Description: FIELD OF THE INVENTION
This invention relates to a solid oral fixed dose pharmaceutical composition comprising Metformin, Glimepiride and Voglibose or their pharmaceutically acceptable salt thereof. The composition of the invention comprises a coated solid oral dosage form comprising an extended release matrix core comprising Metformin, rate controlling polymers and excipients. The compressed cores are then coated with first functional coating comprising Voglibose and second functional coating comprising Glimepiride such that the total weight of active ingredients in a unit composition is 70-90% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 10-30% of the total weight of composition and and wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm. 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 globally. According to the Centers for Disease Control and Prevention, 463 million adults have diabetes worldwide. In the United States alone, 34.2 million adults have diabetes, which is 10.5% of the population. A new analysis from the Centers for Disease Control and Prevention states that if the current trend continues, as many as 1 in 3 U.S. adults could have diabetes by 2050. 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. In 2019, diabetes was the ninth leading cause of death with an estimated 1.5 million deaths directly caused by diabetes.

Diabetes is a chronic disease. Initial treatment of diabetes involves diet, physical activity and administration of oral antidiabetic drugs. Oral antidiabetics involve compounds belonging to class of sulfonylureas, biguanides, thiazolidinones, alpha glucosidase inhibitors etc. According to the UK Prospective Diabetes (UKPDS) study, glycemic control using a single oral hypoglycemic agent is likely to be ineffective in the longer duration of disease, thus, unavoidably, many patients will require combination therapy to achieve their target glucose level (Chawla A, Chawla R, Jaggi S: Microvascular and macrovascular complications in diabetes mellitus: Distinct or continuum?. Indian J Endocr Metab. 2016, 20:546-551). Type 2 diabetes is a progressive disorder characterized by increasing hyperglycemia and the need to gradually intensify therapy in order to achieve and maintain glycemic control. Early initiation of combination therapy has been proposed as an approach to achieve glycemic goals earlier and delay the deterioration of glycemic control and with possible better preservation of ß-cell function.

The fixed dose combinations (“FDCs”) provides various advantages:
• FDCs help in formulating two drugs into a single dosage form, thereby minimizing the medication burden to the patient.
• The relative therapeutic adherence rates of type 2 diabetes patients can be improved.
• It improves glycemic control showing better efficacy.
• Medical expenditures due to hospitalization can be reduced.
• It decreases the frequency of drug administration in patients with type 2 diabetes.
• It prevents polypharmacy

Metformin is a biguanide antihyperglycemic compound useful in the first line treatment of non-insulin dependent diabetes mellitus (NIDDM). 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 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.

Glimepiride like glyburide and glipizide, is a "second-generation" sulfonylurea agent. Glimepiride is a sulfonamide, a N-acyl urea and a N-sulfonylurea. It has a role as a hypoglycemic agent and an insulin secretagogue. Glimepiride is an oral diabetes medicine that is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus. Glimepiride is used to lower blood glucose by increasing the secretion of insulin from pancreas and increasing the sensitivity of peripheral tissues to insulin. Glimepiride is completely absorbed from the gastrointestinal tract. The drug is extensively metabolized to two main metabolites, a hydroxy derivative and a carboxy derivative.

Voglibose is an alpha glucosidase inhibitor which reduces intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of a-glucosidase in the intestinal brush border. Inhibition of this enzyme catalyzes the decomposition of disaccharides into monosaccharides and slows the digestion and absorption of carbohydrates; the post- prandial rise in plasma glucose is blunted in both normal and diabetic subjects resulting in improvement of post prandial hyperglycemia and various disorders caused by hyperglycemia. a-Glucosidase inhibitors do not stimulate insulin release and therefore do not result in hypoglycaemia.

A combination of metformin with glimepiride is one of the widely utilized combinations for maintaining blood glucose levels in type 2 diabetic patients. Given that type 2 diabetes is characterized by the continuing loss of ß-cell function, this time-dependent therapeutic failure may be more pronounced when sulfonylureas are combined with Metformin since insulin secretory capacity is likely to be less in a patient who has progressed to two blood glucose-lowering therapies rather than one. This poses an extremely difficult problem for maintaining blood glucose levels over a longer duration. Thus, to have comprehensive and prolonged control over prandial as well as postprandial glucose levels, the addition of third component needs to be added. Voglibose, an a-glucosidase inhibitor, is widely used in the management of type 2 diabetes. It undergoes minimal systemic absorption. Voglibose delays the absorption of carbohydrates due to competitive inhibition of a-glycosidase in the small intestine. Consequently, Voglibose inhibits the postprandial increase in plasma glucose levels, leading to decreased diurnal insulin secretion. An FDC of Voglibose, glimepiride, and metformin is intended to provide an intensive initial blood glucose management regimen in newly diagnosed diabetic patients by simultaneously regulating the fasting as well as the postprandial blood glucose, and thereby delaying the progression of the disease.

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.

PCT Patent Application No. 2001032158A1 discloses a composition comprising Metformin and the other antidiabetic agent is one or more of a sulfonyl urea, a glucosidase inhibitor, a thiazolidinedione, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin, a PPAR a/? dual agonist, a meglitimide, and/or an aP2 inhibitor

PCT Patent Application No. 2002094285 discloses oral pharmaceutical form combining: an active ingredient A consisting of A biguanide, preferably metformin, and at least one other active ingredient B different from A and selected from antidiabetic, preferably antihyperglycaemic.

US Patent Application No. 20070264331A1 discloses a stable pharmaceutical composition in the form of a tablet comprising a core or matrix containing an extended-release biguanide; further comprising an insulating layer or coating comprising a hydrophobic polymer, and further comprising a coating containing an immediate-release sulphonylurea such as immediate release Glimepiride

Fixed dose combination of Metformin, Glimepride and Voglibose are currently marketed by various companies in India including Eris, USV, Sun, Lupin, Micro, Sanofi, Intas, Alkem, Intas. All the marketed fixed dose combination are oblong bilayer compressed tablets which have size having length of more than 18mm, width more than 8mm and height of more than 6mm. This large size, shape and weight of the dosage form of marketed dosage form is due to higher dose of the Metformin.

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. 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 to control the release of the drug from the matrix. Higher dose of Metformin and higher amount of rate controlling polymers and excipients, both, results in formation of tablets with larger size and shape. This large size, shape and weight of the dosage forms containing metformin often leads to patient non-compliance and unacceptability of medication regimens. This large size of tablets is major reason of non-compliance in geriatric or patients.

Further, addition of two other active ingredients plus excipients, the final weight of the tablet is considerably high which results in formation of tablets of very large size and shape. Combining more than one drug in a single dosage form often pose technical challenges. The physical and chemical properties of Metformin, Glimepride and Voglibose are different. Bilayer or multilayer tablets are often used to avoid drug-drug interaction between the drugs of different physical and chemical properties and also for formulating drugs with different release profile eg immediate, delayed, sustained or controlled release profile in different layers in a single tablet. Adding multiple layers each encompassing different active ingredient again increases the size of the tablet.

The technical challenge with drugs with smaller dose is different from the drugs with larger dose. Content uniformity is major concern in drugs with smaller dose, whereas formulating the drug with minimal excipients, size and shape and controlling the release of the drug are major concerns with drug with larger dose. Dose of glimepiride and voglibose is smaller whereas the dose of Metformin is very large.

Therefore, there is a need for developing a fixed dose combination of Metformin, Glimepiride and Voglibose which is not a bilayer or multilayer dosage form but still avoids drug-drug interaction, accommodates drugs with different release profile in a single dosage form, provides release of drug at site of absorption, avoids burst release of metformin from the dosage form, encompass higher amount of active ingredients, 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 is easy for patients to swallow.

Hence, it is an object of the invention to provide a coated tablet composition comprising Metformin, Voglibose and Glimepiride or salts thereof, wherein the which not only comprise three drugs met 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 a coated tablet composition comprising
a) a extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers and excipients,
b) first functional coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 70-90% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 10-30% of the total weight of composition;
wherein the provides a extended release of metformin for at least 12 hours; and
wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water.

Another aspect of the present invention provides a single layer compressed coated tablet composition comprising
a) a extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers and excipients,
b) first functional coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 70-90% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 10-30% of the total weight of composition; wherein the provides a extended release of metformin for at least 12 hours; and wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water.

Another aspect of the present invention provides a process for preparing extended-release coated tablets comprising fixed dose combination of Metformin, Voglibose and Glimepiride or salts thereof, wherein the process comprising the steps of:
i. preparing granules comprising metformin hydrochloride and one or more rate controlling polymer;
ii. granules obtained in step (i) was compressed to form core of tablet;
iii. compressed core of step (ii) was then coated with first functional coating comprising voglibose and/or glimepiride along with one or more pharmaceutically acceptable excipients;
iv. the coated core of step(iii) was then coated with second functional coating comprising voglibose and/or glimepiride along with one or more pharmaceutically acceptable excipients;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 65-85% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 15-35% of the total weight of composition; wherein the said tablets provides a extended release of metformin for at least 12 hours; and wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water.

Another aspect of the present invention provides coated tablet composition comprising
a) an extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers,
b) first functional coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 70-85% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 15-35% of the total weight of composition; wherein the provides a extended release of metformin for at least 12 hours; the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water; and wherein one single tablet contains 500 to 1000mg of Metformin, 0.1 to 2mg of Voglibose and 0.1 to 5mg of Glimepiride.

Another aspect of the present invention provides coated tablet composition comprising
a) an extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers,
b) first functional coating layer comprising voglibose along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 70-85% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 15-35% of the total weight of composition; wherein the provides a extended release of metformin for at least 12 hours; the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water; and wherein voglibose is coated on core using an aqueous coating solution and glimepiride is coated using a non-aqueous coating solution.

Another aspect of the present invention provides use of aforesaid extended release coated tablet 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 a single layer compressed coated tablet composition comprising
a) an extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers and excipients,
b) first functional coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 70-90% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 10-30% of the total weight of composition;
wherein the provides a extended release of metformin for at least 12 hours; and
wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water.

It was observed by inventors of the present invention that the major problem with the marketed composition of Metformin, Voglibose and Glimepiride was their size and shape. As all the marketed products were multilayered, the amount of excipients used in each layer increases the weight of the tablet and ultimately size of the tablet. The common problem associated with these products was their swallowability. Due to large size and shape, these tablets are difficult to swallow especially for geriatric patients. This leads to patient non-compliance.

While working on the development of a fixed dose combination comprising Metformin, Voglibose and Glimepiride, the major challenges that the inventors faced were (i) to prepare a easy swallowable palatable small size tablet containing higher amount of active ingredients especially Metformin along with rate controlling polymers and excipients providing extended release of Metformin and immediate release of Voglibose and Glimepiride, (ii) to incorporate three active ingredients with different physical and chemical properties in one single dosage form with no drug interactions; (iii) to keep the amount of excipients and rate controlling polymers to minimum yet provide extended release of metformin for atleast 12 hours, which is helpful in type-2 diabetes patients to control the basal level of sugar in blood; and (iv) to keep the size and shape of the tablet to minimum so that it is easy to swallow but at the same time the tablet should expand in-vivo so that it is retained in the upper part of intestine where maximum absorption of the drugs occurs here.

After numerous attempts, Inventors of the present invention surprisingly found that when Metformin is compressed as a single layer extended release matrix core containing rate controlling polymers and excipients and then the said core is first coated with voglibose using an aqueous coating solution and secondly coated with Glimepiride using non-aqueous coating solution, the inventors of the present invention were able to prepare a easy swallowable small size tablet compared to marketed formulations, 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 coated tablet containing 500mg of Metformin, 1mg of Glimepiride and 0.2 mg of Voglibose was less than 705mg±5mg. The total weight of the excipients and rate controlling polymers in the tablet was less than 20% of the total weight of the tablet. The longer axis of the tablet was not more than 17mm and shorter axis of the tablets was not more than 6mm.

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 terms “marketed fixed dose combination” or “marketed product” or “marketed tablets” as used herein are used interchangeably and are defined to mean a pharmaceutical composition comprising fixed dose combination comprising Metformin, Voglibose and Glimepiride marketed in India.

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 “extended 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 containing active drug(s). The term “non-functional coating” as used herein refers to a coating which does not contain any active drug.

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 a coated single layer compressed tablet composition comprising
a) an extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers and excipients,
b) first functional coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 80-90% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 10-20% of the total weight of composition;
wherein the provides a extended release of metformin for at least 12 hours; and
wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water.

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 70% 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 80 % w/w to 90% 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 the effective amount of Voglibose or salt thereof used in the pharmaceutical compositions is 0.1 mg to 5mg. In another embodiment the amount of Voglibose used in pharmaceutical compositions of present invention is 0.2mg.

In another embodiment the effective amount of Glimepiride or salt thereof used in the pharmaceutical compositions is 0.1 mg to 10mg. In another embodiment the amount of Glimepiride used in pharmaceutical compositions of present invention is 1mg. Glimepiride used in the formulation is micronized.

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 10 to 20% 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 20% 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 10 to 20% of the total weight of the metformin used in the composition.

The rate controlling polymer used in the composition of present invention are selected from the group consisting of carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, 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. 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.

Pharmaceutical excipients that can be used in the pharmaceutical composition of the invention can be selected from a group comprising binders, diluents, matrix forming agents, 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 the compressed core of the present invention are prepared by the process wet granulation, dry granulation or melt granulation process. In another embodiment, the matrix core of the composition are single layer compressed tablets. In another embodiment, the coating layer is applied by spray coating; perforated pan coaters or fluid bed coaters can be used. In another embodiment of the present invention the compressed cores are coated with seal coat before any functional coating. In another embodiment the compressed core of the present invention, the compositions of the present invention are not multilayer compressed tablets or caplets.

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 size when placed in an aqueous environment.

The composition of present invention upon oral administration to a patient, provides extended release of an effective amount of the metformin to at least one region of the patient's upper gastrointestinal tract for atleast 8hours.

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, rate controlling polymer and one or more pharmaceutically acceptable excipients,
ii. granules obtained in step (i) was compressed to form core of the tablet;
iii. compressed core of step (ii) was then coated with one or more functional coating containing voglibose and/or glimepiride.

Another aspect of the present invention provides a method for treating Type 2 diabetes mellitus, wherein the method comprises administering an extended release coated tablet of the present invention to a patient in need thereof wherein the tablet composition of the present invention exhibits similar dissolution profile compared to the similar marketed fixed dose combination products 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.

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: Coated Tablets
Each film coated tablet contains:
Glimepiride IP……………………………….1 mg
Voglibose IP……………………………….0.2 mg
Metformin Hydrochloride IP………………500 mg (In sustained-release form)

Table 1: Pharmaceutical Composition
Core Tablet
Sr. No Ingredients Quantity/Tablet (mg)
1 Metformin Hydrochloride 500.00
2 Carboxy Methyl Cellulose Sodium 39.63
3 Methyl Paraben 1.30
4 Propyl Paraben ALTA LABOR 0.05
5 Purified Water q.s
6 Colloidal Silicon Dioxide 6.50
7 Magnesium Stearate 4.30
8 H.P.M.C. (K-200 M) VISCOSITY: 2,00,000 CPS 123.22
Avg. weight 675.00
Stage-1 Coating (Seal Coating) Optional
Sr. No Ingredients Qty. For Batch
8 Insta Moistshield White 2.000 kg
10 Isopropyl Alcohol 14.000 L
11 Dichloromethane 21.000 L
Stage-2 Coating (Functional Coating)
Sr. No Ingredients Qty. For Batch
12 Voglibose 0.024 kg
13 H.P.M.C. (E-5) 0.601 kg
14 P.E.G - 6000 0.150 kg
15 Purified Talc 0.125 kg
16 Titanium Dioxide 0.100 kg
17 Purified Water 10.000 L
Stage-3 Coating
Sr. No Ingredients Qty. For Batch
18 Glimepiride Micronized 0.120 kg
19 H.P.M.C. (E-15) 0.505 kg
20 P.E.G - 6000 0.150 kg
21 Purified Talc 0.125 kg
22 Titanium Dioxide 0.100 kg
23 Isopropyl Alcohol 10.000 L
24 Dichloromethane (Methylene Chloride) 20.000 L

Batch size is 1,00,000 Tablets
Process of Preparation
Preparation of Core:
1. Metformin and carboxymethyl cellulose were sifted and loaded in a rapid granulator mixer.
2. Binder solution was prepared by boiling hot water and adding HPMC, methylparaben and propylparaben to the said boiling water with continuous stirring.
3. The powder of Step 1 was granulated by spraying the binder solution of step 2.
4. The granules so obtained were semidried in fluidized bed drier and then milled through 4.00 mm perforated screen and then finally dried. The granules so formed are checked for Loss on drying (LOD). LOD of dried granules should between 3-4%w/w/w.
5. The dried granules of Step 4 were lubricating with colloidal silicon dioxide and magnesium stearate.
6. The mixture of Step 5 was compressed into tablets using punch size of 16.00 X 8.00 mm. The physical properties of the tablet so obtained were measured.
Coating:
Coating 1: (Seal Coating; Optional)
7. Insta moistshield white (cellulose based coating system) was suspended in isopropyl alcohol solution. To this suspension dichloromethane was added with slow stirring.
8. Core tablets obtained in Step 6 were loaded into coating pan and were coated with coating solution of step 7.
9. The physical parameters of coated tablet were evaluated.
Coating 2: (API Functional Coating)
10. Voglibose is dissolved in purified water
11. HPMC was dissolved in purified water.
12. Solution of Step 10 and 11 were mixed.
13. To the Solution of Step 12, PEG6000 was added under mechanical stirring
14. Titanium dioxide and purified talc were shifted and added in purified water under continuous stirring to make slurry.
15. The slurry of Step 14 was added to solution of Step 12
16. Coated tablets were loaded into coating pan and were coated with coating solution of step 16.
Coating 2: (API Functional Coating)
17. Glimepiride was dissolved in dichloromethane
18. HPMC was dissolved in isopropyl alcohol and dichloromethane
19. Solution of Step 17 and 18 were mixed
20. To the solution of Step 19, PEG6000 was added under mechanical stirring
21. Titanium dioxide and purified talc were shifted and dissolved in Isopropyl alcohol to make slurry
22. The slurry of step 21 is added to Solution of Step 20
23. Coated tablets obtained from Step 16 were then loaded into a clean, dry coating pan and dry for 10 minutes at 0.5 rpm at 30?C - 40?C

Table 2: Physical properties of Coated 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 2.

Table 2: Physical properties of Coated Tablet of Example 1
S. No. PARAMETERS OBSERVED RESULT
1. Description White coloured, biconvex, elongated, film coated tablets, scored on one side and plain on other side.
2. Average Weight of tablets 705.0 mg
3. Group weight of 20 Tablets 14.10 gm
4. Uniformity of Tablet weight 705.0 mg
5. Length: 16.20 mm
6. Width: 8.20 mm
7. Thickness 5.90 mm

Example 3: 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 phosphate buffer pH 6.8 at 37°C, 100rpm. The dissolution profile of formulation of Example 1 was compared with dissolution profile of marketed fixed dose products containing same API in same quantity. The dissolution profile of formulation of Example 1 was found to be comparable with the marketed fixed dose products.
Example 4: Comparison of Marketed Products with Composition of Present Invention
A. Measurement of Physical Parameters
The length (longer axis), width and height (shorter axis) of marketed fixed dose products and dosage form of Example 1 were measured using vernier calliper. The results are provided in Table 3.

Table 3: Marketed Products with Windlas Product
S. No. Brand Name L W H
1 AMARYL MV 1 TABLETS 20.10 mm 9.40 mm 6.75 mm
2 VOGS-GM 1 TABLETS 18.10 mm 8.10 mm 6.40 mm
3 VOGLYSON GM 1 TABLETS 18.10 mm 8.10 mm 6.40 mm
4 JUBIGLIM MV 1 TABLETS 18.10 mm 8.10 mm 6.20 mm
5 ZUVOG TRIO 1 TABLETS 20.10 mm 9.40 mm 6.60 mm
6 WINDLAS 16.20 mm 8.20 mm 5.90 mm

B. Pictorial Comparison of Marketed Products Vs Tablets of Present Invention
Tablets of Marketed Products containing the fixed dose combination of Metformin, Voglibose and Glimipiride in same dose as compositions of present invention were photographed along with Tablets of present invention (Windlas). Figure 1 provides Top and side view of the said tablets. Figure 2 provides the Longitudinal View of the said tablets.

Claims: 1. A coated tablet composition comprising
a) an extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers and excipients,
b) first functional coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 70-90% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 10-30% of the total weight of composition; wherein the provides a extended release of metformin for at least 12 hours; and wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water.

2. The tablet composition as claimed in claim 1, wherein the rate controlling polymer is selected from the group consisting of carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, 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 as claimed in claim 2, wherein the rate controlling polymer is hydroxylpropyl methylcellulose.

4. The tablet composition as claimed in claim 1, wherein the weight of metformin is 80% w/w to 90 % w/w of the total weight of the coated tablet.

5. The tablet composition as claimed in claim 1, wherein total weight of the rate controlling polymers and other excipients in the tablet is 10% w/w to 20% w/w of the total weight of the coated tablet.

6. The tablet composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients is selected from the group comprising binders, diluents, lubricants, matrix forming agents, disintegrating agents, glidants, stabilizers, and surface-active agents.

7. The tablet composition as claimed in claim 1, wherein the extended release matrix core is optionally coated with a seal coat.

8. The tablet composition as claimed in claim 1, wherein the core is prepared by the process of wet granulation, dry granulation or direct compression of granules in single layer.

9. A process for preparing extended-release tablets as claimed in claim 1, wherein the process comprising the steps of:
i. preparing granules comprising metformin hydrochloride and one or more rate controlling polymer;
ii. granules obtained in step (i) was compressed to form core of tablet;
iii. compressed core of step (ii) was then coated with first functional coating comprising voglibose and/or glimepiride along with one or more pharmaceutically acceptable excipients;
iv. the coated core of step(iii) was then coated with second functional coating comprising voglibose and/or glimepiride along with one or more pharmaceutically acceptable excipients;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 65-85% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 15-35% of the total weight of composition; wherein the said tablets provides a extended release of metformin for at least 12 hours; and wherein the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water.
.
10. A coated tablet composition comprising
a) an extended release matrix core comprising Metformin or salts thereof along with one or more rate controlling polymers,
b) first functional coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients; and
c) second functional coating layer over first coating layer comprising voglibose and/or glimepiride optionally along with one or more pharmaceutically acceptable excipients functional coating;
wherein and the total weight of metformin, voglibose and glimepiride in composition is 70-85% of the total composition and the total weight of the rate controlling polymers and excipients used in the composition is between 15-35% of the total weight of composition; wherein the provides a extended release of metformin for at least 12 hours; the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm before immersion of the said tablet in water and wherein one single tablet contains 500 to 1000mg of Metformin, 0.1 to 2mg of Voglibose and 0.1 to 5mg of Glimepiride.