DESC:FORM 2
THE PATENTS ACT, 1970
(39 Of 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION COMPRISING LOBEGLITAZONE SULFATE AND ITS COMBINATION
2. APPLICANT(S)
(a) Name: GLENMARK PHARMACEUTICALS LIMITED,
(b) Nationality: INDIAN
(c) Address: B/12 MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD, 22, MUMBAI, MAHARASHTRA- 400026
3. PREAMBLE TO THE DESCRIPTION

PROVISIONAL COMPLETE
The following specification describes the invention The following specification particularly describes the invention and the manner in which it is to be performed.

This application claims the priority date from the provisional application no. 202121028279 filed on date Jun 23, 2021 and provisional application no. 202121054190 filed on date Nov 24, 2021.

TECHNICAL FIELD OF THE INVENTION
The invention relates to a pharmaceutical composition comprising a combination of lobeglitazone or pharmaceutically acceptable salt thereof and one or more antidiabetic agent. In particular, the invention relates to a pharmaceutical composition comprising combination of lobeglitazone sulfate and glimepiride. The pharmaceutical composition of the present invention additionally comprising metformin hydrochloride in an extended release form. Further the combination products of the present invention effectively controls the blood glucose levels in patients with diabetes.

BACKGROUND OF THE INVENTION
Diabetes is one of the largest global public health concerns, imposing a heavy global burden on public health as well as socio-economic development. As per the estimates of the International Diabetes Federation (IDF), 451 million adults lived with diabetes worldwide in 2017 which is projected increase to 693 million by 2,045. Diabetes is one of the top 10 causes of death globally. Diabetes, cardiovascular disease, cancer and respiratory disease together account for over 80% of all premature non-communicable diseases (NCDs) deaths. Patients with diabetes have a 2–3 folds increased risk of all-cause mortality. Presence of diabetes is associated with increased mortality from infections, cardiovascular disease, stroke, chronic kidney disease, chronic liver disease, and cancer. Diabetes is the second biggest negative total effect on reducing global health adjusted life expectancy worldwide. Management concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications. Oral therapeutic options for the treatment of type 2 diabetes mellitus include agents known as: biguanides (metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors. These agents are all indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate.
The thiazolidinediones are a class of heterocyclic compounds consisting of a five-membered C3NS ring. Thiazolidinediones act by activating PPARs (peroxisome proliferator-activated receptors), a group of nuclear receptors, specific for PPAR? (PPAR-gamma, PPARG). The endogenous ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor binds to DNA in complex with the retinoid X receptor (RXR), another nuclear receptor, increasing transcription of a number of specific genes and decreasing transcription of others. The main effect of expression and repression of specific genes is an increase in the storage of fatty acids in adipocytes, thereby decreasing the amount of fatty acids present in circulation. As a result, cells become more dependent on the oxidation of carbohydrates, more specifically glucose, in order to yield energy for other cellular processes lead to a reduction in blood glucose levels. Therefore, thiazolidinediones have potential use in the treatment of type 2 diabetes.
Lobeglitazone is thiazolidinedione class drug approved in South Korea. Lobeglitazone is also known as 5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione has the following formula

Lobeglitazone primarily functions as an insulin sensitizer by binding and activating Peroxisome Proliferator-Activated Receptors (PPAR) gamma within fat cells. By activating PPAR-gamma and promoting the binding of insulin at fat cells, lobeglitazone thereby has been shown to reduce blood sugar levels, lower hemoglobain A1C (HbA1C) levels, and improve lipid and liver profiles.
Lobeglitazone was approved by the Ministry of Food and Drug Safety (South Korea) in 2013, as brand name of Duvie. Lobeglitazone is also approved in combination with metformin since 2016, as brand name of Duvimet XR®.
Sulfonylureas are a group of medicines used to treat type 2 diabetes. With type 2 diabetes, the body doesn't use the hormone insulin properly, leading to elevated levels of blood sugar (glucose). The drugs work by increasing the release of insulin from the pancreas. Sulfonylureas are only one part of a treatment plan for type 2 diabetes, which should also include diet and exercise to help control blood sugar levels. Taking sulfonylureas, along with adopting a healthy lifestyle, can reduce your risk of developing serious or life-threatening complications of diabetes, which may include heart disease, stroke, nerve damage, kidney problems, or eye problems.
Glimepiride is an oral anti-hyperglycemic agent (anti-diabetic drug) of the Sulfonylurea class of drugs. Glimepiride is known as 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcycloh exyl)urea and represented by formula:

Glimepiride is approved globally as brand name of AMARYL®. Glimepiride also approved in combination with metformin as brand name of AMARYL M® in many countries like India and South Korea.
Metformin is known as N,N-Dimethylimidodicarbonimidic diamide represented by formula

International Patent Application Publication No. WO2003080605 relates to lobeglitazone.
U.S. Patent No. 4,379,785 discloses glimepiride.
International Patent Application Publication No. WO2016072748 relate to pharmaceutical composition of lobeglitazone and having cellulose derivatives.
WO1998036755 and WO1998057649 disclose certain combination of sulfonylurea and glitazone, but do not disclose lobeglitazone under the glitazone class, further there is no disclosure of specific combination of lobeglitazone and glimepiride. Moreover, lobeglitazone is not even identified in these two PCT applications.
WO2000027401 relates to triple combination of thiazolidinedione, sulfonylureas and biguanides, however, this application does not describe specific combination of lobeglitazone sulfate, glimepiride and metformin.
The management of diabetes and associated complications often requires combining drugs with supplemental mechanisms of action. Lack of adherence to the multidrug therapy, possibly due to greater number of pills, higher administration frequency and poor tolerability, may lead to deficiency in the clinical outcomes. One way of addressing these problems is through a use of fixed-dose combinations that improve the medication compliance by reducing the pill burden of the patients thus proving more effective than the monotherapy.
There are always challenges to combine two or more drugs within one composition. Due to different physical and chemical properties of each drugs, maintaining in-process parameters and avoiding problems like sticking and clogging is always concern for the formulator. Moreover, maintaining drugs’ properties in finished product like dissolution, stability, impurity profile, etc. are also concern, while formulating fix dose composition. Combination of three drugs may even create more hurdles than combination of two drugs. Inventors of this patent application come up with versatile formulation and manufacturing process to tackle such problems and maintaining stability of each drug in fix dose combination of lobeglitazone sulfate and glimepiride as well as triple combination of lobeglitazone sulfate, glimepiride and metformin hydrochloride.
SUMMARY OF INVENTION
The present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof in combination with glimepiride or a pharmaceutically acceptable salts thereof for the treatment of diabetes mellitus.
In one aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof in combination with glimepiride or a pharmaceutically acceptable salts thereof for the treatment of type 2 diabetes mellitus.
In still another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof in combination with glimepiride or a pharmaceutically acceptable salts thereof and optionally with metformin or a pharmaceutically acceptable salts thereof for the treatment of type 2 diabetes mellitus.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof, glimepiride or a pharmaceutically acceptable salts thereof and optionally metformin or a pharmaceutically acceptable salts thereof, wherein lobeglitazone is present in an amount of about 0.1 mg to about 2 mg.
In still another embodiment, lobeglitazone is present in an amount of about 0.5 mg or about 1 mg, more preferably in an amount of about 0.5 mg.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride or a pharmaceutically acceptable salts thereof and optionally metformin or a pharmaceutically acceptable salts thereof, wherein glimepiride is present in an amount of about 0.5 mg to about 5 mg.
In still another embodiment, glimepiride is present in an amount of about 1 mg or about 2 mg or about 5 mg, more preferably in an amount of about 1 mg
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride or a pharmaceutically acceptable salts thereof and optionally metformin or a pharmaceutically acceptable salts thereof, wherein metformin is present in an amount of about 100 mg to about 2500 mg.
In still another embodiment, metformin hydrochloride is present in an amount of about 500 mg or about 1000 mg.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein lobeglitazone sulfate is present in an amount of about 0.5 mg, wherein glimepiride is present in an amount of about 1 mg and wherein the metformin hydrochloride is present in an amount of about 500 mg or about 1000 mg.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein weight ratio of lobeglitazone sulfate: glimepiride: metformin hydrochloride is about 1:2:1000 or about 1:2:2000.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate in an amount of 0.5 mg, glimepiride in an amount of 1 mg and optionally metformin hydrochloride in an amount of 500 mg or 1000 mg to be administered once a day or twice a day as single or divided doses.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein the composition is bilayer tablet and wherein lobeglitazone sulfate and glimepiride present in each layer of the tablet.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride is immediate release tablet, wherein lobeglitazone sulfate and glimepiride release not less than 70 % of the labeled amount within 45 minutes.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride,
wherein the composition is bilayer tablet; and
wherein glimepiride present in first layer and metformin hydrochloride is present in second layer, while lobeglitazone sulfate is coated on bilayer tablet.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride, wherein lobeglitazone sulfate and glimepiride are in immediate release form, while metformin is in extended release form.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is stable at 25°C ± 2°C & 60% RH ± 5 % RH.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is stable at 30°C ± 2°C & 75% RH ± 5 % RH.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is stable at 40°C ± 2°C & 75% RH ± 5 % RH.
According to embodiments of the present invention, the pharmaceutical compositions disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of type 2 diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.

DETAILED DESCRIPTION OF THE INVENTION
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.
The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, which are also effective and safe.
The term lobeglitazone refers to lobeglitazone, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof. Lobeglitazone or a pharmaceutically acceptable salt thereof such as sulfate, all of which are collectively referred to as lobeglitazone.
The term metformin refers to metformin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof, all of which are collectively referred to as metformin.
The term glimepiride refers to glimepiride, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof, all of which are collectively referred to as glimepiride.
The term "immediate release (IR)" used throughout the specification means the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging dissolution or absorption of drug.
The term "extended release (ER)" means the drug is formulated to make it available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (e.g., as a solution or an immediate release dosage form).
The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating metabolic disorders, produces an intended therapeutic benefit in a subject.
The term “active ingredient” (used interchangeably with “active” or “active substance” or “drug”) as used herein includes lobeglitazone or a pharmaceutically acceptable salt thereof, glimepiride or a pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salts thereof.
The term “treating” or “treatment” as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by drugs of the present invention in a mammal.
The term "patient" includes mammals like human and other animals. Preferably, the patient is a human.
The term “pharmaceutically acceptable excipients”, it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
The term “combination” includes administration of one or more active pharmaceutical ingredients either in a single dosage form or in separate dosage forms; in fixed dose combination or administered separately as adjuvant therapy.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Diabetes is a metabolic syndrome characterized by hyperglycemia, which results from an absolute deficiency in insulin secretion (type 1 diabetes) or from resistance to insulin action combined with an inadequate compensatory increase in insulin secretion (type 2 diabetes). The term "diabetes" as employed herein refers to type 2 diabetes and type 1 diabetes, usually type 2 diabetes. Management of diabetes concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications. Oral therapeutic options for the treatment of type 2 diabetes mellitus include agents known as: SGLT2 inhibitors, DPP IV inhibitor, biguanides (metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors.
The present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof in combination with glimepiride or a pharmaceutically acceptable salts thereof for the treatment of diabetes mellitus.
In one embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof in combination with glimepiride or a pharmaceutically acceptable salts thereof for the treatment of type 2 diabetes mellitus.
In still another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof in combination with glimepiride or a pharmaceutically acceptable salts thereof and optionally with metformin or a pharmaceutically acceptable salts thereof for the treatment of type 2 diabetes mellitus.
In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone or a pharmaceutically acceptable salts thereof, glimepiride or a pharmaceutically acceptable salts thereof and optionally metformin or a pharmaceutically acceptable salts thereof, wherein lobeglitazone is present in an amount of about 0.1 mg to about 2 mg.
In still another embodiment, lobeglitazone or a pharmaceutically acceptable salts thereof is lobeglitazone sulfate.
In still another embodiment, lobeglitazone sulfate is present in an amount of about 0.5 mg or about 1 mg, more preferably in an amount of about 0.5 mg.
In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride or a pharmaceutically acceptable salts thereof and optionally metformin or a pharmaceutically acceptable salts thereof, wherein glimepiride is present in an amount of about 0.5 mg to about 5 mg.
In still another embodiement, glimepiride or a pharmaceutically acceptable salts thereof is glimepiride base.
In still another embodiment, glimepiride is present in an amount of about 1 mg or about 2 mg or about 5 mg, more preferably in an amount of about 1 mg.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride or a pharmaceutically acceptable salts thereof and optionally metformin or a pharmaceutically acceptable salts thereof, wherein metformin is present in an amount of about 100 mg to about 2500 mg.
In still another embodiment, metformin or a pharmaceutically acceptable salts thereof is metformin hydrochloride.
In still another embodiment, metformin hydrochloride is present in an amount of about 500 mg or about 1000 mg.
In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein lobeglitazone sulfate is present in an amount of about 0.5 mg, wherein glimepiride is present in an amount of about 1 mg and wherein the metformin hydrochloride is present in an amount of about 500 mg.
In another embodiment, the solid oral pharmaceutical composition comprising therapeutically effective amount of lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein lobeglitazone sulfate is present in an amount of about 0.5 mg, wherein glimepiride is present in an amount of about 1 mg and wherein the metformin hydrochloride is present in an amount of about 1000 mg.
In another embodiment, a weight ratio of lobeglitazone sulfate and metformin hydrochloride ranges from about 1:500 to about 1:3000. In still another embodiment, the weight ratio of lobeglitazone sulfate and metformin hydrochloride is about 1:1000 or about 1:2000.
In another embodiment, a weight ratio of lobeglitazone sulfate and glimepiride ranges from about 1:1 to about 1:10. In still another embodiment, the weight ratio of lobeglitazone sulfate and glimepiride is about 1:2 or about 1:8.
In another embodiment, a weight ratio of glimepiride and metformin hydrochloride ranges from about 1:500 to about 1:1500. In still another embodiment, the weight ratio of glimepiride and metformin hydrochloride is about 1:500 or about 1:1000.
In preferred embodiment, the weight ratio of lobeglitazone sulfate: glimepiride: metformin hydrochloride is about 1:2:1000 or about 1:2:2000.
The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
In still another embodiment, the solid oral pharmaceutical composition is administered once or twice daily in a single or divided doses to achieve the glycemic control in patient suffering from type 2 diabetes mellitus.
In still another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate in an amount of 0.5 mg and glimepiride in an amount of 1 mg to be administered once a day or twice a day.
In still another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate in an amount of 0.5 mg and glimepiride in an amount of 1 mg to be administered once a day.
In still another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate in an amount of 0.5 mg and glimepiride in an amount of 1 mg to be administered twice a day.
In still another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate in an amount of 0.5 mg, glimepiride in an amount of 1 mg and metformin hydrochloride in an amount of 500 mg or 1000 mg to be administered once a day.
In still another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate in an amount of 0.5 mg, glimepiride in an amount of 1 mg and metformin hydrochloride in an amount of 500 mg or 1000 mg to be administered twice a day.
The dosage form of the present invention may be in form of a tablet, capsule, granules, tablet in tablet, pellets, beads, tablet/s in capsule, granules/pellets in capsule, bilayer tablet, trilayer tablet, inlay tablet, caplet, dry syrup or suspension.
In still another embodiment, the solid oral pharmaceutical composition is tablet, wherein the tablet can be coated or uncoated.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is monolayer tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is multilayer tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein the composition is monolayer tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein the both drugs are mixed together in matrix form.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein the composition is bilayer tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein the composition is bilayer tablet and wherein lobeglitazone sulfate and glimepiride present in each layer of the tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein the composition is bilayer tablet and wherein lobeglitazone sulfate and glimepiride present in same layer of the tablet and second layer is drug free.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein the composition is immediate release tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein composition is prepared using wet granulation process or dry granulation process or direct compression process.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride, wherein composition is bilayer tablet and each layer is prepared using wet granulation process or dry granulation process or direct compression process.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride is immediate release tablet, wherein lobeglitazone sulfate and glimepiride release not less than 70 % of the labeled amount within 45 minutes.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride is immediate release tablet, wherein lobeglitazone sulfate and glimepiride release not less than 90 % of the labeled amount within 45 minutes
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate and glimepiride is immediate release tablet, wherein lobeglitazone sulfate and glimepiride release not less than 95 % of the labeled amount within 45 minutes.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is multilayer tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride, wherein the composition is multilayer tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride, wherein the composition is trilayer tablet and lobeglitazone sulfate, glimepiride and metformin hydrochloride present in each layer of the tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride, wherein the composition is bilayer tablet.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride, wherein the composition is bilayer tablet, and wherein lobeglitazone sulfate and glimepiride present in first layer, while metformin hydrochloride is present in second layer.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride,
wherein the composition is bilayer tablet; and
wherein lobeglitazone sulfate present in first layer and metformin hydrochloride is present in second layer, while glimepiride is coated on bilayer tablet.
In still another embodiment, there is an optional seal coat layer present between bilayer tablet and glimepiride comprising layer.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride,
wherein the composition is bilayer tablet;
wherein lobeglitazone sulfate present in first layer and metformin hydrochloride is present in second layer, while glimepiride is coated on bilayer tablet; and
wherein the bilayer tablet and glimepiride layer are separated by seal coat layer.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride,
wherein the composition is bilayer tablet; and
wherein glimepiride present in first layer and metformin hydrochloride is present in second layer, while lobeglitazone sulfate is coated on bilayer tablet.
In still another embodiment, there is an optional seal coat layer present between bilayer tablet and lobeglitazone sulfate comprising layer.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride,
wherein the composition is bilayer tablet;
wherein glimepiride present in first layer and metformin hydrochloride is present in second layer, while lobeglitazone sulfate is coated on bilayer tablet; and
wherein the bilayer tablet and lobeglitazone sulfate layer are separated by seal coat layer.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and metformin hydrochloride, wherein lobeglitazone sulfate and glimepiride are in immediate release form, while metformin is in extended release form.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride,
wherein the composition is bilayer tablet; and
wherein each layer is prepared using wet granulation process or dry granulation process or direct compaction process.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition comprises one or more excipients.
The excipients may include rate controlling polymers or non-polymers, diluents, disintegrants, binders, bulking agents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, anti-tacking agents, emulsifiers, surfactants, plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents and the like used either alone or in combination thereof.
Further the composition comprises blend of granules of active ingredients with pharmaceutically acceptable excipients filled in capsule or compressed in tablets.
Non-limiting examples of diluents include one or more of microcrystalline cellulose, silicified microcrystalline cellulose microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sugars such as dextrose, mannitol, sorbitol, or sucrose and combinations thereof more preferabally lactose and microcrystalline cellulose.The lactose and microcrystalline cellulose are present in ratio of about 1:3 to about 1:10
Non limiting examples of disintegrants suitable for use herein include, crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants. Several specific types of disintegrant are suitable for use in the compositions described herein. For example, any grade of crospovidone can be used, including for example crospovidone XL-10, and includes members selected from the group consisting of Kollidon CL.RTM., Polyplasdone XL.RTM., Kollidon CL-M.RTM., Polyplasdone XL-10.RTM., and Polyplasdone INF-10.RTM. In one embodiment, the disintegrant, if present, of the stock granulation is sodium starch glycolate, croscarmellose sodium and/or crospovidone. These materials are also referred to as insoluble polyvidone, insoluble PVP, crosslinked PVP, and PVPP. The crospovidone can be substituted with croscarmellose sodium, sodium starch glycolate. The disintegrant according to current invention are present in an amount 1-50% w/w.
Non-limiting examples of glidants and lubricants include one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate. The glidant according to current invention are present in an amount 0.01-10% w/w.
Non limiting examples of binder include starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, hydroxypropyl methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and starch.
Non-limiting examples of preservatives include one or more of phenoxyethanol, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and mixtures thereof. Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof. Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives. The binder according to current invention are present in an amount 0.1-50% w/w.
Suitable plasticizers include, but are not limited to, one or more of diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, and polyethylene glycol. The solvents comprise one or more of dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water or mixture thereof.
Suitable rate controlling polymers are selected from, but not limited to, methacrylic acid copolymer dispersion, polyvinylpyrrolidone (PVP) and its derivatives such as copolyvidone, mixtures of PVP and polyvinylacetates, such as Kollidon SR; cellulosic polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose; vinyl acetate copolymers; polysaccharides (such as alginate, xanthan gum, guar gum etc.), starch and starch-based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof.
Suitable rate controlling non-polymers includes, but not limited to fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester or any combinations thereof.
Non-limiting examples of solvents include one or more of water; tetrahydrofuran; alcohols, e.g., methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g., pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons, e.g., chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride acetates, e.g., ethyl acetate.
Examples of suitable lubricants include stearic acid, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, zinc stearate, calcium stearate, silica, talc, polyethylene glycol, paraffin or the mixtures thereof.
Suitable anti-tacking agents may be selected from stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; sodium benzoate; sodium acetate and the like.
The surfactants and emulsifiers may be ionic or nonionic. Specific examples of surfactants and emulsifiers are such as poloxamers, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil, etc.
Moreover, the composition of the present invention may include stabilizers like gums, agar; taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins; coloring agents like titanium dioxide, natural food colors, dyes suitable for food, drug and cosmetic applications.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is stable at 25°C ± 2°C & 60% RH ± 5 % RH.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is stable at 30°C ± 2°C & 75% RH ± 5 % RH.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein the composition is stable at 40°C ± 2°C & 75% RH ± 5 % RH.
In another embodiment, the solid oral pharmaceutical composition comprising lobeglitazone sulfate, glimepiride and optionally metformin hydrochloride, wherein composition exhibits a synergistic effect.
The pharmaceutical compositions disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of type 2 diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.

Examples
EXAMPLE 1: Pharmaceutical compositon comprising combination of Lobeglitazone (L) and Glimepiride (G).
Note: In Examples 1-4: (L) stands for Lobeglitazone Sulphate and (G) stands for Glimepiride
Sr.No Ingredient %w/w
(0.1mg L+1mg G)
%w/w
(0.25mg L+1mg G)
%w/w
(0.5mg L+1mg G)
%w/w
(2 mg L+1mg G)

LOBEGLITAZONE PART
Dry mix in RMG
1 Lobeglitazone Sulphate 0.04 0.09 0.19 0.75
2 Lactose Monohydrate 30.81 30.75 30.66 30.09
3 Crosscarmellose sodium 0.94 0.94 0.94 0.94
4 Microcrystalline Cellulose 9.43 9.43 9.43 9.43
Binder preparation
5 Povidone K 30 2.42 2.42 2.42 2.42
6 Purified Water q.s q.s q.s q.s
LUBRICATION
7 Pregelatinised Starch 0.94 0.94 0.94 0.94
8 Low substituted Hydroxypropyl cellulose 2.36 2.36 2.36 2.36
9 Magnesium Stearate 0.23 0.23 0.23 0.23

GLIMEPIRIDE PART
Dry mix in RMG
1 Glimepiride 0.38 0.38 0.38 0.38
2 Lactose Monohydrate 41.11 41.11 41.11 41.11
3 Microcrystalline cellulose 7.51 7.51 7.51 7.51
4 Ferric oxide yellow 0.03 0.03 0.03 0.03
Binder preparation
5 Isopropyl Alcohol q.s q.s q.s q.s
6 Methylene Chloride (Dichloromethane) q.s q.s q.s q.s
7 Povidone K - 30 0.79 0.79 0.79 0.79
LUBRICATION
8 Sodium Starch Glycolate 2.64 2.64 2.64 2.64
9 Magnesium Stearate 0.38 0.38 0.38 0.38
Total

EXAMPLE 2: pharmaceutical compositon comprising combination of Lobeglitazone and Glimepiride
Sr.No Ingredient %w/w
(0.1mg L+0.5mg G)
%w/w
(0.25mg L+0.5mg G)
%w/w
(0.5mg L+0.5mg G)
%w/w
(2 mg L+0.5mg G)

LOBEGLITAZONE PART
Dry mix in RMG
1 Lobeglitazone Sulphate 0.04 0.09 0.19 0.75
2 Lactose Monohydrate 30.81 30.75 30.66 30.09
3 Crosscarmellose sodium 0.94 0.94 0.94 0.94
4 Microcrystalline Cellulose 9.43 9.43 9.43 9.43
Binder preparation
5 Povidone K 30 2.42 2.42 2.42 2.42
6 Purified Water
LUBRICATION
7 Pregelatinised Starch 0.94 0.94 0.94 0.94
8 Low substituted Hydroxypropyl cellulose 2.36 2.36 2.36 2.36
9 Magnesium Stearate 0.23 0.23 0.23 0.23

GLIMEPIRIDE PART
Dry mix in RMG
1 Glimepiride 0.19 0.19 0.19 0.19
2 Lactose Monohydrate 41.29 41.29 41.29 41.29
3 Microcrystalline cellulose 7.51 7.51 7.51 7.51
4 Ferric oxide yellow 0.03 0.03 0.03 0.03
Binder preparation 0.79 0.79 0.79 0.79
5 Isopropyl Alcohol q.s q.s q.s q.s
6 Methylene Chloride (Dichloromethane) q.s q.s q.s q.s
7 Povidone K - 30 0.79 0.79 0.79 0.79
LUBRICATION
8 Sodium Starch Glycolate 2.64 2.64 2.64 2.64
9 Magnesium Stearate 0.38 0.38 0.38 0.38
Total

EXAMPLE 3: pharmaceutical compositon comprising combination of Lobeglitazone and Glimepiride
Sr.No Ingredient %w/w
(0.1mg L+2mg G)
%w/w
(0.25mg L+2mg G)
%w/w
(0.5mg L+2mg G)
%w/w
(2 mg L+2mg G)

LOBEGLITAZONE PART
Dry mix in RMG
1 Lobeglitazone Sulphate 0.04 0.09 0.19 0.75
2 Lactose Monohydrate 30.81 30.75 30.66 30.09
3 Crosscarmellose sodium 0.94 0.94 0.94 0.94
4 Microcrystalline Cellulose 9.43 9.43 9.43 9.43
Binder preparation
5 Povidone K 30 2.42 2.42 2.42 2.42
6 Purified Water q.s q.s q.s q.s
LUBRICATION
7 Pregelatinised Starch 0.94 0.94 0.94 0.94
8 Low substituted Hydroxypropyl cellulose 2.36 2.36 2.36 2.36
9 Magnesium Stearate 0.23 0.23 0.23 0.23

GLIMEPIRIDE PART
Dry mix in RMG
1 Glimepiride 0.75 0.75 0.75 0.75
2 Lactose Monohydrate 40.73 40.73 40.73 40.73
3 Microcrystalline cellulose 7.51 7.51 7.51 7.51
4 Ferric oxide yellow 0.03 0.03 0.03 0.03
Binder preparation
5 Isopropyl Alcohol q.s q.s q.s q.s
6 Methylene Chloride (Dichloromethane) q.s q.s q.s q.s
7 Povidone K - 30 0.79 0.79 0.79 0.79
LUBRICATION
8 Sodium Starch Glycolate 2.64 2.64 2.64 2.64
9 Magnesium Stearate 0.38 0.38 0.38 0.38
Total

EXAMPLE 4: pharmaceutical compositon comprising combination of Lobeglitazone and Glimepiride
Sr.No Ingredient %w/w
(0.1mg L+5mg G) %w/w
(0.25mg L+5mg G) %w/w
(0.5mg L+5mg G) %w/w
(2 mg L+5mg G)

LOBEGLITAZONE PART
Dry mix in RMG
1 Lobeglitazone Sulphate 0.04 0.09 0.19 0.75
2 Lactose Monohydrate 30.81 30.75 30.66 30.09
3 Crosscarmellose sodium 0.94 0.94 0.94 0.94
4 Microcrystalline Cellulose 9.43 9.43 9.43 9.43
Binder preparation
5 Povidone K 30 2.42 2.42 2.42 2.42
6 Purified Water
LUBRICATION
7 Pregelatinised Starch 0.94 0.94 0.94 0.94
8 Low substituted Hydroxypropyl cellulose 2.36 2.36 2.36 2.36
9 Magnesium Stearate 0.23 0.23 0.23 0.23

GLIMEPIRIDE PART
Dry mix in RMG
1 Glimepiride 1.89 1.89 1.89 1.89
2 Lactose Monohydrate 39.60 39.60 39.60 39.60
3 Microcrystalline cellulose 7.51 7.51 7.51 7.51
4 Ferric oxide yellow 0.03 0.03 0.03 0.03
Binder preparation
5 Isopropyl Alcohol q.s q.s q.s q.s
6 Methylene Chloride (Dichloromethane) q.s q.s q.s q.s
7 Povidone K - 30 0.79 0.79 0.79 0.79
LUBRICATION
8 Sodium Starch Glycolate 2.64 2.64 2.64 2.64
9 Magnesium Stearate 0.38 0.38 0.38 0.38
Total

EXAMPLE 5: pharmaceutical compositon comprising combination of Lobeglitazone and Glimepiride

Sr.No Ingredient %w/w
LOBEGLITAZONE PART
Dry mix in RMG
1 Lobeglitazone Sulphate 0.19
2 Lactose Monohydrate 9.43
3 Crosscarmellose sodium 0.94
4 Microcrystalline Cellulose 30.66
Binder preparation
5 Povidone K 30 2.42
6 Purified Water
LUBRICATION
7 Pregelatinised Starch 0.94
8 Low substituted Hydroxypropyl cellulose 2.36
9 Magnesium Stearate 0.23

GLIMEPIRIDE PART
Dry mix in RMG
1 Glimepiride 0.38
2 Lactose Monohydrate 7.51
3 Microcrystalline cellulose 41.11
4 Ferric oxide yellow 0.03
Binder preparation
5 Isopropyl Alcohol
6 Methylene Chloride (Dichloromethane)
7 Povidone K - 30 0.79
LUBRICATION
8 Sodium Starch Glycolate 2.64
9 Magnesium Stearate 0.38
Total 100

EXAMPLE 6: pharmaceutical compositon comprising combination of Lobeglitazone and Glimepiride

Sr.No Ingredient %w/w
LOBEGLITAZONE PART
Dry mix in RMG
1 Lobeglitazone Sulphate 0.03-0.75
2 Lactose Monohydrate 5-50
3 Crosscarmellose sodium 1-30
4 Microcrystalline Cellulose 5-50
Binder preparation
5 Povidone K 30 0.1-30
6 Purified Water
LUBRICATION
7 Pregelatinised Starch 1-30
8 Low substituted Hydroxypropyl cellulose 1-30
9 Magnesium Stearate 0.01-10

GLIMEPIRIDE PART
Dry mix in RMG
1 Glimepiride
2 Lactose Monohydrate 5-50%
3 Microcrystalline cellulose 5-50%
4 Ferric oxide yellow 0.001-5
Binder preparation
5 Isopropyl Alcohol
6 Methylene Chloride (Dichloromethane)
7 Povidone K - 30 0.1-30
LUBRICATION
8 Sodium Starch Glycolate 1-30
9 Magnesium Stearate 0.01-10
Total 100

Manufacturing process of Lobeglitazone blend
a) Co-sift calculated quantity of lobeglitazone, lactose monohydrate, crosscarmellose sodium and microcrystalline cellulose
b) Prepare binder solution using purified water and povidone K-30.
c) Granulate the content of RMG (Step (b)) with binder solution of (step c)
d) Dry wet sifted material.
e) Sift dried granules
f) Mill the oversized granules through Comill using suitable screen
g) Sift, pregelatinised starch and low substituted hydroxypropyl cellulose and mix with dried granules.
h) Sift magnesium stearate.
Manufacturing of glimepiride blend
a. Co-sift calculated quantity of glimepiride, lactose monohydrate, microcrystalline cellulose and ferric oxide yellow
b. Prepare binder solution using isopropyl alcohol, methylene chloride and povidone K – 30.
c. Granulate the content of RMG (Step (b)) with binder solution of (step c).
d. Dry wet sifted material of (step d)
e. Sift dried granules using vibratory sifter.
f. Sift, sodium starch glycolate and mix with dried granules.
g. Sift magnesium stearate.
Compression: Compress the granules of lobeglitazone as well as of glimepiride in to bilayer tablet punching machine.
Optionally, coat the bilayer tablet using opadry based coating solution.
EXAMPLE 7: pharmaceutical compositon comprising combination of Lobeglitazone, Glimepiride and metformin (0.5 mg + 1 mg + 500 mg)
Sr.No Ingredients % w/w

METFORMIN HYDRCHLORIDE ER PART
I Dry mix
1 Metformin HCl 47.39
2 Guar Gum 6.35
3 Carboxy Methyl Cellulose Sodium 3.95
II Binder preparation
4 Purified. Water -
V Lubrication
5 Hydroxypropyl methyl Cellulose
(Methocel K100M Premium) 8.28
6 Pregelatinised Starch 0.85
7 Polyethylene Oxide 3.79
8 Hydrogenated Castor Oil 0.47
9 Magnesium Stearate 0.47

I Dry Mixing
1 Lactose Monohydrate 11.37
II
2 Glimeperide (API) 0.19
3 Hydroxy propyl cellulose (HPC- L) 0.57
4 Colour ferric oxide yellow 0.003
5 Colour ferric oxide red 0.007
6 Colloidal silicon dioxide 0.02
7 Isopropyl alcohol (IPA) -
III Sizing -
1 Dry Mixing
1 Lactose Monohydrate 11.37
II Granulation
2 Lobeglitazone Sulfate (API) 0.05
3 Hydroxy propyl cellulose-L (HPC-L) 0.28
4 Colour ferric oxide yellow 0.003
5 Colour ferric oxide red 0.006
6 Purified Water --
7 Isopropyl alcohol (IPA) --
I Lubrication
1 Microcrystalline Cellulose 2.9
2 Sodium starch Glycolate 0.9
3 Low Hydroxy propyl cellulose 0.4
4 Magnesium Stearate 0.3
Wt. of Bilayer tablet 100.0

Manufacturing process of metformin blend
a. Co-sift calculated quantity of metformin, guar gum and carboxymethyl cellulose Sodium
b. Load sifted blend from step (a) in to RMG Prepare binder solution
c. Granulate the content of RMG (Step (b)) with binder solution of (step c)
d. Dry wet sifted material of (step d)
e. Sift dried granules
f. Mill the oversized granules through comill using suitable.
g. Sift using vibratory sifter, hydroxypropyl methyl cellulose, pregelatinized starch, polyethylene oxide and hydrogenated castor oil and mix with dried granules.
h. Sift magnesium stearate
Manufacturing of glimepiride blend
a. Co-sift calculated quantity of glimepiride, lactose monohydrate, microcrystalline cellulose and ferric oxide yellow
b. Load sifted blend from step (a) in to RMG
c. Prepare binder solution
d. Granulate the content of RMG (Step (b)) with binder solution of (step c).
e. Dry wet sifted material of (step d.
f. Sift dried granules.
g. Mill the oversized granules through comill using suitable screen
h. Sift sodium starch glycolate and mix with dried granules.
i. Sift magnesium.
Compression: Compress the Granules of metformin as well as of Glimepiride in to bilayer tablet punching machine.
Seal coating:
a. Prepare seal coating solution using hydroxypropyl methyl cellulose, PEG 400, talc, titanium dioxide, isopropyl alcohol and methylene chloride.
b. Coating the seal coating solution on bilayer tablet of metformin and glimepiride.
Lobeglitazone drug layering:
a. Prepare lobeglitazone sulfate drugs solution by mixing lobeglitazone sulfate with hydroxypropyl methyl cellulose, dibutyl phthalate, talc, titanium dioxide, isopropyl alcohol and methylene chloride.
b. Coating the lobeglitazone drug solution on seal coated bilayer tablet of metformin and glimepiride.

EXAMPLE 8: pharmaceutical compositon comprising combination of Lobeglitazone, Glimepiride and metformin (0.5 mg + 1 mg + 1000 mg)
Sr.No Ingredients % w/w
METFORMIN HYDRCHLORIDE ER PART
I Dry mix
1 Metformin hydrochloride 65.57
2 Carboxy Methyl Cellulose Sodium 3.93
II Binder preparation
3 Purified Water
Q.S
V Lubrication
4 Hydroxy propyl methyl cellulose 9.18
5 Hydroxy propyl Methyl Cellulose 5 cps 0.66
6 Maize Starch 0.66
7 Magnesium Stearate 0.33
Metformin layer weight --
1225
I Dry Mixing
1 Lactose Monohydrate 7.87
II Granulation
2 Glimepiride (API) 0.13
3 Hydroxy propyl cellulose (HPC- L) 0.39
4 Colour ferric oxide yellow 0.002
5 Colour ferric oxide red 0.005
6 Colloidal silicon dioxide 0.02
7 Isopropyl alcohol (IPA) -
III Sizing
1 Dry Mixing
1 Lactose Monohydrate 7.87
II Granulation
2 Lobeglitazone Sulfate (API) 0.03
3 Hydroxy propyl cellulose-L (HPC-L) 0.20
4 Colour ferric oxide yellow 0.002
5 Colour ferric oxide red 0.004
6 Purified Water
7 Isopropyl alcohol (IPA)
I Lubrication
1 Microcrystalline Cellulose 2.0
2 Sodium starch Glycolate 0.7
3 Low Hydroxy propyl cellulose 0.3
4 Magnesium Stearate 0.2
Wt. of Bilayer tablet 100.0

Manufacturing process of metformin blend
a. Co-sift calculated quantity of metformin, guar gum and carboxymethyl cellulose Sodium
b. Load sifted blend from step (a) in to RMG c. Prepare binder solution.
d. Granulate the content of RMG (Step (b)) with binder solution of (step c)
e. Dry wet sifted material of (step d).
f. Sift dried granules.
g. Mill the oversized granules.
h. Sift using vibratory sifter, hydroxypropyl methyl cellulose, pregelatinized starch, polyethylene oxide and hydrogenated castor oil and mix with dried granules.
i. Sift magnesium stearate.
Manufacturing of glimepiride blend
a. Co-sift calculated quantity of lactose monohydrate, microcrystalline cellulose and ferric oxide yellow
b. Dissolve Povidone followed by Glimepiride.
c. Sift all lubricantion ingredients and mix well with dried granules.
d. Compress the bilayer tablet
Compression: Compress the Granules of metformin as well as of Glimepiride in to bilayer tablet punching machine.
Seal coating:
c. Prepare seal coating solution using hydroxypropyl methyl cellulose, PEG 400, talc, titanium dioxide, isopropyl alcohol and methylene chloride.
d. Coating the seal coating solution on bilayer tablet of metformin and glimepiride.
Lobeglitazone drug layering:
c. Prepare lobeglitazone sulfate drugs solution by mixing lobeglitazone sulfate with hydroxypropyl methyl cellulose, dibutyl phthalate, talc, titanium dioxide, isopropyl alcohol and methylene chloride.
Coating the lobeglitazone drug solution on seal coated bilayer tablet of metformin and glimepiride..
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention.

EXAMPLE 9- Comparative Cumulative Dissolution Profile for Glimepiride was carried out with Lobeglitazone Sulfate 0.5 mg and Glimepiride 1mg Tablets as test product and Glimepiride Tablet IP 1 mg (Azulix-1) as reference product in Phosphate buffer pH 7.8 with 1.0 % SLS IP with Apparatus -I (Paddle) of 900ml at 75 rpm and 37°C (± 0.5°C)
Time in Minutes % Drug Released in Avg.
Test Reference
10 84.1 95.8
15 86.9 95.7
30 93.8 95.8
45 96.6 95.7

EXAMPLE 10- Comparative Cumulative Dissolution Profile for Glimepiride was carried out with Lobeglitazone Sulfate 0.5 mg and Glimepiride 1mg Tablets as test product and Glimepiride Tablet IP 1 mg (Azulix-1) as reference product in Phosphate buffer pH 6.8 with 1.0 % SLS with Apparatus -I (Paddle) of 900ml at 75 rpm and 37°C (± 0.5°C)
Time in Minutes % Drug Released in Avg.
Test Reference
10 80.4 95.4
15 87.1 95.3
30 89.5 95.4
45 94.2 95.2

EXAMPLE 11- Comparative Cumulative Dissolution Profile for Glimepiride was carried out with Lobeglitazone Sulfate 0.5 mg and Glimepiride 1mg Tablets as test product and Glimepiride Tablet IP 1 mg (Azulix-1) as reference product in Acetate Buffer pH 4.5 with 1.0 % SLS with Apparatus -I (Paddle) of 900ml at 75 rpm and 37°C (± 0.5°C)
Time in Minutes % Drug Released in Avg.
Test Reference
10 84.8 98.9
15 94.2 101.4
30 98.2 103.2
45 101.5 104.4

EXAMPLE 12- Comparative Cumulative Dissolution Profile for Lobeglitazone Sulfate was carried out with Lobeglitazone Sulfate 0.5 mg and Glimepiride 1mg Tablets as test product and Lobeglitazone Sulfate (Duvie Tablets) - 0.5 mg as reference product in Phosphate buffer pH 7.8 with 1.0 % SLS with Apparatus -I (Paddle) of 900ml at 75 rpm and 37°C (± 0.5°C)
Time in Minutes % Drug Released in Avg.
Test Reference
10 98.2 92.5
15 98.0 92.3
30 98.8 92.7
45 99.0 91.8

EXAMPLE 13- Comparative Cumulative Dissolution Profile for Lobeglitazone Sulfate was carried out with Lobeglitazone Sulfate 0.5 mg and Glimepiride 1mg Tablets as test product and Lobeglitazone Sulfate (Duvie Tablets) - 0.5 mg as reference product in Phosphate buffer pH 6.8 with 1.0 % SLS with Apparatus -I (Paddle) of 900ml at 75 rpm and 37°C (± 0.5°C)
Time in Minutes % Drug Released in Avg.
Test Reference
10 98.9 101.5
15 98.7 100.5
30 99.0 100.8
45 99.5 100.7

EXAMPLE 14- Comparative Cumulative Dissolution Profile for Lobeglitazone Sulfate was carried out with Lobeglitazone Sulfate 0.5 mg and Glimepiride 1mg Tablets as test product and Lobeglitazone Sulfate (Duvie Tablets) - 0.5 mg as reference product in Acetate Buffer pH 4.5 with 1.0 % SLS with Apparatus -I (Paddle) of 900ml at 75 rpm and 37°C (± 0.5°C)
Time in Minutes % Drug Released in Avg.
Test Reference
10 97.9 103.9
15 97.9 105.7
30 98.4 107.0
45 98.5 108.2
Table 1: Stability studies data of bilayer tablet of Lobeglitazone sulfate and glimipride at 300C ± 20C & 75% RH ± 5 % RH for 3 months and 6 months.
Tests Initial analysis Analysis After
3 Months 6 Months
Avg. Wt. of tablets in mg : 265 mg (± 5%)
[Min : 251.75 mg & Max: 278.25 mg] 266.9 267.7 266.0
Disintegration Time
[Lt : Not more than 15 minutes] 2 mins,
05 sec’s 2 mins,
18 sec’s 2 mins,
25 sec’s
Hardness (Lt. Not less than 50 Newton’s) 70 73 72
Friability (Lt: Not more than 1.0 % w/w) 0.12 0.16 0.15
Dissolution for Lobeglitazone Sulfate
(Lt :NLT 70 %(D) of the L.A of drug is dissolved in 45 mins) 109.0 104.0 101.6
Dissolution for Glimepiride
(Lt :NLT 70 %(D) of the L.A of drug is dissolved in 45 mins) 91.5 102.4 107.8
Related Substances for Lobeglitazone Sulfate
i) Identified known Imp. A (Lt: Not more than 1.0%)
0.06
0.08
0.04
ii) Identified known Imp. B (Lt: Not more than 1.0%) 0.02 ND ND
iii) Identified known Imp. C (Lt: Not more than 1.0%) 0.22 0.26 0.29
iv) Single Max. Unknown Impurity (Lt: Not more than 0.5 %) 0.20 0.39 0.28
v) Total impurities (Lt: Not more than 2.0%) 0.57 1.08 0.73
Related Substances for Glimepiride
i) Glimepiride Related Compound B (Lt: Not more than 2.5%) 0.17 0.53 0.79
ii) Single Max. Unknown Impurity, (Lt: Not more than 0.5 %) 0.02 0.03 0.09
iii) Total impurities (Incl. Related compound B)
(Lt: Not more than 3.5 %) 0.23 0.79 1.02
iv) Total impurities (Excl. Related compound B)
(Lt: Not more than 1.0 %) 0.06 0.06 0.33
Assay for Lobeglitazone Sulfate
(Lt: NLT 90.0 % and NMT 110.0 % of L.A) 109.1 106.3 106.4
Assay for Glimepiride(Lt:NLT 90.0 %&NMT 110.0 % of L.A) 104.1 103.6 108.8
Microbiological Examination Test
A) Microbial Enumeration Tests
a) Total Aerobic Microbial Count
(Limit: Not more than 103 cfu/g)
b) Total combined Yeast and Moulds Count
(Limit: Not more than 102 cfu/g)
B) Test For Specified Micro-organisms
Escherichia coli (Limit: should be Absent/ g)

< 10 cfu/g

< 10 cfu/g

Absent

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Table 2: Stability studies data of bilayer tablet of Lobeglitazone sulfate and glimipride at 400C ± 20C & 75% RH ± 5 % RH for 3 months and 6 months.
Tests Initial analysis Analysis After
3 Months 6 Months
Avg. Wt. of tablets in mg : 265 mg (± 5%)
[Min : 251.75 mg & Max: 278.25 mg] 266.9 265.8 265.6
Disintegration Time
[Lt : Not more than 15 minutes] 2 mins,
05 sec’s 2 mins,
25sec’s 2 mins,
32 sec’s
Hardness (Lt. Not less than 50 Newton’s) 70 75 74
Friability (Lt: Not more than 1.0 % w/w) 0.12 0.15 0.18
Dissolution for Lobeglitazone Sulfate
(Lt :NLT 70 %(D) of the L.A of drug is dissolved in 45 mins) 109.0 101.8 101.6
Dissolution for Glimepiride
(Lt :NLT 70 %(D) of the L.A of drug is dissolved in 45 mins) 91.5 103.3 107.8
Related Substances for Lobeglitazone Sulfate
i) Identified known Imp. A (Lt: Not more than 1.0%)
0.06 0.07 0.05
ii) Identified known Imp. B (Lt: Not more than 1.0%) 0.02 ND ND
iii) Identified known Imp. C (Lt: Not more than 1.0%) 0.22 0.41 0.31
iv) Single Max. Unknown Impurity (Lt: Not more than 0.5 %) 0.20 0.34 0.23
v) Total impurities (Lt: Not more than 2.0%) 0.57 1.15 0.96
Related Substances for Glimepiride
i) Glimepiride Related Compound B (Lt: Not more than 2.5%)
0.17
1.26 2.21
ii) Single Max. Unknown Impurity, (Lt: Not more than 0.5 %) 0.02 0.03 0.17
iii) Total impurities (Incl. Related compound B)
(Lt: Not more than 3.5 %) 0.23 1.31 2.53
iv) Total impurities (Excl. Related compound B)
(Lt: Not more than 1.0 %) 0.06 0.05 0.32
Assay for Lobeglitazone Sulfate
(Lt: NLT 90.0 % and NMT 110.0 % of L.A) 109.1 103.9 103.7
Assay for Glimepiride(Lt:NLT 90.0 %&NMT 110.0 % of L.A) 104.1 102.4 106.6
Microbiological Examination Test
A) Microbial Enumeration Tests
a) Total Aerobic Microbial Count
(Limit: Not more than 103 cfu/g)
b) Total combined Yeast and Moulds Count
(Limit: Not more than 102 cfu/g)
B) Test For Specified Micro-organisms
Escherichia coli (Limit: should be Absent/ g)

< 10 cfu/g

< 10 cfu/g

Absent

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< 10 cfu/g

< 10 cfu/g

Absent

Clinical study:

Title: A Phase 3 clinical trial to study the efficacy and safety of lobeglitazone sulfate and fixed dose combination of lobeglitazone sulphate and glimepiride in the treatment of type 2 diabetes mellitus.

Study design:
This study is a randomized, double blind, double- dummy, three arm -active controlled, parallel group, multi-centre trial comparing the safety and efficacy of lobeglitazone sulphate (0.5 mg) given once daily and FDC of Lobeglitazone sulfate 0.5 mg and Glimepiride 1 mg once daily. The study will be 2-arms double-blind 16 weeks study Lobeglitazone 0.5 mg once daily vs. Pioglitazone 15 mg once daily followed by 3-arms 12 week study of FDC of Lobeglitazone sulfate 0.5 mg and Glimepiride 1 mg once daily vs. Lobeglitazone vs. Pioglitazone. The study will be conducted in subjects with T2DM who have inadequate glycemic control with stable dose of metformin as monotherapy. The subjects will continue to receive metformin at stable doses of = 1500 mg per day, throughout the study period in an open label manner.
The study consists of screening period of up to 3 weeks (including 2 week run in period).
In part A of the study the subjects will receive double blind study treatment for 16 weeks, post step 1 analysis, in part B treatment with open label study treatment for 12 weeks.
The primary outcome measures will be mean change from baseline in HbA1c at week 16 for part A and week 12 for part B. Any adverse event (AE), either clinical/laboratory, will be recorded and assessed for severity, seriousness and causality.
Primary outcome/s:
• Mean change from baseline in HbA1c levels at week 16 in Lobeglitazone sulfate group compared to Pioglitazone group.
• Mean change from baseline in HbA1c levels at week 12 in FDC of Lobeglitazone sulfate and Glimepiride group compared to Lobeglitazone sulfate group.
Secondary outcome/s:
• Mean change from baseline in HbA1c levels at week 12 in Lobeglitazone sulfate group compared to Pioglitazone group
• Mean change from baseline in fasting plasma glucose (FPG) levels at week 16 in Lobeglitazone sulfate group compared to Pioglitazone group
• Mean change from baseline in fasting plasma glucose (FPG) levels at week 12 FDC of Lobeglitazone sulfate and Glimepiride group compared to Lobeglitazone sulfate group
• Mean change from baseline in post-prandial plasma glucose (PPG) at week 16 in Lobeglitazone sulfate group compared to Pioglitazone group
•Mean change from baseline in post-prandial plasma glucose (PPG) at week 12 in FDC of Lobeglitazone sulfate and Glimepiride group compared to Lobeglitazone sulfate group
• Proportion of subjects achieving a therapeutic glycaemic response, at week 16 in Lobeglitazone sulfate group compared to Pioglitazone group, defined as:
- HbA1c responders: =0.7% reduction from baseline in HbA1c or a target HbA1c of < 7 %
-FPG responders: =30 mg/dL reduction from baseline in FPG or a target FPG of <126 mg/dL
• Proportion of subjects achieving a therapeutic glycaemic response, at week 12 in FDC of Lobeglitazone sulfate and Glimepiride group compared to Lobeglitazone sulfate group defined as:
- HbA1c responders: =0.7% reduction from baseline in HbA1c or a target HbA1c of <7%
- FPG responders: = 30 mg/dL reduction from baseline in FPG or a target FPG of <126 mg/dL
• Proportion of subjects requiring rescue medication for hyperglycaemia during study treatment in Lobeglitazone sulfate group compared to Pioglitazone group
• Proportion of subjects requiring rescue medication for hyperglycaemia during study treatment in FDC of Lobeglitazone sulfate and Glimepiride group compared to Lobeglitazone sulfate group
• Change from baseline in fasting insulin, HOMA-IR and HOMA-ß at week 16 in Lobeglitazone sulfate group compared to Pioglitazone group
• Change from baseline in fasting insulin, HOMA-IR and HOMA-ß at week 12 in FDC of Lobeglitazone sulfate and Glimepiride group compared to Lobeglitazone sulfate group.
Inclusion criteria
1. Subjects must be willing and able to provide written informed consent.
2. Male and female subjects = 18 and = 65 years of age, diagnosed with T2DM.
3. Subjects who have received stable dose of metformin = 1500 mg/day as monotherapy for at least 10 weeks prior to screening and having inadequate glycemic control at screening defined as HbA1c levels of =7.5% to =10.5%. For FDC Lobeglitazone/glimepiride arm inclusion criteria for HbA1c will be =8% to =11%.
4. Willing and able to comply with all aspects of the protocol.
5. Subjects with left ventricular ejection fraction of =50% as measured using 2D echocardiography at screening.
Exclusion Criteria:
1 History of Type 1 diabetes mellitus or secondary diabetes mellitus or diabetes insipidus
2. History of metabolic acidosis or diabetic ketoacidosis
3. FPG < 126 mg/dL or >270 mg/dL at screening.
4. History of more than one episode of severe hypoglycemia within 6 months prior to screening visit
5. BMI = 45.0 kg/m2 at screening
6. Subjects with elevated thyroid stimulating hormone (TSH) level at screening requiring initiation of intervention
7. Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 × ULN or total serum bilirubin >2.0 mg/dL at screening
8. Congestive heart failure defined as New York Heart Association (NYHA) class III/IV, unstable or acute congestive heart failure.
9. Significant cardiovascular history defined as: myocardial infarction, unstable angina pectoris, transient ischemic attack, unstable or previously undiagnosed arrhythmia, cardiac surgery or, or cerebrovascular accident.
10. Subjects with edema at screening during run-in period or at randomization visit
11. History of osteoporosis or history of bone fracture any time before screening or subjects receiving treatment for osteoporosis.
12. Subjects with uncontrolled hypertension with sitting systolic BP = 160 mmHg and/or diastolic BP = 100 mmHg at screening.
13. Any abnormality on 12-lead ECG at screening that is clinically significant and is judged as potential risk for subject’s participation in the study.
14. For male subjects with mean QTcF =450 msec or female subjects with mean QTcF =470 msec, triplicate ECG will be performed.
15. Patients with history of hereditary QT prolongation syndrome or patients having history of Torsades de pointes.
16. Patients with history of abdominal surgery or intestinal obstruction.
17. Patients with history of acute pancreatitis.
18. Uninvestigated macroscopic haematuria at screening, during the run-in period or within 1 month before screening
19. History of haemoglobinopathy and/or haemoglobin at screening <10 g/dL for men; haemoglobin at screening <9 g/dL for women
20. Donation or transfusion of blood, plasma, or platelets within the past 3 months prior to enrolment
21. History of malignancy within the last 5 years prior to enrolment, excluding non-melanoma skin cancer or treated carcinoma-in-situ of cervix.
22. History of Intolerance, contraindication or potential allergy/hypersensitivity to any of the ingredients of study medication or any other Thiazolidinediones or Sulfonylureas
23. Subject with a positive result for hepatitis B surface antigen or hepatitis C antibody at screening.
24. Subject is known to be seropositive for HIV based on history.
26. Subject with any condition or laboratory finding or physical examination finding which, in the judgment of the Investigator, may render the subject unable to complete the study or which may pose a significant risk to the subject.
27. Employee of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
30. Pregnant or breastfeeding women
31. Subjects with a history of substance abuse or dependence that in the opinion of the Investigator is considered to interfere with the subject’s participation in the study

We claim:

1. A solid oral pharmaceutical composition comprising lobeglitazone or a pharmaceutically acceptable salts thereof and glimepiride or a pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients for the treatment of diabetes mellitus.
2. The solid oral pharmaceutical composition as per claim 1, wherein lobeglitazone or a pharmaceutically acceptable salts thereof is present in an amount of 0.1 mg to 2 mg and glimepiride in an amount of 0.5 mg to 5 mg.
3. The solid oral pharmaceutical composition as per claim 2, wherein lobeglitazone or a pharmaceutically acceptable salts thereof is present in an amount of 0.5 mg and glimepiride or a pharmaceutically acceptable salts thereof is present in an amount of 1 mg.
4. The solid oral pharmaceutical composition comprising as per claim 1, wherein the composition is a coated tablet, uncoated tablet, matrix tablet, monolayer tablet, bilayer tablet or multilayer tablet.
5. The solid oral pharmaceutical composition comprising as per claim 1wherein the composition is a bilayer tablet.
6. The solid oral pharmaceutical composition comprising as per claim 1, wherein the pharmaceutically acceptable excipients comprises binder, diluents, disintegarnts, lubricants and glidants.
7. A pharmaceutical composition according to claim 1, wherein one or more pharmaceutically acceptable excipients comprises of
- diluent selected from the group comprising lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, low substituted hydroxy propyl cellulose and mannitol
- binder selected from group comprising low substituted hydroxy propyl cellulose, hydroxy propyl cellulose, starch, pregelatinize starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- lubricant selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil ,sodium stearyl fumarate, silica and talc
- disintegrant selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinised starch corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
- glidant selected from group comprising stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.
8. The solid oral pharmaceutical composition comprising as per claim 1, wherein the diluent is microcrystalline cellulose and lactose and in ratio of 1:3 to 1:10.
9. The solid oral pharmaceutical composition as per claim 1, wherein lobeglitazone sulfate and glimepiride release not less than 70 % within 45 minutes from the pharmaceutical composition.
10. An extended release solid oral pharmaceutical composition comprising lobeglitazone or a pharmaceutically acceptable salts thereof, glimepiride or a pharmaceutically acceptable salts thereof and metformin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients for the treatment of diabetes mellitus.
11. The solid oral pharmaceutical composition as per claim 10, wherein lobeglitazone or a pharmaceutically acceptable salts thereof is present in an amount of 0.1 mg to 4 mg, glimepiride or a pharmaceutically acceptable salts thereof is present in an amount of 0.5 mg to 10 mg and metformin or a pharmaceutically acceptable salts thereof is present in an amount of 100 mg to 2500 mg.
12. The solid oral pharmaceutical composition as per claim 10, wherein lobeglitazone sulfate is present in an amount of 0.5 mg, glimepiride is present in an amount of 1 mg or 2 mg and metformin hydrochloride is present in an amount of 500 mg or 1000 mg.
13. The solid oral pharmaceutical composition as per claim 10 wherein lobeglitazone sulfate and glimepiride are present in immediate release form, while metformin is present in extended release form.
14. The solid oral pharmaceutical composition comprising as per claim 1, wherein the pharmaceutically acceptable excipients comprises binder, diluents, disintegarnts,rate controlling plymers, lubricants and glidants.
15. The solid oral pharmaceutical composition as per claim 10 is to be administered once a day.

16. A pharmaceutical composition according to claim 10, wherein one or more pharmaceutically acceptable excipients comprises of
- diluent is selected from the group comprising lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, low substituted hydroxy propyl cellulose and mannitol
- binder is selected from group comprising low substituted hydroxy propyl cellulose, hydroxy propyl cellulose, starch, pregelatinize starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- lubricant is selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil ,sodium stearyl fumarate, silica and talc
- disintegrant is selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinised starch corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
-glidant is selected from group comprising stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumaraterate
-rate controlling polymer is selected from group comprising starch-based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives, Xantan gum, guar gum, polyvinylpyrrolidone (PVP),low substituted hydroxy propyl cellulose and hydroxy propyl cellulose.

Dated 21st day of June 2022
Digitally Signed by
Dr. Pramod Sagar
Deputy General Manager, IPM
Glenmark Pharmaceuticals Limited

ABSTRACT
The invention relates to a pharmaceutical composition comprising a combination of lobeglitazone or pharmaceutically acceptable salt thereof and one or more antidiabetic agent. In particular, the invention relates to a pharmaceutical composition comprising combination of lobeglitazone sulfate and glimepiride. The pharmaceutical composition of the present invention additionally comprising metformin hydrochloride in an extended release form. Further the combination products of the present invention effectively control the blood glucose levels in patients with diabetes.

,CLAIMS:1. A solid oral pharmaceutical composition comprising lobeglitazone or a pharmaceutically acceptable salts thereof and glimepiride or a pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients for the treatment of diabetes mellitus.
2. The solid oral pharmaceutical composition as per claim 1, wherein lobeglitazone or a pharmaceutically acceptable salts thereof is present in an amount of 0.1 mg to 2 mg and glimepiride in an amount of 0.5 mg to 5 mg.
3. The solid oral pharmaceutical composition as per claim 2, wherein lobeglitazone or a pharmaceutically acceptable salts thereof is present in an amount of 0.5 mg and glimepiride or a pharmaceutically acceptable salts thereof is present in an amount of 1 mg.
4. The solid oral pharmaceutical composition comprising as per claim 1, wherein the composition is a coated tablet, uncoated tablet, matrix tablet, monolayer tablet, bilayer tablet or multilayer tablet.
5. The solid oral pharmaceutical composition comprising as per claim 1wherein the composition is a bilayer tablet.
6. The solid oral pharmaceutical composition comprising as per claim 1, wherein the pharmaceutically acceptable excipients comprises binder, diluents, disintegarnts, lubricants and glidants.
7. A pharmaceutical composition according to claim 1, wherein one or more pharmaceutically acceptable excipients comprises of
- diluent selected from the group comprising lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, low substituted hydroxy propyl cellulose and mannitol
- binder selected from group comprising low substituted hydroxy propyl cellulose, hydroxy propyl cellulose, starch, pregelatinize starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- lubricant selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil ,sodium stearyl fumarate, silica and talc
- disintegrant selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinised starch corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
- glidant selected from group comprising stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.
8. The solid oral pharmaceutical composition comprising as per claim 1, wherein the diluent is microcrystalline cellulose and lactose and in ratio of 1:3 to 1:10.
9. The solid oral pharmaceutical composition as per claim 1, wherein lobeglitazone sulfate and glimepiride release not less than 70 % within 45 minutes from the pharmaceutical composition.
10. An extended release solid oral pharmaceutical composition comprising lobeglitazone or a pharmaceutically acceptable salts thereof, glimepiride or a pharmaceutically acceptable salts thereof and metformin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients for the treatment of diabetes mellitus.
11. The solid oral pharmaceutical composition as per claim 10, wherein lobeglitazone or a pharmaceutically acceptable salts thereof is present in an amount of 0.1 mg to 4 mg, glimepiride or a pharmaceutically acceptable salts thereof is present in an amount of 0.5 mg to 10 mg and metformin or a pharmaceutically acceptable salts thereof is present in an amount of 100 mg to 2500 mg.
12. The solid oral pharmaceutical composition as per claim 10, wherein lobeglitazone sulfate is present in an amount of 0.5 mg, glimepiride is present in an amount of 1 mg or 2 mg and metformin hydrochloride is present in an amount of 500 mg or 1000 mg.
13. The solid oral pharmaceutical composition as per claim 10 wherein lobeglitazone sulfate and glimepiride are present in immediate release form, while metformin is present in extended release form.
14. The solid oral pharmaceutical composition comprising as per claim 1, wherein the pharmaceutically acceptable excipients comprises binder, diluents, disintegarnts,rate controlling plymers, lubricants and glidants.
15. The solid oral pharmaceutical composition as per claim 10 is to be administered once a day.

16. A pharmaceutical composition according to claim 10, wherein one or more pharmaceutically acceptable excipients comprises of
- diluent is selected from the group comprising lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, low substituted hydroxy propyl cellulose and mannitol
- binder is selected from group comprising low substituted hydroxy propyl cellulose, hydroxy propyl cellulose, starch, pregelatinize starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- lubricant is selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil ,sodium stearyl fumarate, silica and talc
- disintegrant is selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinised starch corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
-glidant is selected from group comprising stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumaraterate
-rate controlling polymer is selected from group comprising starch-based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives, Xantan gum, guar gum, polyvinylpyrrolidone (PVP),low substituted hydroxy propyl cellulose and hydroxy propyl cellulose.