FIELD OF THE INVENTION
This invention relates to a solid oral pharmaceutical composition comprising metformin or pharmaceutically acceptable salt thereof. The composition of the invention comprises a solid oral dosage form which provides sustained release of the metformin. Specifically, the composition is provided in the form of sustained release tablet. Such compositions exhibit reproducible sustained release profile and improved storage stability. The invention also includes a process of preparing such compositions and method of treating type-2 diabetes mellitus by administering the composition to a patient in need thereof.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a common disorder more prevalent in developed countries. In the United States diabetes mellitus affects approximately 7.5 million people. It is characterized by its clinical manifestations, namely the non-insulin-dependent or maturity onset form, also known as Type 2 diabetes and the insulin-dependent or juvenile onset form, also known as Type 1 diabetes. Type 2 diabetes is a disease characterized by high-circulating blood glucose, insulin and corticosteroid levels.
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 first line 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 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.
It is well known in the prior art that Metformin is absorbed in the upper small intestine (duodenum and jejunum) and has a relatively low oral bioavailability that ranges between 29 and 60%. After absorption through the upper small intestine, Metformin is then delivered to the liver, circulates unbound essentially, and finally is eliminated by the kidneys in unchanged form. It is known in the art that absorption of metformin is the rate-limiting step in drug disposition because metformin’s absorption is transporter dependent and saturatable, which causes bioavailability to diminish as dosage increases. For sustaining the absorption of the Metformin from a dosage form, one requires that the dosage form should be retained in stomach or upper intestine and the release of the drug from the dosage form should be continuous and at a controlled rate.
The daily recommended oral dose of Metformin for treatment of diabetes is very high - 500 mg to 850 mg for children and maximum 3 grams daily for adults, taken in three divided doses. As the daily dose of metformin is considerably very high, the final weight of any dosage form comprising 500mg to 1g of metformin along with excipients will be considerably more and the tablet formed will be of very large size and shape. This large size, shape and weight of the dosage form of metformin hydrochloride sometimes leads into the patient non-compliance, acceptability of medication regimens or could lead to medication errors. While taking patient compliance in consideration, US FDA has issued guidance for Size, Shape and Other Physical Attributes of Generic Tablets and Capsules.
Furthermore, Metformin Hydrochloride is water soluble drug, for sustaining the release of Metformin or pharmaceutically acceptable salt thereof from a dosage

form for an extended period requires use of considerable amount of rate controlling polymers.
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 of coating layer followed by slow diffusion of drug through rate controlling 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. Attempts have also been made to control the release of drug through coating composition comprising plasticizers and pore formers.
US Patent No. 8,323,692 describe a controlled release oral dosage form comprising:
a) a core, wherein said core comprises: i) an effective amount of metformin
hydrochloride, and ii) at least one first pharmaceutically acceptable excipient, and
b) a stable controlled release monolithic coating surrounding the core.
US Patent No. 7,780,987 describe a pharmaceutical oral dosage form comprising an oral dosage form coated with a stable controlled release monolithic coating, wherein the stable controlled release monolithic coating is applied onto the oral dosage form by a process comprising coating the oral dosage form with a coating composition to form a coated oral dosage form, and curing the coated oral dosage form at a temperature of at least 55°C. to form the stable controlled release monolithic coating.
US Patent No. 6,723,340 describe a controlled-release tablet for releasing a drug into at least a portion of a region defined by the stomach and the upper gastrointestinal tract, said tablet comprising a solid monolithic matrix with said drug dispersed therein, said matrix comprising a combination of poly(ethylene

oxide) and hydroxypropyl methylcellulose at a weight ratio that causes said matrix to swell upon contact with gastric fluid to a size large enough to provide gastric retention.
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.
US Patent No. 6,488,962 describe a controlled-release oral drug dosage form comprising a solid monolithic matrix with said drug contained therein, said matrix being one that swells in an unrestricted manner along both such axes upon imbibition of water, the longer such axis having a maximum length of 3.0 cm when said matrix is unswollen, and the shorter such axis achieving a minimum length of 1.2 cm within one hour of immersion of said dosage form in water and wherein said matrix has a shape which when projected onto a plane, is either an oval or a parallelogram.
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.
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.

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.
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.
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.
PCT 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.
PCT 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.
Therefore, there is a need for developing a sustained release dosage form of Metformin which should provide constant release of metformin for absorption at the site of absorption, avoids burst release of metformin from the dosage form, encompass higher amount of active metformin, has minimum amount of rate controlling polymers and excipients, has lower total weight of the dosage form so that it is palatable, and has a size and shape which not only helps in retention of the dosage form in stomach for at least 12h and at the same time easy to swallow for patients.
Hence, it is an object of the invention to provide a novel gastro retentive dosage form of metformin or pharmaceutically acceptable salt thereof, which retains its shape in stomach for at least 12hours and at the same time controls the release of metformin with use of minimum amount of rate controlling polymers and excipient such that the final weight of the composition is low and tablet has suitable size and shape which aids in swallowing and thereby increases the patient compliance.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to an extended release solid oral gastro-retentive dosage form, wherein the dosage form comprises:
a) an immediate release core comprising granules of metformin along with one or more pharmaceutically acceptable excipients, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1

optionally along with one or more pharmaceutically acceptable
excipients; and c) optionally a non-functional coating;
wherein the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin and the dosage form provides a pH independent sustained release of metformin for at least 12 hours.
Another aspect of the present invention provides an extended release gastro retentive tablet composition comprising
a) an immediate release core comprising granules of metformin along with one or more pharmaceutically acceptable excipients, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the rate controlling coating layer is devoid of plasticizer and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin; wherein the composition provides a pH independent sustained release of metformin for at least 12 hours by controlling the ingress of water in the composition by altering the ratio of rate controlling polymers.
Another aspect of the present invention provides a controlled release gastro-retentive floating drug delivery composition, wherein the composition comprises: (i) a core comprising granules of metformin and one or more pharmaceutically acceptable excipients having bulk density between 0.2 g/ml to 0.5g/ml; and (ii) a controlled release coating consisting essentially of combination of polyacrylate and hydrophilic cellulose polymer along with one or more excipients;

wherein the core is devoid of any rate controlling polymer and controlled release coating is devoid of any plasticizer and wherein the bulk density of granules is lesser than the bulk density of powder from which granules are prepared.
One of the aspect of the present invention provides a controlled release gastro-retentive floating drug delivery composition, wherein the composition comprises (i) a core comprising granules of metformin and one or more pharmaceutically acceptable excipients;
(ii) a controlled release coating consisting essentially of a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1, surfactant and one or more non-functional or non-rate controlling excipients;
wherein the granules are prepared by granulating a powder comprising metformin and one or more pharmaceutically acceptable excipient with a binder solution in fluidized bed pan;
wherein the core is devoid of any rate controlling polymer and controlled release coating is devoid of any plasticizer;
wherein the bulk density of granules is lesser than the bulk density of the powder; wherein the bulk density of granule is between 0.2 g/ml to 0.5g/ml.
In another aspect of the present invention provides a controlled release gastro
retentive floating tablet composition comprising
(i) a core comprising granules of metformin and one or more pharmaceutically
acceptable excipients; wherein the granules have bulk density between 0.2g/ml to
0.5g/ml, and
(ii) a controlled release coating consisting essentially of a combination of
polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1, surfactant and
one or more non-functional or non-rate controlling excipients;
wherein the core is devoid of any rate controlling polymer and controlled release
coating is devoid of any plasticizer;
wherein the excipients used in the composition is not more than 40% of the total
weight of metformin;

wherein the composition provides a pH independent sustained release of metformin for at least 12 hours.
Another aspect of present invention provides a process for preparing extended-release gastro-retentive tablet of metformin, rate controlling polymers and pharmaceutically acceptable excipients, wherein the process comprising the steps of:
i. preparing granules comprising metformin hydrochloride and one or more pharmaceutically acceptable excipients such that the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml; ii. granules obtained in step (i) was compressed to form core of tablet; iii. compressed core of step (ii) was then coated with polymer solution comprising combination of rate controlling polymers - polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 along with one or more pharmaceutically acceptable excipients;
wherein the coating composition is devoid of plasticizers and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin.
Another aspect of the present invention provides an extended release oval or a parallelogram shaped gastro retentive tablet composition comprising
a) an immediate release core comprising granules of metformin along with one or more pharmaceutically acceptable excipients, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;

wherein the rate controlling coating layer is devoid of plasticizer and the total dry weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin; wherein upon ingestion the tablet composition, the coating layer swells marginally by imbibing water, floats and controls the ingress of water and release of dissolved metformin from the coating composition and provides a pH independent sustained release of metformin for at least 12 hours. wherein the tablet composition exhibits the following dissolution profile when tested in a USP type I apparatus at 100 rpm in 1000ml of 0.1N HCL at 37°C: not more than 20% of metformin or salt thereof is released within 1 hours; 45-65% of the metformin or salt thereof is released at 4 hours; 65-85% of the metformin or salt thereof is released at 6 hours; and not less than 85% of the metformin or salt thereof is released after 14 hours.
Another aspect of the present invention provides an extended release oval or a parallelogram shaped gastro retentive tablet composition comprising
a) an immediate release core comprising (i) granules consisting essentially of metformin, microcrystalline cellulose, silicon dioxide, and polyvinyl alcohol; and (ii) extra granular excipients selected from the group consisting of diluent, lubricant, disintegrants, glidant or combination thereof, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polymethyl methacrylate and hydroxypropylmethylcellulose in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the rate controlling coating layer is devoid of plasticizer and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin;

wherein the tablet composition exhibits the following dissolution profile when tested in a USP type I apparatus at 100 rpm in 1000ml of 0.1N HCL at 37°C: not more than 20% of metformin or salt thereof is released within 1 hours; 45-65% of the metformin or salt thereof is released at 4 hours; 65-85% of the metformin or salt thereof is released at 6 hours; and not less than 85% of the metformin or salt thereof is released after 14 hours..
One aspect of the present invention relates to an extended release solid oral gastro-retentive dosage form for use in treatment of Type 2 diabetes mellitus, wherein the treatment comprises administering dosage form comprising:
a) an immediate release core comprising granules of metformin along with one or more pharmaceutically acceptable excipients, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin and the dosage form provides a pH independent sustained release of metformin for at least 12 hours.
Another aspect of the present invention provides use of aforesaid extended release gastro-retentive pharmaceutical composition for use in the treatment of Type 1 diabetes, Type 2 diabetes mellitus, obesity and Polycystic ovarian syndrome (PCOD).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an extended release solid oral gastro-retentive floating dosage form, wherein the dosage form comprises:

a) an immediate release core comprising granules of metformin along with one or more pharmaceutically acceptable excipients, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin and the dosage form provides a pH independent sustained release of metformin for at least 12 hours.
While working on the development of a gastroretentive dosage form of metformin, the major challenge that the inventors faced was to incorporate 1000mg of metformin in dosage form in a controlled release drug delivery system with minimum use of rate controlling polymers and excipients. It was essential to keep the final weight of the dosage form to the minimum as with more weight the tablet becomes bulky and difficult to swallow. At the same time the other challenge was to retain the dosage form in stomach for atleast 12hours to provide constant release of metformin in stomach and upper part of small intestine where maximum amount of absorption occurs. The constant release of metformin for atleast 12 hours is helpful in type-2 diabetes patients to control the basal level of sugar in blood. Inventors of the present invention surprisingly found that when a combination of rate controlling polymers – polyacrylate polymers and cellulosic polymers is used in a ratio of 1:4 to 4:1 along with immediate release composition of metformin comprising granules of bulk density 2g/ml to 0.5g/ml formulated using minimum amount of excipients such that the total weight of the rate controlling polymer and excipients used in the formulation is not more than 40% of the total weight of the metformin, it is possible to formulate a floatable gastro retentive stable sustained release pharmaceutical composition of metformin or pharmaceutically acceptable

salt thereof, which not only release metformin for atleast 12hours but also has a low weight, acceptable size and shape and exhibits superior chemical and physical stability. The final weight of the dosage form containing 1000mg of metformin was less than 1400mg.
As used herein the terms “pharmaceutical composition” or “dosage form” as used herein are used interchangeably and are defined to mean a pharmaceutical composition, preparation or system in which doses of medicine or active drug are included.
As used herein the term “immediate release” refers to the dosage forms which provide a substantially immediate rate of release of the active drug when administered in gastrointestinal tract.
As used herein, the term “sustained/ extended/controlled release” refers to a pharmaceutical composition which exhibit a “sustained release”, “extended release”, or “controlled release” of the active drug, as used herein are used interchangeably and defined to mean dosage forms that provide a release of the active drug over an extended period of time compared to an immediate release dosage form, such that plasma concentrations of the active drug are maintained for a longer time at a therapeutic level, and provides a therapeutic benefit over a period of time (e.g. a 12-hour or 24-hour period).
The term “core” as used herein is defined to mean a solid vehicle in which at least one active drug is uniformly or non-uniformly dispersed.
As used herein, the term “functional coating” as used herein refers to a coating that affects the rate of in-vitro or in-vivo release of the active drug(s). The term “non¬functional coating” as used herein refers to a coating which does not affect the rate of in-vitro or in-vivo release of the active drug.

The term “plasticizer” as used herein includes any compounds capable of plasticizing or softening a polymer. Plasticizers are generally used in the prior art to modify the properties and characteristics of the polymers in the coatings or core of the dosage form for convenient processing during manufacture of the coatings and/or the core of the dosage form.
The term “gastro retentive” or “Floatable gastrorententive” as used herein means the pharmaceutical composition or dosage form upon ingestion floats and retained in the stomach.
As used herein, the term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
One of the aspects of the present invention provides an extended release gastro retentive tablet composition comprising
a) an immediate release compressed core comprising granules consisting of metformin, binder, diluent and glidant mixed with disintegrants, glidants and lubricants, wherein the granules and uncompressed core have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer applied over the compressed cores, wherein the rate controlling coating comprise a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1, surfactant optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the rate controlling coating layer is devoid of plasticizer and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin; wherein the provides a pH independent sustained release of metformin for at least 12 hours.

In one of the aspect of the present invention, the pharmaceutical composition or dosage form is tablet or caplet.
In another embodiment provided a pharmaceutical composition; wherein the metformin or pharmaceutically acceptable salt thereof is present in the range of 60 % w/w to 90% w/w of the total weight of the composition or dosage form. In preferred embodiment of the present invention, the metformin or pharmaceutically acceptable salt thereof is present in the range of 70 % w/w to 80% w/w of the total weight of the composition or dosage form.
In another embodiment the effective amount of metformin or salt thereof used in the pharmaceutical compositions is 500 mg to 1500g. In another embodiment the amount of metformin used in pharmaceutical compositions of present invention is 1000mg of metformin hydrochloride.
In another embodiment provided a pharmaceutical composition; the total amount of rate controlling polymer and excipients used in the invention are not more than 30% of the total weight of the composition or dosage form. In preferred embodiment of the present invention the total amount of rate controlling polymer and excipients used in the invention are in range of 20 to 28% of the total weight of the composition or dosage form.
In another embodiment provided a pharmaceutical composition; the total amount of rate controlling polymer and excipients used in the invention are not more than 40% of the total weight of the metformin used in the composition. In preferred embodiment of the present invention the total amount of rate controlling polymer and excipients used in the invention are in range of 25 to 35% of the total weight of the metformin used in the composition.

The “cellulose”, “cellulosic” or “hydrophilic cellulose polymer” that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to hydroxypropyl methylcellulose (HPMC) (e.g. Pharmacoat® 606 or Hypromellose), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, or hydroxyethyl methylcellulose.
The polyacrylate polymer can be selected from the group consisting of methacrylic acid copolymers, a salt of a homopolymer of acrylic acid, hydroxyacrylic acid or methacrylic acid, or a copolymer thereof containing at least about 80% by weight of units derived from said acids and the remainder of said units being derived from the group consisting of vinyl chloride, vinyl alcohol, furan, acrylonitrile, methacrylonitrile, vinyl acetate, methyl acrylate, methyl methacrylate, styrene, alpha-methylstyrene, vinyl methyl ether, vinyl ethyl ether, vinyl propyl ether, ethylene, propylene, 3-butenoic acid, and mixtures thereof. The polyacrylate polymers which may be preferably used for coating composition may be a copolymer composed of free-radical polymerized units of more than 95% by weight, in particular to an extent of at least 98% by weight, preferably to an extent of at least 99% by weight, in particular to an extent of at least 99% by weight, more preferably to an extent of 100% by weight, of (meth)acrylate monomers with neutral moieties especially C1- to C4-alkyl moieties. These kinds of polymers do not dissolve in water or are only swellable in water over of the whole range of pH 1 - 14. Suitable (meth)acrylate monomers with neutral moieties are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Preference is given to methyl methacrylate, ethyl acrylate and methyl acrylate.
Methacrylate monomers with anionic functional groups, for example acrylic acid and/or methacrylic acid, may be present in small amounts of less than 5% by weight, preferably not more than 2% by weight, more preferably not more than 1 or 0.05 to 1% by weight. Suitable examples are neutral or virtually neutral (meth)acrylate copolymers composed of 20 to 40% by weight of ethyl acrylate, 60 to 80% by

weight of methyl methacrylate and 0 to less than 5% by weight, preferably 0 to 2 or 0.05 to 1% by weight of methacrylic acid or any methacrylic acid (EUDRAGIT® NE 30D or EUDRAGIT® NM 30D type).
EUDRAGIT® NE 30D and Eudragit® NM 30D are dispersions containing 30 % by weight of copolymers composed of free-radically polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate.
In another embodiment of the present invention, the rate controlling coating layer is formed by a process that excludes usage of an organic solvent.
Pharmaceutical excipients that can be used in the pharmaceutical composition of the invention can be selected from a group comprising binders, diluents, lubricants, disintegrating agents, glidants, stabilizers, and surface-active agents.
The binders that can be used in the pharmaceutical compositions of the invention
can be selected from a group comprising carboxymethyl cellulose sodium, ethyl
cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose,
hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, polyvinyl alcohol, copovidone, starch or combinations thereof.
The diluents that can be used in the pharmaceutical compositions according to the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives, sodium chloride, sucrose, talc, xylitol or the combinations thereof.

The lubricants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate, glyceryl behenate or combinations thereof.
The disintegrating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or combinations thereof.
The glidants that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, magnesium trisilicate, corn starch, talc and the like or combinations thereof.
The surface-active agent that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to poloxamer, dioctyl sodium sulfosuccinate (DSS), triethanolamine, polysorbates, sodium lauryl sulphate (SLS), polyoxy ethylene sorbitan and poloxalkol derivatives or quaternary ammonium salts.
In another embodiment provided a solid pharmaceutical composition comprising; wherein the pharmaceutical composition prepared by the wet granulation, dry granulation or melt granulation process. The compressed core of the present invention were prepared by fluid bed process.
In another embodiment, the coating layer is applied by spray coating; perforated pan coaters or fluid bed coaters can be used.

In another embodiment, there is provided a method of treating type-2 diabetes mellitus in a patient which method comprising administering the pharmaceutical composition in accordance with the present invention.
In another embodiment, there is provided an extended release pharmaceutical formulation as per the present invention is intended for oral administration to a subject in need thereof.
In another embodiment the extended release dosage form of the present invention expands in a dimensionally restricted manner and floats when placed in an aqueous environment.
The composition of present invention upon oral administration to a patient, provides controlled release of an effective amount of the metformin to at least one region of the patient's upper gastrointestinal tract for atleast 12hours.
Another aspect of the present invention provides an extended release oval or a parallelogram shaped gastro retentive tablet composition comprising
a) an immediate release core comprising (i) granules consisting essentially of metformin, microcrystalline cellulose, silicon dioxide, and polyvinyl alcohol; and (ii) extra granular excipients selected from the group consisting of diluent, lubricant, disintegrants, glidant or combination thereof, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polymethyl methacrylate and hydroxypropylmethylcellulose in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the rate controlling coating layer is devoid of plasticizer and the total weight of the rate controlling polymers and excipients used in the composition is

not more than 40% of the total weight of metformin; wherein the tablet composition exhibits the following dissolution profile when tested in a USP type I apparatus at 100 rpm in 1000ml of 0.1N HCL or phosphate buffer pH 6.8 at 37°C: not more than 20% of metformin or salt thereof is released within 1 hours; 45-65% of the metformin or salt thereof is released at 4 hours; 65-85% of the metformin or salt thereof is released at 6 hours; and not less than 85% of the metformin or salt thereof is released after 14 hours.
In another embodiment of present invention provides a process of preparation of an
extended release tablet composition, wherein the process comprising the steps of:
i. preparing granules comprising metformin hydrochloride and one or more
pharmaceutically acceptable excipients,
ii. granules obtained in step (i) was compressed to form core of tablet;
iii. compressed core of step (ii) was then coated with one or more rate controlling
polymers.
Another aspect of the present invention provides a method for treating Type 2 diabetes mellitus, wherein the method comprises administering an extended release oval or a parallelogram shaped gastro retentive tablet of the present invention to a patient in need thereof wherein the tablet composition exhibits the following dissolution profile when tested in a USP type I apparatus at 100 rpm in 1000ml of 0.1N HCL or phosphate buffer pH 6.8 at 37°C: not more than 20% of metformin or salt thereof is released within 1 hours; 45-65% of the metformin or salt thereof is released at 4 hours; 65-85% of the metformin or salt thereof is released at 6 hours; and not less than 85% of the metformin or salt thereof is released after 14 hours.
Although the preferred embodiment as well as the construction and use have been specifically described, it should be understood that variations in the preferred embodiment could be achieved by a person skilled in the art without departing from the spirit of the invention. The invention has been described with reference to

specific embodiment which is merely illustrative and not intended to limit the scope of the invention as defined in the claims.
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
EXAMPLES
Example 1:

Sr. No Ingredients Quantity/Tablet (mg)
1 Metformin Hydrochloride 1000
2 Microcrystalline Cellulose 50-70
3 Colloidal silicon dioxide 15-30
4 Polyvinyl Alcohol 25-40
5 Purified water Q.S.
6 Crospovidone 30-40
7 Glyceryl Behenate 30-40
Avg. weight 1200
Stage-1 Coating
8 Polyacrylate Polymer 10-60
9 Hypromellose 15-45
10 Polysorbate 80 20-35
11 Talc 20-35
12 Purified water Q.S.
Stage-2 Coating
13 Opadry II white 10-15
14 Purified water Q.S.

Process of Preparation Preparation of Core:
1. Metformin, part of colloidal silicon dioxide, microcrystalline cellulose and mixed thoroughly and loaded into fluidized bed dryer bowl.
2. Binder solution was prepared dissolving polyvinyl alcohol into hot water with continuous stirring till the clear solution was obtained
3. The powder of Step 1) was granulated by spraying the binder solution of step 2.
4. The granules so obtained were mixed with remaining colloidal silicon dioxide, crospovidone and glyceryl behenate. The bulk density and tapped density of powder of step 4 was measured.
5. The mixture of Step 4) was compressed and the physical properties of the tablet so obtained were measured. The tablets were oval shaped with 20.00x11.30 mm in length and breadth
Coating: Coating 1:
1. Hypromellose, talc and polysorbate 80 were dissolved individually in purified water into separate containers.
2. Talc dispersion was added into Hypromellose solution under slow stirring.
3. The dispersion of step 2) was added to Polyacrylate polymer under stirring followed by addition of polysorbate 80 solution to obtain the coating solution.
4. Core tablets were loaded into coating pan and were coated with coating solution of step 3.
5. The physical parameters of coated tablet were evaluated.
Coating 2:
6. Opadry II was dissolved in purified water.
7. Coated tablets were loaded into coating pan and were coated with coating solution of step 6.

Granule Bulk Density
The bulk density and tapped density of powder of step 4 of Example 1 was measured using standard procedures known in the field of invention. The results are produced below in Table 2.
Table 2: Physical properties of Granules/Powder
Physical Properties of Cores and Coated Tablet:
The physical properties of compressed cores/tablets of Example 1 were measured using standard procedures known in the field of invention. The results are produced below in Table 3.
Table 3: Physical properties of Cores/Tablet of Example 1
The physical properties of coated tablets of Example 1 were measured using standard procedures known in the field of invention. The results are produced below in Table 4.
Table 4: Physical properties of coated tablets of Example 1
Dissolution profile:
The dissolution profile of coated tablets of Example 1 was obtained by placing the tablets in USP type I apparatus containing 1000ml of 0. IN HCL or phosphate buffer

pH 6.8 at 37°C, lOOrpm. The results of dissolution profile in phosphate buffer pH 6.8 and 0. IN HCl are reproduced in table 4.
Table 4: Dissolution Profile

We Claim:
1. An extended release gastro retentive tablet composition comprising
a) an immediate release core comprising granules of metformin along with one or more pharmaceutically acceptable excipients, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the rate controlling coating layer is devoid of plasticizer and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin; wherein the provides a pH independent sustained release of metformin for at least 12 hours by controlling the ingress of water in the composition by altering the ratio of rate controlling polymers.
2. The tablet composition of claim 1, wherein the rate controlling polyacrylate polymer is selected from the group consisting of methacrylic acid copolymers, a salt of a homopolymer of acrylic acid, hydroxyacrylic acid or methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate or combinations thereof.
3. The tablet composition of claim 2, wherein the rate controlling polymer polyacrylate polymer is copolymer of ethyl acrylate and methyl methacrylate.
4. The tablet composition of claim 1, wherein the rate controlling cellulose polymer is selected from the group consisting of hydroxypropyl

methylcellulose (HPMC) (e.g. Pharmacoat® 606 or Hypromellose), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose or mixture thereof.
5. The tablet composition of claim 1, wherein the rate controlling cellulose polymer is hydroxypropyl methylcellulose.
6. The tablet composition of claim 1, wherein the metformin is present in the range of 60% w/w to 90 % w/w of the composition.
7. The tablet composition of claim 1, wherein the one or more pharmaceutically acceptable excipients is selected from the group comprising binders, diluents, lubricants, disintegrating agents, glidants, stabilizers, and surface-active agents.
8. A process for preparing extended-release tablets of claim 1, wherein the process comprising the steps of:
i. preparing granules comprising metformin hydrochloride and one or
more pharmaceutically acceptable excipients such that the granules have
mean bulk density ranging from 0.2g/ml to 0.5g/ml;
ii. granules obtained in step (i) was compressed to form core of tablet;
iii. compressed core of step (ii) was then coated with polymer solution
comprising combination of rate controlling polymers - polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 along with one or more pharmaceutically acceptable excipients; wherein the coating composition is devoid of plasticizers and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin.
9. An extended release oval or a parallelogram shaped gastro retentive tablet
composition comprising

a) an immediate release core comprising granules of metformin along with one or more pharmaceutically acceptable excipients, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,
b) a rate controlling coating layer comprising a combination of polyacrylate polymer and cellulose polymer in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the rate controlling coating layer is devoid of plasticizer and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin; wherein upon ingestion the tablet composition, the coating layer swells marginally by imbibing water, floats and controls the ingress of water and release of dissolved metformin from the coating composition and provides a pH independent sustained release of metformin for at least 12 hours. wherein the tablet composition exhibits the following dissolution profile when tested in a USP type I apparatus at 100 rpm in 1000ml of 0.1N HCL at 37°C: not more than 20% of metformin or salt thereof is released within 1 hours; 45-65% of the metformin or salt thereof is released at 4 hours; 65-85% of the metformin or salt thereof is released at 6 hours; and not less than 85% of the metformin or salt thereof is released after 14 hours.
10. An extended release oval or a parallelogram shaped gastro retentive tablet composition comprising
a) an immediate release core comprising (i) granules consisting essentially of metformin, microcrystalline cellulose, silicon dioxide, and polyvinyl alcohol; and (ii) extra granular excipients selected from the group consisting of diluent, lubricant, disintegrants, glidant or combination thereof, wherein the granules have mean bulk density ranging from 0.2g/ml to 0.5g/ml,

b) a rate controlling coating layer comprising a combination of polymethyl methacrylate and hydroxypropylmethylcellulose in ratio of 1:4 to 4:1 optionally along with one or more pharmaceutically acceptable excipients; and
c) optionally a non-functional coating;
wherein the rate controlling coating layer is devoid of plasticizer and the total weight of the rate controlling polymers and excipients used in the composition is not more than 40% of the total weight of metformin; wherein the tablet composition exhibits the following dissolution profile when tested in a USP type I apparatus at 100 rpm in 1000ml of 0. IN HCL at 37°C: not more than 20% of metformin or salt thereof is released within 1 hours; 45-65% of the metformin or salt thereof is released at 4 hours; 65-85% of the metformin or salt thereof is released at 6 hours; and not less than 85% of the metformin or salt thereof is released after 14 hours.