FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"A COATED FORMULATION OF METFORMIN"

We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bungalows, Bodakdev, Ahmedabad-380 054, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
1903 MUM 2008
9 SEP 2008

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Field of Invention:
The invention relates to a coated formulation of Metformin. The invention also relates to a method of making the said solid dosage form. Background of Invention:
Diabetes mellitus of type II is a progressive metabolic disorder with diverse pathologic manifestations and is often associated with lipid metabolism and glycometabolic disorders. The long-term effects of diabetes result from its vascular complications; the microvascular complications of retinopathy, neuropathy and nephropathy and the macrovascular complications of cardiovascular, cerebrovascular and peripheral vascular diseases. Initially, diet and exercise is the mainstay of treatment of type II diabetes. However, these are followed by administration of oral hypoglycemic agents. Current drugs used for managing type II diabetes and its precursor syndromes such as insulin resistance, include classes of compounds, such as, among others, biguanides, thiazolidinediones and sulfonylureas.
Biguanides, represented principally by metformin hydrochloride, phenformin and buformin, help in the control of blood glucose by inhibiting hepatic glucose production, reducing intestinal absorption of glucose and enhancing peripheral glucose uptake. Biguanides. especially metformin hydrochloride, lowers both basal and post-prandial plasma glucose and thus improves tolerance of glucose in patients. Metformin hydrochloride exerts normoglycemic action with reduced risk of lactic acidosis and is also known to lower blood triglyceride levels. It is therefore a preferred mode of therapy among biguanides.
Metformin hydrochloride has intrinsically poor permeability in the lower portion of the GIT leading to absorption almost exclusively in the upper part of GIT. Its oral bioavailability is in the range of 40 to 60% decreasing with increasing dosage which suggests some kind of saturable absorption process, or permeability limited absorption. It also has a very high water solubility (>300 mg/ml at 25°C). This is the challenge or difficulty in providing the active pharmaceutical agent at slow rate and also controlling the initial burst effect from the dosage unit. These difficulties are further compounded by high unit doses of 500-mg, 750-mg and 1000-mg usually required for Metformin hydrochloride. The gastrointestinal tract functions to propel ingested material from the alimentary canal and the absorption is maximum in the upper part of GI tract, where as in the large intestine water is absorbed/secreted as part of body fluid regulation.
In the case of metformin hydrochloride, it is desirable to provide a dosage form that allows extended delivery of the drug and has a prolonged gastric residence via swelling of the
system rather than unfolding or expanding of a folded device, and that may be manufactured
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on a commercial scale. The prolonged gastric residence time is required due to the window of absorption seen with metformin hydrochloride. Another problem for extended delivery of metformin hydrochloride is its very high water solubility. High levels of polymer would be needed if one desires to provide controlled release of the drug. More over, the use of hydrophilic polymers alone for controlled drug release could result in a rapid and variable initial release (burst) of drug from an extended release dosage form. This thus may give rise to difficulty in providing a true control of drug release and minimal inter-patient variability in drug plasma levels (arising from the possibility of variable burst of drug from tablets given to different patients).
There are number of different modified release dosage forms available commercially. However, some of these are expensive to manufacture and can be difficult to swallow, particularly in elderly patients. However since many modified release dosage forms contain comparatively large amounts of active ingredient it is often necessary to include large amounts of suitable excipients to achieve appropriate controlled release profiles which results in increase in the size of the dosage form.
Some of the techniques to make modified release dosage form of drugs as described in prior art are as follows:
W099/47128 discloses a method of prolonging the release of a highly water-soluble drug. A biphasic controlled release delivery system for metformin hydrochloride, which has prolonged gastric residence and that swells following hydration is described.
WO 02/28181 describes a monolithic sustained release formulation of metformin hydrochloride. The method of making the formulation involves hot melt granulation followed by wet granulation with binders of extrusion.
WO 2004/012699 A2 discloses modified release dosage form comprising of a highly soluble active ingredient, which utilizes dual retard technique comprising micro matrix particles containing active ingredient(s) and one or more hydrophobic release controlling agents and coating of one or more hydrophobic release controling agents.
US20030170302 discloses extended release pharmaceutical tablet of metformin comprising a core containing metformin and a coating permeable to metformin. US 6475521 describes biphasic controlled release delivery system for high solubility pharmaceutical using biphasic controlled release delivery system for treating diabetes.
US application US20040086566 describes a waxy matrix dosage forms comprising a pharmaceutically effective amount of metformin and a waxy matrix material. This publication relies on the use of waxy matrix for the preparation of tablets or other dosage forms. Here, the process of melting requires use of special equipment and the process is quite
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tedious. It is in a way expensive also. In brief one can say. the process is tedious, expensive and time consuming as the manufacture of such dosage forms requires special equipment, time for heating and cooling the mass, difficulty in sieving the molten mass and higher wear and tear associated with the process. Here, the use of high temperature melting devices is associated with the risk of acciental injury or burns. Summary of the invention:
The present invention aims to provide a production method of a preparation coated with metformin, which is useful as a therapeutic agent for diabetes and the like and superior in preservation stability and the characteristics of the preparation such as dissolution property of metformin.
The present inventors have found, in producing a preparation coated with metformin, that a coated preparation that shows superior dissolution property (particularly, dissolution property within 15 min from the start of dissolution test) of metformin can be obtained by coating with an aqueous dispersion of metformin comprising a coating material having a low viscosity. The present inventors have further studied based on this finding and completed the present invention. Detailed description:
Accordingly, the present invention relates to
1) a production method of a coated preparation, which comprises coating with an aqueous dispersion of metformin comprising a coating material having a low viscosity;
2) a coated preparation obtained according to the production method of the aforementioned
(1);
3) the production method of the aforementioned (1). wherein the coating material having a low viscosity in its 5% aqueous solution shows a viscosity of not more than 35 mPa.s at 20° C;
4) the production method of the aforementioned 1), wherein the coating material having a low viscosity is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethylene glycol graft copolymer;
5) the production method of the aforementioned 1), wherein a core comprising an active ingredient is coated with an aqueous dispersion of metformin comprising a coating material having a low viscosity;
6) a coated preparation obtained according to the production method of the aforementioned 1), which releases not less than 50% of metformin in 15 minutes in a dissolution test by a rotating basket method using a hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37 °C, 100 rpm;
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The concentration of metformin in an aqueous dispersion is, for example, 1-25% (W/W), preferably 1-15% (W/W). A concentration of these ranges is preferable from the aspects of coating workability, content uniformity of metformin in the obtained coated preparation and the like.
An "aqueous dispersion of metformin" (hereinafter sometimes to be abbreviated as a dispersion of the present invention) contains a coating material having a low viscosity. As used herein, by the coating material having a low viscosity is meant, for example, a coating material whose 5% (W/V) aqueous solution has a viscosity of not more than 35 mPa.s (preferably not more than 30 mPa.s, more preferably not more than 25 mPa.s) at 20 °C. The viscosity of the coating material may vary when concentration of the coating material in an aqueous solution, measurement conditions such as measurement temperature and the like are different. When the measurement conditions are different, all coating materials having a viscosity value within the aforementioned viscosity range on conversion to the viscosity of a 5% (W/V) aqueous solution at 20 °C. are encompassed in the "coating material having a low viscosity" of the present invention.
As the "coating material having a low viscosity", for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, a premix of hydroxypropyl cellulose and hydroxypropyl methylcellulose, Polyvinyl alcohol-polyethylene glycol graft copolymer [Kollicoat IR] and the like can be mentioned.
The above-mentioned coating material may be a mixture of two or more kinds thereof in an appropriate ratio. When a coating material mixture obtained by combining one or more kinds selected from the above-mentioned coating materials and one or more kinds of coating materials having high viscosity at an appropriate ratio is a "coating material whose 5% (W/V) aqueous solution has a viscosity of not more than 35 mPa.s at 20°C", this mixture can be used as "a coating material having a low viscosity" of the present invention. As used herein, by the "coating material having high viscosity" is meant, for example, a coating material whose 5% (W/V) aqueous solution has a viscosity of more than 35 mPa.s at 20°C. Specific examples thereof include hydroxypropyl cellulose, hydroxypropyl methylcellulose and the like.
A coating material having a low viscosity preferably includes hydroxypropyl cellulose SL (viscosity of 5% aqueous solution at 20°C: about 24 mPa.s; and/or viscosity of 2% aqueous solution at 20°C: 3.0-5.9 mPa.s), hydroxypropyl cellulose SSL (viscosity of 5% aqueous solution at 20°C: about 8 mPa.s; and/or viscosity of 2% aqueous solution at 20°C.: 2.0-2.9 mPa.s). Polyvinyl alcohol-polyethylene glycol graft copolymer [Kollicoat IR
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(trademark). BASF, Germany] (viscosity of 5% aqueous solution at 20°C: about 18 mPa.s) and the like.
A coating material having a low viscosity may be dissolved or suspended in the dispersion of the present invention. For efficient production of a coated preparation superior in content uniformity of metformin and strength of the preparation, the coating material is preferably dissolved in the dispersion of the present invention. The dispersion of the present invention may further contain a coating additive. As the coating additive, for example, shading agents and/or coloring agents such as titanium oxide, talc, ferric oxide and the like; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbates and the like; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid and the like; lactose, D-mannitol, low-substituted hydroxypropyl cellulose, carmellose calcium, crospovidone and the like can be mentioned.
When the coating additive is not water soluble, the average particle size thereof is preferably not more than 500 urn, more preferably not more than 150 urn, particularly preferably not more than 75 urn. When a coating additive having such average particle size is used, a coated preparation superior in content uniformity of metformin and strength of the preparation can be obtained efficiently.
The concentration of the coating material having a low viscosity in the dispersion of the present invention is, for example, 1-30%) (W/W), preferably 1-25% (W/W), more preferable 2-25% (W/W). Concentrations in these ranges are preferable in view of coating workability, content uniformity of metformin in the obtained coated preparation, and the like. The concentration of the coating additive in the dispersion of the present invention is, for example, 0.2-35% (W/W), preferably 0.2-30% (W/W), more preferable 0.5-15% (W/W). Concentrations in these ranges are preferable in view of coating workability, content uniformity of metformin in the obtained coated preparation, and the like. As the core to be coated with an aqueous dispersion of metformin comprising a coating material having a low viscosity (hereinafter sometimes to be abbreviated as a core of the present invention), for example, solid preparations such as tablet, capsule, granule, powder, troche and the like can be mentioned. The solid preparation may be a controlled release preparation such as immediate release preparation, release sustaining preparation (sustained release preparation) and the like. The solid preparation may contain a conventional additive in the field of pharmaceutical preparation and can be also produced according to a known method. As the additive, for example, excipient, disintegrant, binder, lubricant, coloring agent, pH regulator, surfactant, release-sustaining agent, stabilizer, sour agent, flavor, glidant and the like can be mentioned. These additives are used in an amount conventionally
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employed in the field of pharmaceutical preparation. As the excipient, for example, starches such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like; sugars and sugar alcohols such as lactose, fructose, glucose, D-mannitol, sorbitol and the like; anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate and the like can be mentioned.
As the disintegrant, for example, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like are used. The amount of the disintegrant to be used is preferably 0.5-25 parts by weight, more preferably 1-15 parts by weight, per 100 parts by weight of the solid preparation. As the binder, for example, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gum arabic powder and the like can be used. The amount of the binder to be used is preferably 0.1-50 parts by weight, more preferably 0.5-40 parts by weight, per 100 parts by weight of the solid preparation. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose esters of fatty acids, sodium stearyl fumarate and the like. As the coloring agent, for example, food colors such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2 and the like, food lake colors, ferric oxide and the like can be mentioned. As the pH regulator, citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like can be mentioned.
As the surfactant, sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol and the like can be employed.
As the release-sustaining agent, for example, cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose (preferably hydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208 and the like), cellulose acetate (preferably cellulose acetate having an acetyl content of 39.3-40%), cellulose diacetate, cellulose triacetate, cellulose acetate propionate, ethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose sodium carboxymethyl cellulose and the like; sodium alginate, carboxyvinyl polymer; acrylic acid polymers such as aminoalkylmethacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer suspension and the like can be mentioned. The release-sustaining agent may contain, for example, flux enhancers (e.g., sodium chloride, potassium chloride, sucrose, sorbitol, D-mannitol, polyethylene glycol (preferably polyethylene glycol 400 and the like), propylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate. polyvinyl alcohol, methacrylic acid polymer), plasticizers (e.g., triacetin, acetylated
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monoglyceride, grape seed oil, olive oil. sesame oil, acetyltributyl citrate, acetyltriethyl citrate, glycerin sorbitol, diethyl oxalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, glycerol tributyrate) and the like. Preferable examples of the release-sustaining agent include (1) a semipermeable membrane coating containing cellulose acetate (preferably cellulose acetate having an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol 400 and the like) and triacetin; (2) a release-sustaining composition containing sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208 and microcrystalline cellulose; and the like.
As the stabilizer, for example, tocopherol, tetrasodium edetate, nicotinamide, cyclodextrins and the like can be mentioned.
As the sour agent, for example, ascorbic acid, citric acid, tartaric acid, malic acid and the like can be mentioned.
As the flavor, for example, menthol, peppermint oil, lemon oil, vanillin and the like can be mentioned.
As the glidant, for example, light anhydrous silicic acid, hydrated silicon dioxide and the like can be mentioned.
The above-mentioned additives may be used in a mixture of two or more kinds thereof in an appropriate ratio.
The core of the present invention is preferably a tablet containing metformin hydrochloride. The shape of the tablet may be any from round, caplet, oblong and the like. The tablet can be produced by, for example, mixing or granulating the metformin hydrochloride with the aforementioned additives, and then compression-molding the obtained mixture or granules after mixing, according to methods conventionally employed in the field of pharmaceutical preparation.
Here, mixing is done using, for example, a mixer such as a V-type mixer, a tumbler mixer and the like, and granulation is done using, for example, a high speed mixer granulator, a fluid bed granulator and the like
In the production method of the present invention, the coating is done according to
known methods. For example, coating is done using a film coating equipment.
In addition, coating is done such that the core of the present invention is generally 50-99 parts
by weight, preferably 70-99 parts by weight, more preferably 70-98 parts by weight, per 100
parts by weight of the obtained coated preparation.
Furthermore, the "preparation coated with metformin" obtained according to the production method of the present invention (hereinafter sometimes to be abbreviated as a coated
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preparation of the present invention) may be coated with the aim of improving preparation strength, improving a bitter taste, increasing light resistance, coloring and the like of the coated preparation. Such coating can be applied according to a known method and using, for example, the aforementioned coating material and the like.
As the dosage form of the coated preparation of the present invention, for example, tablet, capsule, granule, powder, troche and the like can be mentioned. The dosage form of the coated preparation is preferably a tablet. The shape of the tablet may be any from round, caplet oblong and the like. In addition, a mark or a letter may be printed on the tablet for identifiability, and a separating line may be made to facilitate division. The amount of the active ingredient in the coated preparation of the present invention is, for example, generally 0.01-99 parts by weight, preferably 0.1-99 parts by weight, per 100 parts by weight of the coated preparation.
The dose of the coated preparation of the present invention is 7.5-60 mg/day, preferably 15-60 mg/day, more preferably 15-45 mg/day, based on the amount of metformin, for an adult (body weight 60 kg).
Use of the production method of the present invention when producing a preparation coated with metformin can afford a coated preparation superior in the dissolution property (particularly, dissolution property immediately after administration to the body or within 15 min. from the start of a dissolution test) of metformin. EXAMPLE 1
Hydroxypropyl cellulose (26.4 g, (viscosity of 5% aqueous solution at 20°C: 8 mPa.s), polyethylene glycol 6000 (1.32 g), titanium oxide (2.64 g) and metformin (16.5 g) were dispersed in water (297 g) to give a coating solution. The tablets (300 g) obtained in Reference Example 1 were fed in a film coating equipment and coated with the aforementioned coating solution at an inlet temperature of 70°C. to give a coated preparation weighing 260.9 mg per tablet. EXAMPLE 2
Hydroxypropyl cellulose (24 g) (viscosity of 5% aqueous solution at 20°C: 24 mPa.s), polyethylene glycol 6000 (1.2 g), titanium oxide (2.4 g) and metformin (15 g) were dispersed in water (344.7 g) to give a coating solution. The tablets (250 g) obtained in Reference Example 2 were fed in a film coating equipment and coated with the aforementioned coating solution at an inlet temperature of 75 °C to give a coated preparation weighing 381 mg per tablet.
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EXAMPLE 3
Hydroxypropyl cellulose (24 g) (viscosity of 5% aqueous solution at 20°C: 8 mPa.s), polyethylene glycol 6000 (1.2 g), titanium oxide (2.4 g) and metformin (15 g) were dispersed in water (344.7 g) to give a coating solution. The tablets (250 g) obtained in Reference Example 2 were fed in a film coating equipment and coated with the aforementioned coating solution at an inlet temperature of 75°C. to give a coated preparation weighing 382 mg per tablet. EXAMPLE 4
Polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, 48.0 g, BASF, Germany) (viscosity of 5% aqueous solution at 20°C: 18 mPa.s), polyethylene glycol 6000 (2.4 g), titanium oxide (4.8 g) and metformin (30.0 g) were dispersed in water (540 g) to give a coating solution.
The tablets (250 g) obtained in Reference Example 4 were fed in a film coating equipment and coated with the aforementioned coating solution at an inlet temperature of 90°C. to give a coated preparation weighing 461 mg per tablet. REFERENCE EXAMPLE 1
D-mannitol (2176 g) and corn starch (918 g) were charged in a fluid bed granulator and granulated while spraying an aqueous solution (1700 g) containing hydroxypropyl cellulose (102 g), which was followed by a drying step to give granules. Microcrystalline cellulose (160.2 g) and magnesium stearate (32 g) were added to the obtained granule powder (3012 g) and mixed. The obtained granule powder mixture was tableted by a tableting machine (tablet size: 8.5 mm, compression pressure 9 KN/punch) to give tablets weighing 244 mg per tablet. REFERENCE EXAMPLE 2
Lactose (2470 g), corn starch (315 g) and carmellose calcium (157.5 g) were charged in a fluid bed granulator and granulated while spraying an aqueous solution (1575 g) containing hydroxypropyl cellulose (94.5 g), which was followed by a drying step to give granules. Carmellose calcium (89.3 g) and magnesium stearate (17.9 g) were added to the obtained granule powder (2868 g) and mixed. The obtained granule powder mixture was tableted by a tableting machine (tablet size: major axis 12 mm, minor axis 7 mm. compression pressure 15 KN/punch) to give tablets weighing 350 mg per tablet. REFERENCE EXAMPLE 3
Lactose (1976 g), corn starch (252 g) and carboxymethylcellulose calcium (126 g) were charged in a fluid bed granulator and granulated while spraying an aqueous solution (1260 g) containing hydroxypropyl cellulose (75.6 g), which was followed by a drying step to
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give granules. Carboxy methylcellulose calcium (71.4 g) and magnesium stearate (14.3 g) were added to the obtained granule powder (2294 g) and mixed. The obtained granule powder mixture was tableted by a tableting machine (tablet size: 9 mm, compression pressure 7 KN/punch) to give tablets weighing 300 mg per tablet. REFERENCE EXAMPLE 4
The tablets (400 g) obtained in Reference Example 2 were fed in a film coating equipment, coated with a coating solution containing aqueous ethylcellulose dispersion (148.2 g), talc (2.2 g), triethyl citrate (13.3 g), yellow ferric oxide (0.36 g) and water (231.1 g) at an inlet temperature of 90° C, whereby tablets weighing 391 mg per tablet were obtained. Furthermore, the tablets were coated with a solution of hydroxypropyl methylcellulose (47.3 g), polyethylene glycol 6000 (9.5 g), titanium oxide (6.3 g) and ferric oxide (0.09 g) in water (473 g) under the similar conditions as above to give tablets weighing 416 mg per tablet. INDUSTRIAL APPLICABILITY
The coated preparation obtained by the production method of the present invention is
useful as a therapeutic agent for diabetes and the like and superior in the characteristics of the
preparation such as dissolution property (particularly, dissolution property immediately after
administration to the body or within 15 minutes from the start of a dissolution test) of
metformin and the like and preservation stability.
Moreover, according to the production method of the present invention, preparations coated with metformin can be conveniently produced. Therefore, the production method of the present invention is useful as an industrial production method for the mass production of the aforementioned coated preparation.
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Claims:
1. A method for the manufacture of a coated preparation, which comprises coating a core with an aqueous dispersion of metformin comprising a coating material having a low viscosity.
2. The method as claimed in claim 1, wherein the coating material having a low viscosity in its 5% aqueous solution shows a viscosity of not more than 35 mPa.s at 20°C.
3. The method as claimed in claim claim 1, wherein the coating material having a low viscosity is hydroxypropyl cellulose, hydroxypropyl cellulose or polyvinyl alcohol-polyethylene glycol graft copolymer.
4. The method as claimed in claim 1, wherein a core comprising metformin is coated with an aqueous dispersion of metformin comprising a coating material having a low viscosity.
5. A method for improving dissolution of metformin from a preparation coated with metformin, which comprises, when producing said preparation, coating with an aqueous dispersion of metformin comprising a coating material having a low viscosity.
6. A coated preparation obtained according to the production method of claim 1.
7. A coated preparation as claimed in claim 6, which releases not less than 50% of metformin in 15 minutes in a dissolution test by a rotating basket method using a hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37°C, 100 rpm.
8. A pharmaceutical formulation of metformin as is hereinbefore described.
Dated this the 08th day of September 2008
of SUBRAMANIAM, NATARAJ & ASSOCIATES ATTORNEY FOR THE APPLICANTS