One such attempt was made in US Patent No. 6,117,451 which describes the use of specific excipients of particular size and density range to improve the flow and compressibility of metformin hydrochloride. These excipients are blended with metformin and the blend is then directly compressed.
Our pending PCT patent application, WO 03/39527 describes 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. Further it is also emphasized that the anionic and non-ionic polymers are 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
We have now discovered that controlled release tablets of metformin, which maintain therapeutic blood level concentrations of the medicament in a patient for sufficiently long time, can be formulated as a monolithic matrix , which slowly releases the active agent over a prolonged period of time.
According to one aspect, controlled release metformin tablets are formulated as a monolithic matrix comprising metformin, hydrophilic polymers and other pharmaceutically acceptable excipients, wherein the hydrophilic polymers comprise anionic and non-ionic polymers in ratios of about 1:5 to about 1:50.
According to yet another aspect, the controlled release metformin tablets are provided which can incorporate a high dose of metformin and are of acceptable size, making it convenient for oral administration.
In another aspect, the controlled release metformin tablet comprises a monolithic system that delivers highly soluble metformin over extended periods of time and is easy to manufacture.

It is one general aspect to provide 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, a process is provided for preparing controlled release tablets of metformin or non-toxic acid addition salts thereof, which comprises dry blending metformin with hydrophilic polymers consisting of anionic and nonionic polymers in a ratio 1:5 to 1:50, and optionally other excipients, granulating the blend, drying, sizing, and lubricating the granules, and compressing the lubricated granules into monolithic matrix.
In another general aspect, a process is provided for preparing controlled release tablets of metformin or non-toxic acid addition salts thereof, which comprises blending of the ingredients followed by roller compaction or slugging. The compacts are suitably sized lubricated and compressed to form tablets.
According to our co-pending Indian patent application, 1002/DEL/2001 which is incorporated herein by reference, metformin may be moisture conditioned before blending with hydrophilic polymers and other excipients to further improve the flow properties. Alternatively, metformin may be blended with the hydrophilic polymers and/or other excipients and then moisture-conditioned.
Accordingly, a process for preparing controlled release metformin tablets comprises:
a. moisture conditioning metformin,
b. blending with hydrophilic polymers and other pharmaceutically acceptable
excipients,
c. compacting / slugging,
d. milling or crushing the compacted / slugged material of step (b) into granules,
e. lubricating and compressing the granules to form tablets.
Alternatively, another process for preparing controlled release metformin tablets comprises:
a. blending metformin, hydrophilic polymers and other pharmaceutically acceptable excipients,

b. moisture conditioning the blend,
c. compacting / slugging,
d. milling or crushing the compacted / slugged material of step (b) into granules,
e. lubricating and compressing the granules to form tablets.
Accordingly, another process for preparing controlled release metformin tablets comprises:
(a) blending metformin, hydrophilic polymers and other pharmaceutically acceptable
excipients,
(b) granulating the blend,
(c) drying and sizing the granules,
(d) lubricating and compressing the granules to form tablets.
In certain embodiments, controlled release metformin tablets are provided, wherein the tablets provide the following in vitro profile when tested in USP type 2 apparatus at 50 rpm in 900 ml of simulated intestinal fluid (pH 6.8 phosphate buffer) at 37°±0.5°C:
from about 20% to about 50% metformin released after 1 hour;
from about 50% to about 85% metformin released after 4 hours;
not less than 65%metformin released after 8 hours.
It is another aspect to provide a method for lowering insulin resistance or treating non-insulin dependent diabetes mellitus in a patient in need thereof, comprising administering controlled release tablets comprising metformin and hydrophilic polymers; wherein the hydrophilic polymers comprise anionic and non-ionic polymers in a ratio of about 1:5 to about 1:50.
The controlled release tablets may further include one or more of sulfonylureas, insulin, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.
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 to which this invention belongs. 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.
In 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.
Detailed description
Metformin as used herein means metformin base or acid addition salts of inorganic or organic acids. These acids are exemplified by, but are not limited to, acids such as hydrochloric acid, formic acid, acetic acid, maleic acid, succinic acid, tartaric acid or fumarie acid.
Non-ionic hydrophillic polymers are selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethyl cellulose; in particular, hydroxypropyl methylcellulose having 19-24% methoxyl substitution and 4-12% hydroxypropyl substitution.
Such polymers include those sold by Dow Chemical Co. under the tradenames Methocel K4M, Methocel K15M and Methocel K100M (normal and premium CR grades).
Anionic hydrophilic polymers can include sodium carboxymethylcellulose.
Metformin is highly soluble in water and therefore the release of the drug from a matrix system is mainly through diffusion. Therefore, it is necessary for controlled release of metformin to have high viscosity polymers in the matrix system. Combination of hydroxypropyl methylcellulose and sodium carboxymethylcellulose results in Theological synergism whereby the resultant viscosity is considerably higher than the arithmetic mean

of the viscosity of the two polymers . This is attributed to the fact that a strong hydrogen bond induced cross-linking takes place between the carboxylic group of sodium carboxymethylcellulose and the hydroxyl group of the hydroxypropyl methylcellulose.
Metformin HCI tablets prepared with a combination of hydroxypropyl methylcellulose with an average molecular weight in the range of 1,80,000 to 2,50,000 with a methoxy degree of substitution ranging from 19 to 24% and hydroxypropyl molar substitution ranging from 4 to 12% and sodium carboxymethylcellulose as hydrophilic polymers exhibit excellent compressibility and show lower friability values. Moreover tablets produced have extended release up to 12 hrs.
In addition to the active and hydrophilic polymers, the formulations of the present invention may contain other excipients, which act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents. Careful selection of the diluent not only improves the flow and compressibility characteristics of the blend but also aids in solving the problem of capping. However, as metformin is a high dosage drug, addition of diluent is not necessary. If required, lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose and mannitol may be used as diluent.
Binders may be selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl celluloses, dextrin, carbohydrate gums, alginates, polyacrylic acid, polyvinylalcohol or mixtures thereof.
Lubricants may be selected from talc, magnesium stearate, other alkali earth metal stearates like zinc, calcium stearate etc; sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, glyceryl behenate and polyethylene glycol.
Glidants may be selected from colloidal silicon dioxide and talc.
Other conventional ingredients which may optionally be present include stabilizers, anti-adherents and colorants.

For the purpose of the present invention the dry blend of metformin could be prepared with hydrophilic polymer(s): hydroxypropyl methylcellulose and sodium carboxymethylcellulose, and optionally other excipients. The powder blend may be sifted through a screen of suitable fineness to remove or break up lumps. This screening also affords additional mixing. For large quantities of powder twin shell blender, double cone blender, planetary mixers may be used.
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 are dried in trays or in fluidized bed dryer. In drying, it is desirable to maintain a residual amount of moisture in the granulation. This is necessary to maintain the various granulation ingredients such as polymers in a hydrated state. Also, the residual moisture content contributes to the reduction of the static electric charges on the particles. The stability of the product containing moisture sensitive active ingredients may be related to the moisture content of the product. In the present invention the preferred residual moisture content of the granules is between 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 is moisture conditioned by addition of water or by exposing to higher humidity or by choosing excipients having high water content; compacting or slugging, milling or crushing the compacted / slugged material into granules, lubricating and compressing the granules to form tablets.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention anyway.

EXAMPLE 1

S.No. Ingredients Percent w/w
1 Metformin 66.1
2 Hydroxypropyl methylcellulose 27.1
3 Sodium carboxy methylcellulose 1.3
4 Polyvinylpyrrolidone 2.6
5 Magnesium stearate 0.7
6 Colorant Qs
7 Purified water Qs
Process:
1. Metformin was blended with sodium carboxymethylcellulose and hydroxypropyl
methylcellulose.
2. 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 the 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 dissolution methodology for tablets consists of 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 (900ml), USP 2 at 50 rpm.

Time Percent release from tablets of Example 1
0.5 27
1.0 35
2.0 50
4.0 71
6.0 84
8.0 93
10.0 99
12.0 101
EXAMPLE 2

S.No. Ingredients Percent wAw
1 Metformin 69.0
2 Hydroxypropyl methylcellulose 19.0
3 Sodium carboxy methylcellulose 1.7
4 Microcrystalline cellulose 5.5
5 Magnesium stearate 0.3
6 Colloidal silicon dioxide 1.5
7 Purified water qs
Process:
1. The ingredients were weighed and sifted through suitable sieves.
2. Metformin and microcrystalline cellulose were mixed in a blender and sprayed
with required quantity of purified water.

3. The blend of step 2 was mixed with sodium carboxy methyl cellulose,
hydroxypropyl methyl cellulose, magnesium stearate and colloidal silicon
dioxide.
4. The mass of step 3 was sifted and then compacted using a roller compactor.
5. Compacted material was suitably sized.
6. Sized granules were lubricated and compressed into tablets.
Table 2 provides the in-vitro release profile of the controlled release tablets of metformin prepared by the composition and process of example 2 in phosphate buffer pH 6.8 (900 ml), USP 2 at 50 rpm.
Table 2: Release profile of the controlled release tablets of metformin prepared as per Example 2 in Phosphate buffer pH 6.8 (900ml), USP 2 at SO rpm.

Time Percent release from tablets of Example 2
0.5 28
1.0 36
2.0 51
4.0 71
6.0 85
8.0 93
10.0 96
12.0 99
Pharmacokinetic evaluation
Extended release metformin tablets (750 mg) prepared according to Example 1 and Example 2 were subjected to pharmacokinetic investigation along with Glucophage XR , 750 mg tablets, currently marketed by Bristol Myers Squibb, in normal healthy male subjects under fasting/fed conditions.

Values for pharmacokinetic parameters, including observed Cmax, AUCo-tand AUCo^c, 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)

Parameters
Cmax (ng/ml) AUC (0-t) (ng.hr /ml) AUC (o**) (ng.hr /ml)
Ratio % (A/R) 91.4 92.49 91.02
Ratio % (B/R) 91.06 87.59 88.35
Table 4: Summary of pharmacokinetic parameters (Fed)

Parameters
Cmax (ng/ml) AUC (o-t, (ng.hr/ml) AUC jo-*) (ng.hr /ml)
Ratio % (A/R) 105.03 100.10 104.90
Ratio % (B/R) 108.92 98.28 96.79
Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative limitation. Accordingly, it is not intended that the invention be limited, except as by the appended claims.