DESC: The following specification particularly describes the invention and the manner in which it is to be performed:

EXTENDED RELEASE PHARMACEUTICAL FORMULATIONS COMPRISING METFORMIN

BACKGROUND OF THE INVENTION

The present invention relates to a low weight extended release pharmaceutical formulation comprising metformin and at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

The present invention relates to a low weight extended release pharmaceutical formulation comprising metformin and at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients that are useful in improving glucose tolerance in patients with type 2 diabetes mellitus by lowering both basal and postprandial plasma glucose.

Type II diabetes mellitus is characterized by deficient insulin activity arising from decreased insulin secretion secondary to beta cell failure and/or compromised insulin action in peripheral target tissues (insulin resistance). This abnormal metabolic state leads to excess hepatic glucose production and altered metabolism of proteins and lipids. This along with hyperglycemia contributes to microvascular and macrovascular complications.

Thus it is important to achieve a glycemic control in patients having type II diabetes mellitus that will maintain near normal glucose level to prevent such complications.

Oral antidiabetic therapy includes compounds belonging to class of sulfonylureas, biguanides, thiazolidinones and alpha glucosidase inhibitors.

Metformin is a biguanide antihyperglycemic compound useful in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Metformin is commercially available in USA as Glucophage® tablets containing 500 mg, 850 mg, or 1000 mg of metformin hydrochloride.and Glucophage® XR tablets containing 500 mg and 750 mg of metformin hydrochloride.

Metformin hydrochloride is chemically known as N,N-dimethylimidodicarbonimidic diamide hydrochloride. Metformin hydrochloride is a highly water soluble drug having a relatively low bioavailability (50% - 60%). The bioavailability decreases with increasing dosage which suggests of limited absorption that may be attributed to saturable solubility, low permeability in the lower part of gastrointestinal tract or less transit time at the site of absorption which is upper part of gastrointestinal tract. Thus, in order to maintain the therapeutic plasma levels over a prolonged time, repeated administration may be required for metformin immediate release formulation. Extended release once daily dosage form that provides prolonged residence time of metformin in the upper GI tract would improve patient compliance.

In the past, various successful polymeric sustained release preparations have been developed for release of drugs with different physical properties. Such preparations have been effective for increasing release times for relatively hydrophobic and water-insoluble drugs. However, the predominant release mechanism in such dosage forms is initial drug erosion followed by slow diffusion through the polymer matrices. Highly soluble drugs tend to have a rapid diffusion through polymer matrices leading to initial burst release and thus posing a difficulty to achieve an extended release.

U.S. Patent Application Publication No. 20060057202 provides a multi layered composition containing a drug belonging to the class of Biguanide, or its pharmaceutically acceptable salts, e.g. Metformin HCl, one or more polymers and desired excipients in the first layer as prolonged release component, which is mixed with a second immediate release layer containing a different drug. Said tablet formulation allows pH independent, in-vitro prolonged release of Metformin HCl up to a period of 8-12 hours from selective layer. Granules containing Biguanides such as Metformin HCl are prepared by wet granulating a blend of Metformin HCl having particle size of less than 100 microns, non-biodegradable, inert polymer(s) and other excipients.

U.S. Patent Application Publication No. 20080274180 describes pharmaceutical compositions comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, a gas-generating agent, a hydrophilic polymer as a release retardant, one more hydrophilic or hydrophobic polymer to provide stability to the system and an additional hydrophilic polymer or gum as a release modifier.

Wadher K. et. al. in “Formulation of sustained release metformin hydrochloride tablet using combination of lipophilic waxes by melt granulation technique’’, African Journal of Pharmacy and Pharmacology, Vol. 4(8), pp. 555-561, Aug 2010, provides sustained release matrix tablets of metformin hydrochloride using hydrogenated castor oil, stearic acid and glyceryl monostearate as meltable binder to reduce dosage regimen, better therapeutic efficacy and improved patient compliance with less toxicity. The weight of the tablet of this invention is about 1000 mg for 500 mg of metformin HCl.

US Patent No’s 6,475,521 and 6,660,300 provides a biphasic controlled release system composed of (1) inner solid particulate phase in the form of individual granules or particles containing metformin and an extended release material formed of one or more of hydrophilic and/or hydrophobic polymers and/or other hydrophobic materials such as waxes, fatty alcohols and/or fatty acid esters, and (2) an outer solid continuous phase in which granules or particles of inner solid particulate phase are dispersed and embedded.

The outer solid continuous phase is formed of one or more of hydrophilic and/or hydrophobic polymers and/or other hydrophobic materials such as waxes, fatty alcohols and/or fatty acid esters. 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 gastrointestinal tract. The total tablet weight containing 500 mg of the active is about 1000 mg; two tablets are required for administering the daily dose of 1000 mg metformin. The weight of a tablet containing 1000 mg of the active is about 2 g which is too large for human consumption. A bulky dosage form besides being aesthetically unacceptable also causes a difficulty in swallowing and thus reduces patient compliance.

Attempts have been made to prepare an extended release formulation of metformin with reduced weight.

U.S. Patent No. 5,955,106 discloses pharmaceutical preparations containing metformin and a hydrocolloid-forming retarding agent prepared by granulation with an aqueous solvent. The hydrocolloid-forming agents, on coming in contact with aqueous medium, swell and form a gel matrix which erodes to release the drug. The total tablet weight as per the working examples is up to 1000 mg for 850 mg of metformin hydrochloride.

U.S. Patent No. 6,340,475 describes tablets in which the drugs are incorporated into hydrophilic swellable polymeric matrices that swell upon uptake of water to a size that is large enough to cause retention of the tablet in the stomach. The swollen polymeric matrix remains retard the release of the drugs. The total tablet weight as per the working examples is up to 400 mg for a 250 mg of metformin hydrochloride.

International Patent Application Publication No. WO2011060255 provides reduced mass metformin XR formulations that comprise silicon dioxide or colloidal silicon dioxide with reduced amounts of hydroxypropyl methylcellulose.

International Patent Application Publication No.WO2004110422 discloses extended-release metformin tablets, which comprise 5-25% w/w of rate controlling polymers. The use of lesser amounts of rate controlling polymers ensures that the total weight of the dosage form is low and a single dosage unit is sufficient to provide the therapeutic dosage of the drug.

Indian Patent No. 244433 provides a controlled release delivery system for Metformin comprising of (a) therapeutically effective amount of Metformin or pharmaceutically acceptable salts there of; (b) hydrophilic polymers and (c) hydrophobic lubricating agents(s).

Indian Patent No. 209309 provides a monolithic sustained release composition of metformin hydrochloride with a hydrophobic material, the composition being configured to exhibit a specific in-vitro drug release characteristics of the metformin hydrochloride while in gastric fluid having a pH of 1.2 for a first hour and then in phosphate buffer having a pH of 6.8.

U.S. Patent No. 6,117,451 which describes a direct tableting, free-flowing particulate metformin hydrochloride formulation in the form of a tableting powder, capable of being directly compressed into a tablet having adequate hardness, rapid disintegration time, and an acceptable dissolution pattern.

In addition to weight of a pharmaceutical formulation, the size and shape also should be monitored. The dimensions should be small enough so that the formulation is aesthetically acceptable and can be easily swallowed.

Apart from high water solubility and high unit dose, poor compressibility is another issue related to Metformin that poses challenges for a formulator to make an extended release formulation. While high unit dose limits use of excipients in order to control the weight of the unit dosage form, the poor compressibility requires certain amounts of excipients to be added to ensure adequate flow properties and compression characteristics.

Lakshman J. P. et. al. in ‘Application of melt granulation technology to enhance tabletting of poorly compactible high-dose drugs’, Journal of Pharmaceutical Sciences, Vol. 100, No. 4, April 2011, provides high-dose formulation containing metformin and hydroxypropylcellulose prepared by melt granulation using a twin screw extruder.

There is still need to explore simple, cost effective approaches to prepare a low weight and small size formulation of metformin that is capable of providing an extended drug release over a prolonged period of time. The present invention provides alternative approaches to prepare a low weight, extended release formulations of metformin that are capable of providing extended release of the drug over a prolonged period of time. The pharmaceutical formulations of the present invention have a small size.

SUMMARY OF THE INVENTION

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the content of metformin hydrochloride is more than 65% of the total weight of the formulation.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the content of metformin hydrochloride is more than 65% of the total weight of the formulation.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein weight ratio of metformin hydrochloride to at least one release rate controlling substance and other pharmaceutically acceptable excipients is 1:0.4 or less.

In embodiments, the present invention relates to a low weight small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein weight ratio of metformin hydrochloride to at least one release rate controlling substance and other pharmaceutically acceptable excipients is 1:0.4 or less.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has bulk and tapped densities of less than about 0.8 g/cm3.

In embodiments, the present invention relates to a low weight small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has bulk and tapped densities of less than about 0.8 g/cm3.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the formulation is a compressed tablet comprising 500 mg of metformin hydrochloride having the weight lesser than 750 mg.

In embodiments, the present invention relates to a low weight small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the formulation is a compressed tablet comprising 500 mg of metformin hydrochloride having the volumes that are smaller than cuboid volume of 765 mm3.

In embodiments, the present invention relates to a process of preparation of low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients, wherein the process is melt granulation or wet granulation.

In embodiments, the present invention relates to a melt granulation process for preparation of a low weight, extended release pharmaceutical formulation of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients;

b) Heating the blend of step a) to form a molten slurry;

c) Extruding the slurry of step b);

d) Milling the extrudates of step c);

e) Blending the milled extrudates of step d) with one or more excipients; and;

f) Compressing the blend of step e) into tablets or filling the blend of step e) into capsules.

In embodiments, the present invention relates to a melt granulation process of preparation of a low weight, small size extended release pharmaceutical formulations of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more intra-granular pharmaceutically acceptable excipients;

b) Heating the blend of step a) to form a molten slurry;

c) Extruding the slurry of step b);

d) Milling the extrudates of step c);

e) Blending the milled extrudates of step d) with one or more excipients; and;

f) Compressing the blend of step e) into tablets or filling the blend of step e) into capsules.

In embodiments, the present invention relates to a wet granulation process of preparation of a low weight extended release pharmaceutical formulation of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more intra-granular pharmaceutically acceptable excipients;

b) Granulating the blend of step a) using a granulating solvent;

c) Drying and sifting the granules of step b);

d) Blending the granules of step c) with extra-granular excipients; and;

e) Compressing the blend of step d) into tablets or filling the blend of step e) into capsules.

In embodiments, the present invention relates to a wet granulation process for preparation of a low weight, small size extended release pharmaceutical formulation of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more intra-granular pharmaceutically acceptable excipients;

a) Granulating the blend of step a) using a granulating solvent;

b) Drying and sifting the granules of step b);

c) Blending the granules of step c) with extra-granular excipients; and;

d) Compressing the blend of step d) into tablets or filling the blend of step e) into capsules.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients that provides in-vitro release of metformin hydrochloride such that not less than about 25% of metformin hydrochloride is released within 1 hour and more than about 80% metformin hydrochloride is released within 10 hours.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipient that provides in-vitro release of metformin hydrochloride such that not less than about 25% of metformin hydrochloride is released within 1 hour and more than about 80% metformin hydrochloride is released within 10 hours.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein at least one release rate controlling substance is selected from a group consisting of cellulose ethers such as hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose and carboxymethyl cellulose;

polyvinylpyrrolidones such as cross-linked and non-crosslinked polyvinylpyrrolidone; polyethylene oxide; gums such as xanthan gum, guar gum and tragacanth, natural fats such as coconut, soya, cocoa and their modified forms such as totally or partially hydrogenated castor oil and hydrogenated vegetable oil.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein at least one release rate controlling substance is seleced from a group consisting of cellulose ethers such as hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose and carboxymethyl cellulose; polyvinylpyrrolidones such as cross-linked and non-crosslinked polyvinylpyrrolidone; polyethylene oxide; gums such as xanthan gum, guar gum and tragacanth; natural fats such as coconut, soya, cocoa and their modified forms such as totally or partially hydrogenated castor oil and hydrogenated vegetable oil.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients that are useful in improving glucose tolerance by lowering both basal and postprandial plasma glucose and thus achieve glycemic control in patients with type 2 diabetes mellitus.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and other pharmaceutically acceptable excipients that are useful in improving glucose tolerance by lowering both basal and postprandial plasma glucose and thus achieve glycemic control in patients with type 2 diabetes mellitus.

In embodiments, the pharmaceutical formulation of the present invention may additionally contain other active ingredients. Preferably, the additional active ingredient is an antidiabetic drug. More preferably, the additional active ingredient is selected from the group of sulfonylurea class of antidiabetic drugs. Still more preferably, the active ingredient is glimepiride.

DETAILED DESCRIPTION

The present invention relates to a low weight extended release pharmaceutical formulation comprising metformin, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

The term "low weight" refers to the dosage form wherein the total weight of the dosage form does not exceed by 40 % of the weight of metformin or its pharmaceutically acceptable salts thereof.

The term "extended release" refers to release of a drug from a formulation for an extended period of time, such as more than about 4 hours as determined using an in vitro dissolution method.

The extended release pharmaceutical formulations of the present invention may provide in-vivo drug release such that blood levels of the drug are maintained within the therapeutic range, i.e., at or above a minimum effective concentration (MEC) but below toxic concentrations over an extended period of time such as more than about 4 hours.

Metformin may be present in the form of any of its pharmaceutically acceptable salts, solvates, esters and derivatives thereof. Metformin is present as amorphous form, crystalline form, or mixtures thereof. In a preferred embodiment metformin is present as metformin hydrochloride. The doses of metformin hydrochloride may include from about 200 mg to about 1000 mg.

The term “release rate controlling substance” as used herein refers to any substance which can alter or modify the drug release time, rate, and extent from a formulation in any manner, such as the drug release is obtained over an extended period of time such as more than about 4 hours

The term ‘final blend’ refers to a blend of ingredients that provides the formulations of the present invention after a single processing step.

In embodiments the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

In embodiments the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the content of metformin hydrochloride is more than 65% of the total weight of the formulation.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the content of metformin hydrochloride is more than 65% of the total weight of the formulation.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the weight ratio of metformin hydrochloride to at least one release rate controlling substance and other pharmaceutically acceptable excipients is 1:0.4 or less.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the weight ratio of metformin hydrochloride to at least one release rate controlling substance and other pharmaceutically acceptable excipients is 1:0.4 or less.

‘Final blend’ of the present invention can be characterized for specific flow properties and compression characteristics.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has bulk and tapped densities of less than about 0.8 g/cm3.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has bulk and tapped densities of less than about 0.8 g/cm3.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and on or more other pharmaceutically acceptable excipients wherein the final blend has Hausner’s ratio of less than 1.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has Hausner’s ratio of less than 1.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has compressibility index between 15 to 20.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has compressibility index between 15 to 20.

The ‘final blend’ of the present invention may comprise granules.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend comprises granules having size in the range of about 100 µm to about 1000 µm.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend comprises granules having size in the range of about 100 µm to about 1000 µm.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the formulation is a compressed tablet comprising 500 mg of metformin hydrochloride having the weight lesser than 750 mg.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the formulation is a compressed tablets comprising 500 mg of metformin hydrochloride having the volumes that are smaller than cuboid volume of 765 mm3.

In embodiments, the present invention relates to a process for preparation of a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

In embodiments, the present invention relates to a process for preparation of a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

For high dose formulations, the amount of release-controlling materials and other excipients has to be kept at minimum. Therefore it is important to enhance compressibility of API and other components by using suitable processing techniques.

Granulation provides improved compression characteristics to the powder blend, such as better particle size control, enlargement of particle size to improve flow properties, reduction of segregation in polydisperse powders, prevention of segregation of ingredients, improved appearance of product.

Equipments suitable for processing the pharmaceutical formulations of the present invention include one or more of rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, blenders, roller compacters, extrusion-spheronizers, melt extruders, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multimills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.

In embodiments, the present invention relates to a process for preparation of a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients, wherein the process is melt granulation or wet granulation.

In embodiments, the present invention relates to a process for preparation of a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients, wherein the process is melt granulation or wet granulation.

Melt granulation is a process by which pharmaceutical powders are efficiently agglomerated by the use of a binder or a mixture of binders that melts during the process.

In melt granulation temperatures are maintained below the melting point of a drug substance but above the glass transition temperature (Tg) of binders used.

Metformin hydrochloride has a high melting point of about 226°C and is thermally stable up to 170°C and degrades beyond 200°C. These characteristics renders metformin suitable for utilizing melt granulation technology.

In embodiments, the present invention relates to a melt granulation process for preparation of a low weight extended release pharmaceutical formulation of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients;

b) Heating the blend of step a) to form a molten slurry;

c) Extruding the slurry of step b);

d) Milling the extrudates of step c);

e) Blending the milled extrudates of step d) with one or more excipients; and

f) Compressing the blend of step e) into tablets or filling the blend of step e) into capsules.

In embodiments, the present invention relates to a melt granulation process for preparation of a low weight, small size extended release pharmaceutical formulation of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients;

b) Heating the blend of step a) to form a molten slurry;

c) Extruding the slurry of step b);

d) Milling the extrudates of step c);

e) Blending the milled extrudates of step d) with one or more excipients; and

f) Compressing the blend of step e) into tablets or filling the blend of step e) into
capsules.

In an aspect of the said embodiments molten slurry is prepared using various temperature zones having temperatures about 25°C to about 170°C, using a Pharma 16 mm Thermo Fischer Scientific extruder.

In embodiments, the present invention relates to a wet granulation process for preparation of a low weight extended release pharmaceutical formulation of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more intra-granular pharmaceutically acceptable excipients;

b) Granulating the blend of step a) using a granulating solvent;

c) Drying and sifting the granules of step b);

d) Blending the granules of step c) with extra-granular excipients; and

e) Compressing the blend of step d) into tablets or filling the blend of step d) into capsules.

In embodiments, the present invention relates to a wet granulation process for preparation of a low weight, small size extended release pharmaceutical formulation of metformin hydrochloride, wherein the process comprises the steps of:

a) Blending metformin hydrochloride, at least one release rate controlling substance and one or more intra-granular pharmaceutically acceptable excipients;

b) Granulating the blend of step a) using a granulating solvent;

c) Drying and sifting the granules of step b);

d) Blending the granules of step c) with extra-granular excipients; and

e) Compressing the blend of step d) into tablets or filling the blend of step d) into capsules.

In embodiments, low weight extended release pharmaceutical formulations as per the present invention include granules, pellets, milled extrudates or mini-tablets, which are compressed to form a tablet or filled into a capsule.

In embodiments, low weight small size extended release pharmaceutical formulations as per the present invention include granules, pellets, milled extrudates or mini-tablets, which are compressed to form a tablet or filled into a capsule.

The pharmaceutical formulation of the present invention may be coated further. The coating can be carried out using conventional techniques known to the art such as spray coating, compression coating and powder coating.

The pharmaceutical formulations of the present invention were subjected to in-vitro dissolution testing in a dissolution media. Rate and content of metformin that is released from the formulations were determined using techniques such as high performance liquid chromatography (HPLC).

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients that provides in-vitro release of metformin hydrochloride such that not less than about 25% of metformin hydrochloride is released within 1 hour and more than about 80% metformin hydrochloride is released within 10 hours.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients that provides in-vitro release of metformin hydrochloride such that not less than about 25% of metformin hydrochloride is released within 1 hour and more than about 80% metformin hydrochloride is released within 10 hours.

In embodiments, the release rate controlling substance that is useful in preparing extended release formulations of the present invention is selected from a group consisting of cellulose ethers such as hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethyl cellulose, polyvinylpyrrolidones such as cross-linked and non-crosslinked polyvinylpyrrolidone, polyethylene oxide, gums such as xanthan gum, guar gum and tragacanth, natural fats such as coconut, soya, cocoa and their modified forms such as totally or partially hydrogenated castor oil, hydrogenated vegetable oil, and any mixtures thereof.

In embodiments, the release rate controlling substance that is useful in preparing extended release formulations of the present invention includes but not limited to, hydrophilic substances, hydrophobic substances, lipophilic substances, water soluble excipients, water insoluble excipients, pH dependent polymers, pH independent polymers, swelling polymers, non-swelling polymers, gelling polymers, non-gelling polymers, gums, waxes, oily substances, polyethylene glycol glycerides such as Gelucire® products, hydrogenated vegetable oils, alginic acid and alginates, acrylic and/or methacrylic acid polymers or copolymers, and the like, and any mixtures thereof.

Examples of release rate controlling substances include without limitation thereto, polymers such as cellulose ethers like hydroxypropyl methylcellulose (hypromellose or HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose, ethylcellulose, carboxymethyl celluloses, polyvinylpyrrolidone like cross-linked and non-crosslinked polyvinylpyrrolidone, polyethylene glycol glycerides, polyethylene oxide, polyvinyl alcohol, polysaccharides such as glucan, carrageenan, scleroglucan, mannan, galactomannan, gellan, alginic acid and its derivatives such as sodium alginate, calcium alginate, propylene glycol alginate, polyaminoacids such as gelatin, polymethyl vinyl ether maleic anhydride, polymethacrylates such as copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups, acrylic acid polymers such as carbomer, cellulose acetate, and mixtures thereof.

Examples of lipophilic and hydrophobic substances that can be used in the present disclosure include, without limitation thereto, waxes such as carnauba wax, microcrystalline wax, beeswax, and polyethoxylated beeswax, gums such as xanthan gum, guar gum and tragacanth, natural fats such as coconut, soya, cocoa and their modified forms such as totally or partially hydrogenated castor oil, hydrogenated vegetable oil, fatty acid derivatives such as mono-, bi- and tri-substituted glycerides, phospholipids, glycerophospholipids, glyceryl palmitostearate, glyceryl behenate, glyceryl monostearate, diethyleneglycol palmitostearate, polyethyleneglycol stearate, polyethyleneglycol palmitostearate, polyoxyethylene-glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, fatty alcohols associated with polyethoxylate fatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturated fatty acids and their hydrogenated derivatives, lecithin, cephalins, chitosan and derivatives thereof, sphingolipids, sterols such as cholesterol and its substituted derivatives, and mixtures thereof.

Useful water soluble or insoluble substances include, for example, sugars, zein, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyethylene glycol, poloxamers, ethyl cellulose, gelatin, polyarginine, polyglycine, polyvinylpyrrolidones, vinyl acetate copolymers, and mixtures thereof.

Pharmaceutically acceptable excipients according to the present invention include, for example, any one or more of diluents, binders, stabilizers, lubricants and glidants that are useful in preparation of pharmaceutical formulations.

Various useful fillers or diluents include, but are not limited to, sugars such as lactose monohydrate, lactose anhydrous, mannitol; starches such as maize starch, corn starch; pregelatinized starches such as PCS PC10 from Signet Chemical Corporation and starch 1500; and cellulose derivatives such as crystalline cellulose and powdered cellulose.

Examples of crystalline cellulose products include but are not limited to Ceolus™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PH-112, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include, but are not limited to, etoprolol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders include, but are not limited to, hydroxypropylcellulose, also called HPC (e.g., Klucel™ LF and Klucel™ EXF), various grades of hydroxypropyl methylcellulose, also called hypromellose or HPMC (e.g., Methocel™ products), various grades, polyvinylpyrrolidone or povidone (such as grades K25, K29, K30, and K90), copovidone (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products), methylcellulose, polymethacrylates, and starches.

Useful lubricants include magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and mixtures thereof.

One or more glidant materials, which improve the flow of powder blends, pellets, or mini-tablets, and minimize dosage form weight variations, can be used. Useful glidants include, but are not limited to silicon dioxide, talc, and mixtures thereof.

The low weight extended release pharmaceutical formulations of metformin as per the present invention are cost-effective, do not involve toxic and hazardous solvents, and also are easy to make on a commercial scale.

The low weight small size extended release pharmaceutical formulations of metformin as per the present invention are cost-effective, do not involve toxic and hazardous solvents, and also are easy to make on a commercial scale.

Various solvents that can be used in the processes for preparation of pharmaceutical formulations of the present invention include but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran, and mixtures thereof. These solvents can be used as granulating solvent and coating solvent.

In embodiments, a low weight extended release pharmaceutical formulation as per the present invention is intended for oral administration to a subject in need thereof.

In embodiments, a low weight, small size extended release pharmaceutical formulation as per the present invention is intended for oral administration to a subject in need thereof.

In embodiments, the present invention relates to a low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients that are useful in improving glucose tolerance by lowering both basal and postprandial plasma glucose and thus achieve glycemic control in patients with type 2 diabetes mellitus.

In embodiments, the present invention relates to a low weight, small size extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients that are useful in improving glucose tolerance by lowering both basal and postprandial plasma glucose and thus achieve glycemic control in patients with type 2 diabetes mellitus.

In embodiments, the formulation of the present invention may additionally contain other active ingredients. Preferably, the additional active ingredient is an antidiabetic drug.

More preferably, the additional active ingredient is selected from the group of sulfonylurea class of antidiabetic drugs. Still more preferably, the active ingredient is glimepiride.

The additional active ingredient may be incorporated in the core tablet containing metformin or may be coated over the core tablet. When coated over the core tablet, it is preferred that core tablet containing metformin is separated from coating of glimepiride by a barrier coat (seal coat) layer. The barrier coated core tablets may then be coated with a layer containing an additional active ingredient.

In certain specific aspects, the present invention provided using illustrative examples which should not be construes as limiting the scope of the disclosure.

EXAMPLES

Example 1: Metformin Extended Release Tablets

Manufacturing process:

1. All the ingredients from S. No. 1-7 were weighed and sifted through a sieve of appropriate # mesh size.

2. The sifted excipients of step 1 were blended together

3. The blend of step 2 was heated to form molten slurry.

4. The slurry of step 3 was extruded as thin strips using Thermo Scientific Pharma 16 mm Extruder

5. The required quantity of the extrudates of step 4 was milled to appropriate particle size such that all the particles passed through mesh # 24 ASTM

6. The milled extrudates of step 5 were blended with ingredient of S. No. 8-9 (final blend).

7. The final blend of step 6 was compressed into tablets using suitable toolings.

The tablet formulations of example 1 were subjected to in-vitro dissolution testing using Indian Pharmacopoeia apparatus – I (Basket) at a speed of 100 RPM at the temperature of 37±0.5°C. The dissolution medium used was 1000 ml of phosphate buffer pH 6.8. The cumulative drug release is provided below.

Example 2: Metformin Extended Release Tablets

Manufacturing process:

1. All the ingredients from S. No. 1-6 were weighed and sifted through a sieve of appropriate # mesh size.

2. The sifted excipients of step 1 were blended using a rapid mixture granulator.

3. The blend of step 2 was granulated using purified water.

4. The granules of step 3 were dried, sifted through a sieve of appropriate # mesh size and milled together.

5. The blend of step 4 was further mixed with the ingredients of S. No. 8-9.

6. The blend of step 5 was lubricated with ingredient of S. No. 10 (final blend).

7. The final blend of step 6 was compressed into tablets using suitable toolings.

Example 3: Metformin Extended Release Tablets

Manufacturing process:

1. All the ingredients from S. No. 1-6 were weighed and sifted through a sieve of appropriate # mesh size.

2. The sifted excipients of step 1 were blended using a rapid mixture granulator.

3. The blend of step 2 was granulated using purified water.

4. The granules of step 3 were dried, sifted through a sieve of appropriate # mesh size and milled together.

5. The blend of step 4 was further mixed with the ingredients of S. No. 8-9.

6. The blend of step 5 was lubricated with ingredient of S. No. 10 (final blend).

7. The final blend of step 6 was compressed into tablets using suitable toolings.

Example 4: Metformin Extended Release Tablets

Manufacturing process:

1. Ingredients from S. No. 1 & 2 were weighed and sifted through a sieve of appropriate # mesh size.

2. Sifted ingredients of step 1 were blended in a double cone blender.

3. Ingredients of S. No. 3 was sprayed onto the blend of step 2 to form granules.

4. Granules of step 3 were dried, sifted through a sieve of appropriate # mesh size.

5. Dried granules of step 4 were lubricated with the ingredients of S. No. 4-5 (final blend).

6. The final blend of step 5 was compressed into tablets using suitable toolings.

7. Ingredient of S. No. 7 was dissolved in required quantity of purified water.

8. Solution of step 7 was mixed with Ingredients of S. No. 6.

9. Tablets of step 6 were coated with mixture of step 8 till weight built of about 5.7% w/w.

10. Tablets of step 9 were dried.

Example 5: Metformin Extended Release Tablets

Manufacturing process:

1. Ingredients from S. No. 1-2 were weighed and sifted through a sieve of appropriate # mesh size.

2. Sifted ingredients of step 1 were blended in a double cone blender.

3. Ingredients of S. No. 3 was dissolved in a required quantity of methanol and sprayed onto the blend of step 2 to form granules.

4. Granules of step 3 were dried, sifted through a sieve of appropriate # mesh size.

5. Dried granules of step 4 were lubricated with the ingredients of S. No. 5-6 (final blend).

6. The final blend of step 5 was compressed into tablets using suitable toolings.

The tablet formulations of examples 4 were subjected to in-vitro dissolution testing using Indian Pharmacopoeia apparatus – I (Basket) at a speed of 100 RPM at the temperature of 37±0.5°C. The dissolution medium used was 1000 ml of phosphate buffer pH 6.8. The cumulative drug release is provided below.

CLAIMS:

WE CLAIM:

1. A low weight extended release pharmaceutical formulation comprising metformin hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.

2. A pharmaceutical formulation according to claim 1, wherein the formulation is a small size compressed tablet.

3. A pharmaceutical formulation according to claim 1 or 2, wherein the content of metformin hydrochloride is more than 65% of the total weight of the formulation.

4. A pharmaceutical formulation according to claim 1 or 2, wherein the formulation is a compressed tablet comprising 500 mg of metformin hydrochloride with the weight lesser than 750 mg.

5. A pharmaceutical formulation according to claim 2, wherein the formulation is a compressed tablet comprising 500 mg of metformin hydrochloride with the volume smaller than cuboid volume of 765 mm3.

6. A pharmaceutical formulation according to claim 1 or 2, prepared by a process selected from melt granulation or wet granulation.

7. A pharmaceutical formulation according to claim 1 or 2 that provides in-vitro release of metformin hydrochloride such that not less than about 25% of metformin hydrochloride is released within 1 hour and more than about 80% metformin hydrochloride is released within 10 hours.

8. A pharmaceutical formulation according to claim 1 or 2, wherein the weight ratio of metformin hydrochloride to at least one release rate controlling substance and other pharmaceutically acceptable excipients is 1:0.4 or less.

9. A pharmaceutical formulation according to claim 2, wherein a compressed tablet comprise glimepiride.

10. A pharmaceutical formulation according to claim 9, wherein glimepiride is coated over a core tablet containing metformin hydrochloride.