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 METFORMIN HYDROCHLORIDE
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.

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 metformin in a bilayer tablets. The pharmaceutical composition of the present invention additionally comprises metformin in an extended release form. Further the combination products of the present invention effectively control 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®. International Patent Application Publication No. WO2003080605 relates to lobeglitazone. International Patent Application Publication No. WO2016072748 relate to pharmaceutical composition of lobeglitazone and having cellulose derivatives. International Patent Application Publication No. WO2017073897 relate to core coat pharmaceutical composition of lobeglitazone 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. Further, 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 fixed dose composition. Fixed-dose combinations prepared using core-coat system, having atleast one drug in coating, suffers from various challenges like uniformity of drug content in coating layer, environmental hazard due to drug coating process and potential loss of certain drugs caused by high coating temperature and exhaust settings. The inventors of this patent application come up with versatile formulation and manufacturing process to tackle such problems and maintaining stability of each drug in fixed dose combination of lobeglitazone sulfate and metformin hydrochloride.

SUMMARY OF INVENTION
Preparing bilayer tablets with significantly different weight ratios between the two layers can lead to cracking at the layer interface, separation of the layers, or even cross-contamination of the two layers. The large difference in weight ratio between the metformin and Lobeglitazone provides challenges with regard to maintaining potency and content uniformity of the lower weight layer. Formulations of the Lobeglitazone layer with the exemplified excipients reduced or eliminated cracking, separation, and cross-contamination of the two layers while maintaining potency and uniformity of the second layer. Accordingly, the present invention provides bilayer tablet formulations that reduce or eliminate cracking, separation, and cross-contamination of the metformin and Lobeglitazone and maintains or improves the Lobglitazone layer potency and uniformity.
The present invention relates to a solid oral pharmaceutical composition comprising: (a) a first portion comprising lobeglitazone or salt or ester thereof and a pharmaceutically acceptable excipient and (b) a second portion comprising metformin or salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition is in the form of a bilayer tablet.
The present invention relates to a solid oral pharmaceutical composition comprising: (a) a first portion comprising lobeglitazone or salt or ester thereof and a pharmaceutically acceptable excipient and (b) a second portion comprising metformin or salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition is in the form of a bilayer tablet and wherein each layer is prepared using wet granulation process or dry granulation process or direct compaction process.
In one aspect, the present invention relates to a solid oral pharmaceutical composition comprising: (a) a first portion comprising lobeglitazone or salt or ester thereof and a pharmaceutically acceptable excipient and (b) a second portion comprising metformin or salt or ester thereof and a pharmaceutically acceptable excipient, wherein lobeglitazone sulfate is in immediate release form, while metformin is in extended release form.
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 wherein metformin is present in an amount of about 100 mg to about 2500 mg more preferably in an amount of about 500 mg or about 1000 mg.
In one aspect, the present invention relates to a solid oral pharmaceutical composition comprising: (a) a first portion comprising lobeglitazone or salt or ester thereof and a pharmaceutically acceptable excipient and (b) a second portion comprising metformin or salt or ester thereof and a pharmaceutically acceptable excipient wherein lobeglitazone sulfate and metformin hydrochloride comprising layer comprises intra-granular and extra-granular excipient.
In another aspect, lobeglitazone or salt thereof comprising layer comprises diluent, binder, stabilizer and disintegrating agent as intra-granular excipient and disintegrating agent and lubricant as extra-granular excipient.
In another aspect, metformin or salt thereof comprising layer comprises binder, disintegrating agent and rate controlling polymer as intra-granular excipient and binder, disintegrating agent, rate controlling polymers and lubricant as extra-granular excipient.
In another aspect, lobeglitazone or salt thereof comprising layer comprises diluent, binder, stabilizer and disintegrating agent as intra-granular excipient and disintegrating agent and lubricant as extra-granular excipient wherein
- diluent selected from the group comprising lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, starch, pregelatinized starch, low substituted hydroxy propyl cellulose and mannitol
- binder selected from group comprising low substituted hydroxy propyl cellulose, guar gum, hydroxy propyl cellulose, starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- disintegrant selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
- stabilizer is selected from triethyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, and polyethylene glycol
- lubricant selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil, sodium stearyl fumarate, silica and talc.
In another aspect, metformin comprising layer comprises, binder, disintegrating agent and rate controlling polymer as intra-granular excipient and binder, disintegrating agent, rate controlling polymers and lubricant as extra-granular excipient;
- binder selected from group comprising low substituted hydroxy propyl cellulose, guar gum, hydroxy propyl cellulose, starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- disintegrant selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
- rate controlling polymers selected from the group comprising 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, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methyl-cellulose; 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
- lubricant selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil, sodium stearyl fumarate, silica and talc.
In another aspect, the present invention relates to a bilayer tablet comprising lobeglitazone sulfate and metformin hydrochloride, wherein the composition has dissolution comparable to corecoat composition comprising lobeglitazone sulfate and metformin hydrochloride.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate and 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 and 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 and 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" or “a excipient” includes a single excipient as well as two or more different excipient, 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 "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. Immediate release means the drug exhibits a dissolution profile such that not less than 70% drug is released in 60 mins.
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). Extended release means the drug exhibits a dissolution profile such that not less than 20% and not more than 50% drug is release in 1 hour, not less than 45% and not more than 75% drug is release in 3 hours and not less than 80% drug is released in 10 hours.
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 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 excipient”, as used herein is any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities and 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.
The term “Bilayer tablets” as used herein is defined as any tablet having two layers that may be either of the same drug or of two different drugs.
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: (a) a first portion comprising lobeglitazone or salt or ester thereof and a pharmaceutically acceptable excipient and (b) a second portion comprising metformin or salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition is in the form of a bilayer tablet and wherein each layer is prepared using wet granulation process or dry granulation process or direct compaction process.
In one aspect, the present invention relates to a solid oral pharmaceutical composition comprising: (a) a first portion comprising lobeglitazone or salt or ester thereof and a pharmaceutically acceptable excipient and (b) a second portion comprising metformin or salt or ester thereof and a pharmaceutically acceptable excipient, wherein lobeglitazone sulfate is in immediate release form, while metformin is in extended release form.
In another aspect, the present invention relates to a bilayer tablet composition comprising: (a) a first layer comprising lobeglitazone or salt thereof and a pharmaceutically acceptable excipient and (b) a second layer comprising metformin or salt thereof and a pharmaceutically acceptable excipient, wherein lobeglitazone is in immediate release form and metformin is in extended release form.
In another aspect, the present invention relates to a bilayer tablet composition comprising: (a) a first layer comprising lobeglitazone or salt thereof and a pharmaceutically acceptable excipient and (b) a second layer comprising metformin or salt thereof and a pharmaceutically acceptable excipient, wherein lobeglitazone sulfate is in immediate release form and metformin hydrochloride is in extended release form.
In another aspect, the present invention relates to a bilayer tablet composition comprising: (a) a first layer comprising lobeglitazone or salt thereof and a pharmaceutically acceptable excipient and (b) a second layer comprising metformin or salt thereof and a pharmaceutically acceptable excipient, wherein lobeglitazone sulfate is in immediate release form and metformin hydrochloride is in extended release form for the treatment of diabetes mellitus.
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 wherein metformin is present in an amount of about 100 mg to about 2500 mg more preferably in an amount of about 500 mg or about 1000 mg.
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 daily in a single or divided doses to achieve the glycemic control in patient suffering from type 2 diabetes mellitus.
The dosage form of the present invention may be in the form of a tablet, capsule, granules, tablet in tablet, pellets, beads, tablet/s in capsule, granules/pellets in capsule, bilayer tablet, trilayer tablet, multilayer tablet, inlay tablet, caplet, dry syrup or suspension.
In one embodiment, the solid oral pharmaceutical composition is tablet, wherein the tablet can be coated or uncoated.
In still another embodiment, the solid oral pharmaceutical composition is bilayer tablet, wherein the tablet can be coated or uncoated.
In still another embodiment, the present invention relates to a solid oral pharmaceutical composition comprising: (a) a first portion comprising lobeglitazone or salt or ester thereof and pharmaceutically acceptable excipient and (b) a second portion comprising metformin or salt or ester thereof and pharmaceutically acceptable excipient wherein lobeglitazone sulfate and metformin hydrochloride comprising layer comprises intra-granular and extra-granular excipient.
In still another embodiment, lobeglitazone or salt thereof comprising layer comprises diluent, binder, stabilizer and disintegrating agent as intra-granular excipient and disintegrating agent and lubricant as extra-granular excipient.
In still another embodiment, metformin hydrochloride comprising layer comprises, binder, disintegrating agent and rate controlling polymer as intra-granular excipient and binder, disintegrating agent, rate controlling polymers and lubricant as extra-granular excipient.
In still another embodiment, lobeglitazone or salt thereof comprising layer comprises diluent, stabilizer, binder and disintegrating agent as intra-granular excipient and disintegrating agent and lubricant as extra-granular excipient wherein
- diluent selected from the group comprising lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, starch, pregelatinized starch, low substituted hydroxy propyl cellulose and mannitol
- binder selected from group comprising low substituted hydroxy propyl cellulose, guar gum, hydroxy propyl cellulose, starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- disintegrant selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
- stabilizer is selected from triethyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, and polyethylene glycol.
- lubricant selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil, sodium stearyl fumarate, silica and talc.
In still another embodiment, metformin comprising layer comprises, binder, disintegrating agent and rate controlling polymer as intra-granular excipient and binder, disintegrating agent, rate controlling polymers and lubricant as extra-granular excipient;
- binder selected from group comprising low substituted hydroxy propyl cellulose, guar gum, hydroxy propyl cellulose, starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose and ethylcellulose
- disintegrant selected from the group comprising crosscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose and low substituted hydroxypropyl cellulose
-rate controlling polymers selected from the group comprising 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, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methyl-cellulose; vinyl acetate copolymers; polysaccharides, starch and starch-based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers
- lubricant selected from the group comprising stearic acid, magnesium stearate, hydrogenated castor oil, sodium stearyl fumarate, silica and talc.
The excipient 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, solvents and the like used either alone or in combination thereof. Further the composition comprises blend of granules of active ingredients with pharmaceutically acceptable excipient 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, sucrose and combinations thereof. The preferred diluents are lactose and microcrystalline cellulose. The lactose and microcrystalline cellulose are present in ratio of about 2:1 to about 10:1. Preferably, the lactose and microcrystalline cellulose are present in ratio of about 3:1 to about 5:1. The diluents according to current invention are present in an amount 5%-90% w/w. Preferably, the diluents are present in an amount 10%-50%.
Non limiting examples of disintegrants suitable for use herein include crosscarmellose sodium, starch, potato starch, pregelatinized 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 0.5%-30% w/w. Preferably, the disintegrants are present in an amount 0.5%-5%.
Non-limiting examples of stabilizers 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 stabilizers according to current invention are present in an amount 0.01%-10% w/w. Preferably, the stabilizers are present in an amount 0.05%-2%.
Non-limiting examples of glidants include one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, hydrogenated castor oil and sodium stearyl fumarate. The glidant according to current invention are present in an amount 0.01%-5% w/w. Preferably, the glidants are present in an amount 0.05%-3%.
Non limiting examples of binder include starches, pregelatinized starches, maize starch, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, hydroxypropyl methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and low substituted hydroxy propyl cellulose. The binders according to current invention are present in an amount 0.5%-30% w/w. Preferably, the binders are present in an amount 1%-10%.
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. The preservatives according to current invention are present in an amount 0.01%-5% w/w.
Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof. The buffering agent according to current invention are present in an amount 0.01%-5% w/w.
Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives. The Chelating agent according to current invention are present in an amount 0.01%-5% 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 plasticizers according to current invention are present in an amount 0.01%-10% w/w.
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, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methyl-cellulose; 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. The rate controlling polymer according to current invention are present in an amount 1%-50% w/w. Preferably, the rate controlling polymer is present in an amount 5%-30%. More preferably, the rate controlling polymer is present in an amount 10%-20%.
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, dichloromethane, 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. The solvents according to current invention are present in an amount 1%-50% w/w.
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, hydrogenated castor oil, paraffin or the mixtures thereof. The lubricant according to current invention are present in an amount 0.01%-5% w/w. Preferably, the lubricant is present in an amount 0.05%-3%.
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 anti-tacking agents according to current invention are present in an amount 0.01%-5% w/w.
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. The surfactants and emulsifiers according to current invention are present in an amount 0.01-10% w/w.
Moreover, the composition of the present invention may include 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 aspect, the composition of the present invention is prepared using process known in the art. the composition of the present invention is prepared using wet granulation process or dry granulation process or direct compression process.
In another aspect, the composition is in the form of bilayer tablet wherein each tablet is prepared using using wet granulation process or dry granulation process or direct compression process. The manufacturing process includes steps such as dispensing, sifting, mixing, drying, lubrication, compression and packaging.
In another aspect, the present invention relates to a bilayer tablet comprising lobeglitazone sulfate and metformin hydrochloride wherein the composition exhibits dissolution such that not less than 70% lobeglitazone is released in 60 min.
In another aspect, the present invention relates to a bilayer tablet comprising lobeglitazone sulfate and metformin hydrochloride wherein the composition exhibits dissolution such that not less than 20% and not more than 50% metformin hydrochloride is released in 1 hour.
In another aspect, the present invention relates to a bilayer tablet comprising lobeglitazone sulfate and metformin hydrochloride wherein the composition exhibits dissolution such that not less than 45% and not more than 75% of metformin hydrochloride is released in 3 hours.
In another aspect, the present invention relates to a bilayer tablet comprising lobeglitazone sulfate and metformin hydrochloride wherein the composition exhibits dissolution such that not less than 80% metformin hydrochloride is released in 10 hours.
In another aspect, the present invention relates to a solid oral pharmaceutical composition comprising lobeglitazone sulfate and 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 and 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 and 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.

EXAMPLES

EXAMPLE-1: Pharmaceutical compositon comprising combination of Lobeglitazone 0.5mg and Metformin 500mg.

Sr. No Ingredient Ex 1a
% w/w Ex 1b
% w/w Ex 1c
% w/w
LOBEGLITAZONE PART
Intra-granular
1 Lobeglitazone Sulphate 0.05 0.05 0.045
2 Lactose Monohydrate 20.64 20.62 20.71
3 Crosscarmellose Sodium 0.63 0.63 0.64
4 Iron oxide Red 0.03 0.02 0.02
5 Microcrystalline Cellulose 6.33 6.32 6.35
6 Povidone 1.62 1.62 -
7 Hydroxypropyl methyl Cellulose (Methocel E 5 Premium) - - 1.17
8 Triethyl Citrate - 0.45 0.45
9 Purified Water q.s q.s q.s
Extra-granular
10 Pregelatinized Starch 0.63 0.63 0.64
11 Low Hydroxypropyl Cellulose 1.58 1.58 1.59
12 Magnesium Stearate 0.15 0.15 0.15
METFORMIN PART
Intra-granular
1 Metformin HCl 45.25 45.17 45.37
2 Guar Gum 6.12 6.11 6.14
3 Carboxy Methyl Cellulose Sodium 3.71 3.70 3.72
4 Purified Water q.s q.s q.s
Extra-granular
5 Hydroxypropyl Methyl Cellulose (Methocel K 100M Premium) 7.90 7.89 7.93
6 Pregelatinized Starch 0.81 0.54 0.55
7 Polyethylene Oxide 3.62 3.61 3.63
8 Hydrogenated Castor Oil 0.45 0.45 0.45
9 Magnesium Stearate 0.45 0.45 0.45
Total weight of bilayer tablet 1105mg 1107mg 1102mg

Manufacturing process of Lobeglitazone part:
a) Co-sift calculated quantity of lobeglitazone, lactose monohydrate, crosscarmellose sodium, iron oxide red and microcrystalline cellulose
b) Prepare binder solution using purified water and povidone/ triethyl citrate/ hydroxypropyl methyl cellulose
c) Granulate the content of RMG (Step (a)) with binder solution of (step b)
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) Lubricate with magnesium stearate

Manufacturing of metformin part:
a) Co-sift calculated quantity of metformin and carboxy methyl cellulose sodium
b) Prepare binder solution using guar gum and purified profile
c) Granulate the content of RMG (Step (a)) with binder solution of (step b)
d) Dry wet sifted material
e) Sift dried granules
f) Sift hydroxypropyl methyl cellulose, pregelatinized starch, polyethylene oxide and mix with dried granules
g) Lubricate the granules with hydrogenated castor oil and magnesium stearate.
Compress the granules of lobeglitazone as well as of metformin into bilayer tablet.

EXAMPLE-2: Pharmaceutical compositon comprising combination of Lobeglitazone 0.5mg and Metformin 1000mg.

Sr. No Ingredient Ex 2a
% w/w Ex 2b
% w/w Ex 2c
% w/w
LOBEGLITAZONE PART
Intra-granular
1 Lobeglitazone Sulphate 0.03 0.03 0.03
2 Lactose Monohydrate 14.48 14.17 14.5
3 Crosscarmellose Sodium 0.44 0.44 0.44
4 Iron oxide Red 0.02 0.01 0.011
5 Microcrystalline Cellulose 4.44 4.44 4.44
6 Povidone 1.14 1.14 -
7 Hydroxypropyl methyl Cellulose (Methocel E 5 Premium) - - 0.82
8 Triethyl Citrate - 0.32 0.32
9 Purified Water q.s q.s q.s
Extra-granular
10 Pregelatinized Starch 0.44 0.44 0.44
11 Low Hydroxypropyl Cellulose 1.11 1.11 1.11
12 Magnesium Stearate 0.11 0.11 0.11
METFORMIN PART
Intra-granular
1 Metformin HCl 63.49 63.49 63.49
2 Carboxy Methyl Cellulose Sodium 3.81 3.81 3.81
3 Purified Water q.s q.s q.s
Extra-granular
4 Hydroxypropyl Methyl Cellulose (Methocel K 100M Premium) 8.89 8.88 8.88
5 Hydroxypropyl Methyl Cellulose (E5 Premium) 0.63 0.64 0.64
6 Pregelatinized Starch 0.63 0.64 0.64
7 Magnesium Stearate 0.32 0.32 0.32
Total weight of bilayer tablet 1575mg 1575mg 1575mg

Manufacturing process of Lobeglitazone part:
a) Co-sift calculated quantity of lobeglitazone, lactose monohydrate, crosscarmellose sodium, iron oxide red and microcrystalline cellulose
b) Prepare binder solution using purified water and povidone/ triethyl citrate/ hydroxypropyl methyl cellulose
c) Granulate the content of RMG (Step (a)) with binder solution of (step b)
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) Lubricate with magnesium stearate

Manufacturing of metformin part:
a) Co-sift calculated quantity of metformin
b) Prepare binder solution using carboxy methyl cellulose sodium and purified profile
c) Granulate the content of RMG (Step (a)) with binder solution of (step b).
d) Dry wet sifted material
e) Sift dried granules
f) Sift hydroxypropyl methyl cellulose and starch and mix with dried granules.
g) Lubricate the granules with magnesium stearate.
Compress the granules of lobeglitazone as well as of metformin into bilayer tablet.

EXAMPLE-3: Comparative cumulative dissolution data for bilayer tablet formulation of Ex 1a against reference product.

Dissolution conditions Lobeglitazone Metformin
Apparatus used IP Apparatus-I (peak vessel) IP Apparatus-II (Basket)
Dissolution medium 0.1N HCl + 1.0 %SLS Phosphate buffer pH 6.8
Volume Used 900 mL 1000ml
Time 10, 15, 30, 45 and 60mins 1, 3 and 10 Hours
Speed 100 RPM 100 RPM
Temperature 37oC (±0.5oC) 37oC (±0.5oC)

Time (mins) Lobeglitazone
% Drug released Reference Product (Duvimet XR)
% Drug released
10min 95.81 87.5
15min 97.22 96.3
30min 95.81 96.6
45min 98.09 99.4
60min 105.36 100.3

Time (hrs) Metformin
% Drug released Reference Product (Duvimet XR)
% Drug released
1hr 35.29 32.7
3hr 66.01 61.9
10hr 94.51 92.8

EXAMPLE-4: Stability data for bilayer tablet formulation of Ex 1a

Lobeglitazone Sulfate Limits Initial 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
2M 3M 1M 3M
Disintegration Time NMT 15mins 38 sec 51sec 54sec 56sec 50sec
Dissolution NLT 70% of the LA of drug dissolved in 60min 105.36 101.13 97.63 99.08 101.89
Assay NLT 90.0% & NMT 110.0% of LA 106.52 106.24 106.26 102.37 103.41
Related Substance i) Identified Known Imp.-C
(NMT 1.0%) 0.146 0.152 0.159 0.151 0.132
ii) Single Max Unknown Imp. (NMT 1.0%) 0.206 BDL BDL 0.572 BDL
iii) Total Imp. (Including Imp-C) (NMT 2.0%) 0.539 0.152 0.159 0.723 0.132
NMT: Not More Than; NLT: Not Less Than; NA: Not applicable; ND: Not Detected; LA: Labeled Amount; BDL: Below Detection Limit

Metformin HCl Limits Initial 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
2M 3M 1M 3M
Disintegration Time NMT 15mins 38 sec 51sec 54sec 56sec 50sec
Dissolution 1 Hour
(NLT 20%-NMT 50%) 35.29 36.30 32.05 37.17 34.03
3 Hour
(NLT 45%- NMT75%) 66.01 62.28 65.43 66.65 65.94
10 Hour
(NLT 80%) 94.51 97.95 100.03 93.49 98.84
Assay NLT 90.0% & NMT 110.0% of LA 97.09 97.26 94.68 97.08 97.91
Related Substance ii) Single Max Unknown Imp. (NMT 0.2%) ND BDL BDL BDL BDL
iii) Total Imp.
(NMT 0.6%) ND BDL BDL BDL BDL
NMT: Not More Than; NLT: Not Less Than; NA: Not applicable; ND: Not Detected; LA: Labeled Amount; BDL: Below Detection Limit

The bilayer tablet for lobeglitazone sulfate and metformin HCl was stable for 3 months accelerated storage conditions and 3 months long term storage conditions.
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 application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments. All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:
We claim:

1. A bilayer tablet composition comprising: (a) a first layer comprising lobeglitazone or salt thereof and a pharmaceutically acceptable excipient and (b) a second layer comprising metformin or salt thereof and a pharmaceutically acceptable excipient, wherein lobeglitazone is in immediate release form and metformin is in extended release form.

2. A bilayer tablet composition as claimed in claim 1, wherein lobeglitazone or a pharmaceutically acceptable salts thereof is present in an amount of 0.5 mg and metformin or a pharmaceutically acceptable salts thereof is present in an amount of 500 mg or 1000 mg.

3. A bilayer tablet composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of lobeglitazone is a sulfate.

4. A bilayer tablet composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of metformin is a hydrochloride.

5. A bilayer tablet composition as claimed in claim 1, wherein the said pharmaceutically acceptable excipient comprises diluent, binder, lubricant, disintegrant, stabilizer, rate controlling polymer and glidant wherein
diluent is in amount 10%-50%;
binder is in amount 1%-10%;
lubricant is in amount 0.05%-3%;
disintegrant is in amount 0.5%-5%;
stabilizer is in amount 0.05%-2%;
rate controlling polymer is in amount 10%-20%; and
glidant is in amount 0.05%-3%.

6. A bilayer tablet composition as claimed in claim 1, wherein the composition exhibits dissolution such that not less than 70% lobeglitazone sulfate is dissolved in 60 min.

7. A bilayer tablet composition as claimed in claim 1, wherein the composition exhibits dissolution such that not less than 20% and not more than 50% metformin hydrochloride is released in 1 hour.

8. A bilayer tablet composition as claimed in claim 1, wherein the composition exhibits dissolution such that not less than 45% and not more than 75% of metformin hydrochloride is released in 3 hours.

9. A bilayer tablet composition as claimed in claim 1, wherein the composition exhibits dissolution such that not less than 80% metformin hydrochloride is released in 10 hours.

10. A bilayer tablet composition as claimed in claim 1, wherein the composition is stable at 25°C ± 2°C & 60% RH ± 5 % RH, 30°C ± 2°C & 75% RH ± 5 % RH and 40°C ± 2°C & 75% RH ± 5 % RH conditions.

11. A bilayer tablet composition as claimed in claim 1, wherein the diluents are lactose and microcrystalline cellulose and are present in ratio of 3:1 to 5:1.

12. A bilayer tablet composition as claimed in claim 1, wherein the composition is used for the treatment of diabetes mellitus.

Dated this 12th day of June 2023.
Signature: -- Digitally Signed--
Dr. Mahalaxmi Andheria
Vice President- IPM