FORM 2
THE PATENTS ACT, 1970
(39 Of 1970)
AND
THE PATENTS RULES, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10; rule13)
1. TITLE OF THE INVENTION:
FIXED DOSE PHARMACEUTICAL COMPOSITION COMPRISING COMBINATION OF REMOGLIFLOZIN OR SALT OR ESTER THEREOF AND VILDAGLIPTIN OR SALT THEREOF

TECHNICAL FIELD OF THE INVENTION
The invention relates to a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and DPP-IV inhibitor or salt thereof. In particular, the invention relates to a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof; wherein the combination produces synergistic effect in reducing blood glucose levels in patients with diabetes.
BACKGROUND OF THE INVENTION
Diabetes is becoming an increasing concern across the world as in 2007, approximately 246 million people were affected by the disease, with an additional 7 million people developing the disease each year. As per the one prediction in 2025, around 380 million people will have diabetes. Diabetes is a metabolic syndrome characterized by hyperglycemia, which results from an absolute deficiency in insulin secretion (type I diabetes) or from resistance to insulin action combined with an inadequate compensatory increase in insulin secretion (type II diabetes). Diabetes is associated with macro and micro complications such as retinopathy, nephropathy, and neuropathy. It highly desirable to adopt a healthier lifestyle, failing of which calls for chronic therapy with medicinal agents.
Remogliflozin (base) has been disclosed in PCT publication WO2001/016147 A1.

Remogliflozin etabonate is the pro-drug of remogliflozin. Remogliflozin etabonate also known as 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-β -D-glucopyranoside has the following formula


U.S. Patent No. 7,056,892 is directed to remogliflozin or salt thereof. U.S. Patent No. 7,084,123 is directed to remogliflozin etabonate or salt thereof. These patents also disclose the use of the drugs for prevention or treatment of disease associated with hyperglycemia. Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type II diabetes mellitus. Efforts have been made to develop oral formulations of remogliflozin for the treatment of type II diabetes. Another U.S. Patent No. 8,951,976 is directed to the use of remogliflozin or remogliflozin etabonate or salt thereof for treating disease associated with abnormal accumulation of liver lipids.
Dipeptidyl peptidase IV inhibitors, also known as gliptins, are a class of oral diabetes drugs that inhibit the enzyme DPP-IV which destroys hormone incretin. Incretin helps the body to regulate insulin secretion and glucose metabolism. The use of dipeptidyl peptidase IV inhibitors is very well known in the art, however recently it has been found that some dipeptidyl peptidase IV inhibitors were also able to provide benefit for refractory cases of abnormal accumulation of liver lipids. Vildagliptin is a new oral antidiabetic agent that enhances pancreatic islet cell responsiveness to glucose. An extensive clinical program involving approximately 22,000 patients and 7000 patient-years of exposure to vildagliptin has shown that the agent is well tolerated and efficacious in improving glycemic control in patients with type II diabetes mellitus. Monotherapy trials have shown that significant HbA1c lowering is accompanied by body weight-neutral and lipid-neutral effects, low risk of edema, and low risk of hypoglycemia.
U.S. Patent No. 6,166,063 discloses vildagliptin. International Patent Publication No. WO2012/006398 discloses a combination immediate and delayed release delivery system for remogliflozin etabonate which provides a dosage form that has two distinct phases of

release, a formulation that promotes immediate release of the compound upon ingestion and another formulation which delays the release of the compound. The U.S. Patent No. 8,853,385 (Mitzubishi Tanabe) discloses method for increasing plasma active GLP-1 levels using combination of DPP-IV inhibitor and SGLT-2 inhibitors. The invention does not disclose etabonate salt of remogliflozin. International Patent Publication No. WO 2009/022008 & WO 2009/022009 discloses composition comprising a pyrazole-O-glucoside derivative in combination with a DPP-IV inhibitor. U.S. Patent Application No. 2011/0046076 discloses combination of SGLT2 inhibitor and DPP-IV inhibitor broadly.
The management of diabetes and associated complications often requires combining drugs with complimentary 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. The inventors of present invention have invented a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt thereof and vildagliptin or salt thereof for treatment of diabetes and associated complications.
SUMMARY OF INVENTION
In one embodiment of the invention, disclosed is a fixed dose combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes.
Particularly disclosed is a fixed dose pharmaceutical composition comprising combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof in a weight ratio of 1:0.1 to 1:10 for the treatment of diabetes The fixed dose combination of the present invention produces a synergistic effect in lowering blood glucose levels.
In another embodiment, there is provided a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of

diabetes; wherein a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.1 to 1:10.
In still another embodiment, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.2 to 1:5. In an alternate embodiment, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof is 1:0.5 or 1:0.2.
The fixed dose pharmaceutical composition further comprises a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients are one or more of 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 and chelating agents.
The fixed dose pharmaceutical composition comprises remogliflozin or salt or ester thereof which is present in an amount of 0.5 mg to 500 mg. Alternatively, remogliflozin or salt or ester thereof is present in amount of 50mg or 100mg or 250mg.
The fixed dose pharmaceutical composition comprises vildagliptin or salt thereof which is present in amount of 5mg to 500mg. Alternatively, vildagliptin or salt thereof is present in an amount of 25mg or 50mg or 100mg.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof, vildagliptin or salt thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof and a pharamceutically acceptable excipient, the extra-granular portion comprises vildagliptin or salt thereof and a pharamceutically acceptable excipient; wherein said portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof, vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, the extra-granular portion comprises one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein said portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.

BRIEF DESCRIPTION OF FIGURES
Figure 1: Anti-hyperglycemic effects of remogliflozin etabonate (1mg/kg), vildagliptin (1mg/kg) and combination of both in healthy male rats. Blood glucose concentartion (mg/dl) were measured (0-120min) and AUC(0-120min) for blood glucose was calculated. Data presented as mean ±SEM; n=6 and statistically analysed using One way ANOVA followed by Dunnet’s Multiple comparison test.
DETAIL DESCRIPTION OF INVENTION
There is provided a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt thereof and DPP-IV inhibitor or salt thereof.
In particular, there is provided a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes; wherein a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.1 to 1:15.
The terms used herein are defined as follows.
The term “diabetes” used herein refers to Type I diabetes or Type II diabetes.
The term "remogliflozin" as employed herein refers to remogliflozin, prodrug, salts and ester thereof, in particular remogliflozin etabonate, including hydrates and solvates thereof, amorphous and crystalline forms thereof. Examples of salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like, and salts with inorganic bases such as a sodium salt, a potassium salt and the like.
The term “dipeptidyl peptidase IV inhibitor” used herein to indicate a molecule that exhibits inhibition of the enzymatic activity of dipeptidyl peptidase IV and functionally

related enzymes. Treatment with DPP-IV inhibitors prolongs the duration of action of peptide substrates and increases levels of their intact, undegraded forms leading to a spectrum of biological activities. In a present context "a dipeptidyl peptidase IV inhibitor" is also intended to comprise an active metabolite and a prodrug thereof. An active "metabolite" is an active derivative of the dipeptidyl peptidase IV inhibitor produced when the dipeptidyl peptidase IV inhibitor is metabolized. A "prodrug" is a compound that is either metabolized to a dipeptidyl peptidase IV inhibitor or is metabolized to the same metabolite(s) as that of a dipeptidyl peptidase IV inhibitor.
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 or DR)" 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 “excipient” used throughout the specification refers to a substance with which the drug may be combined to achieve a specific dosage form, formulation or composition for delivery to humans.
In one embodiment of the invention, disclosed is a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof in a weight ratio of 1:0.1 to 1:15. The fixed dose combination of the present invention produces a synergistic effect in lowering blood glucose levels.
In another embodiment, there is provided a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes; wherein a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.1 to 1:10.
In still another embodiment, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.2 to 1:5. In an alternate embodiment, a weight

ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof is 1:0.5 or 1:0.2.
In alternate embodiment, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1: 1 to 10:1. In still another embodiment, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 5: 1. In still another embodiment, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 5: 1.
In one embodiment, the remogliflozin is present as remogliflozin etabonate.
In another embodiment, the DPP-IV inhibitor is vildagliptin or salt thereof. In still another embodiment, the DPP-IV inhibitor is vildagliptin present as base.
In still another embodiment, the concentration of vildagliptin or salt thereof is 50mg.
In still another embodiment, the combination is administered once a daily or twice a daily.
In still another embodiment, the combination is administered to patient in one composition (Single tablet) or separately that is one tablet of having remogliflozin etabonate and other tablet having vildagliptin.
In yet another embodiment, there is provided a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes; wherein a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1: 0.1 to 1:10.
In yet another embodiment, there is provided a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes; wherein a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.2 to 1:5.

In yet another embodiment, there is provided a pharmaceutical composition comprising a fixed dose combination of remogliflozin etabonate and vildagliptin for treatment of diabetes; wherein a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges is 1:0.5 or 1:0.2.
The fixed dose pharmaceutical composition comprises remogliflozin or salt or ester thereof which is present in amount of 0.5 mg to 500 mg. Alternatively, remogliflozin or salt or ester thereof is present in amount of 50mg or 100mg or 250mg.
The fixed dose pharmaceutical composition comprises vildagliptin or salt thereof which is present in an amount of 5mg to 500mg. Alternatively, vildagliptin or salt thereof is present in an amount of 25mg or 50mg or 100mg.
In yet another embodiment, there is provided a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes; wherein a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.1 to 1:10, and wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients are one or more of 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, preservatives, lubricants, glidants, and chelating agents.
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 concentration of rate controlling polymer is 1 to 30% by weight of composition.
Suitable binders are selected from, but not limited to, polyvinyl pyrrolidone, copolymers of vinyl pyrrolidone with other vinylderivatives, hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and starch. The concentration of binder is 1 to 25% by weight of composition.

Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide and magnesium aluminum silicate. The concentration of diluent is 1 to 30 % by weight of composition.
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. The concentration of lubricants is 1 to 15 % by weight of composition.
Example of suitable glidants include, but are not limited to, colloidal silicon dioxide, stearic acid, talk, aluminium silicate or the mixtures thereof. The concentration of glidants is 1 to 15 % by weight of composition.
Suitable disintegrants are selected from microcrystalline cellulose, low-substituted hydroxypropyl cellulose, alginic acid and alginates, modified starches, sodium starch glycolate, sodium carboxy methyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, docusate sodium, guar gum or the mixtures thereof. The concentration of disintegrants is 1 to 30% by weight of composition.
Suitable buffering agents may include, but are not limited to, one or more of a bicarbonate salt of alkali earth metal, amino acids, an acid salt of an amino acid, an alkali salt of an amino acid, and combinations of any of the foregoing.
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 sweeteners include aspartame, neotame, sucralose, sodium saccharine and the like.

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.
Suitable bulking agents, anti-oxidants, colorants, flavoring agents, coating agents, preservatives, chelating agents are selected from the agents known to a person skilled in the art.
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.
The fixed dose pharmaceutical composition of remogliflozin etabonate and vildgliptin of the present invention is administered in the form of oral dosage. The dosage form of the present invention may be in form of a tablet, tablet in tablet, bilayer tablet, trilayer tablet, inlay tablet, capsule, capsule in capsule, tablet/s in capsule, granules and/or pellets in capsule, caplet, granules, pellets, pellets and tablet in capsules, dry syrup or suspension.
The tablet dosage form of the present invention may be a bilayer tablet in which remogliflozin is present in a first layer and vildagliptin is present in the second layer. Alternatively, the formulation may be a film-coated tablet in which remogliflozin is present in the core tablet and vildagliptin is present in the film-coating layer. Alternatively, the tablet may be a trilayer tablet in which the two layers containing only remogliflozin and vildagliptin are separated by a third layer which does not contain any active ingredient. Alternatively, the tablet may be a press-coated tablet, i.e. a tablet in which remogliflozin is contained in small tablets and the vildagliptin is contained in a second granulation or blend and compressed together with one small tablet to one large

press-coated tablet. All types of the herein before mentioned tablets may be without a coating or may have one or more coatings, in particular film-coatings.
The tablet-in-tablet dosage form of the invention may be prepared by compressing remogliflozin with one or more rate controlling polymer or non-polymer to form a core extended release tablet; and compressing remogliflozin and vildagliptin optionally along with one or more pharmaceutically acceptable excipient onto said core tablet to form compressed outer tablet that causes immediate release.
In another embodiment of the present invention, the pharmaceutical composition is formulated as an inlay tablet. Inlay tablets according to the present invention are tablets wherein inner tablet is positioned within a comparatively larger “outer” tablet in such a way that at least one surface of the inner tablet is not in contact with outer tablet. Inlay tablet dosage form of present invention comprises: (a) an inner inlayed tablet comprising remogliflozin and excipient(s) that causes extended release; and (b) an outer tablet comprising remogliflozin and vildagliptin along with excipient(s) to cause immediate release.
In another embodiment, this invention embraces capsule- in- capsule formulations wherein smaller size capsule is encapsulated into a larger capsule. Capsule-in-capsule consists of an external capsule and internal capsule (inner capsule) located therein. It is preferred that smaller size capsule is filled with remogliflozin and excipients so as to cause extended release while larger capsule is filled with remogliflozin and vildagliptin along with excipients for immediate release.
Preferably, the tablet of the invention is monolithic that means having a homogenous matrix of active ingredient and pharmaceutically acceptable excipients. Alternatvely, the the tablet of the invention is formed as a bilayer, wherein the one layer is having active ingredients along with pharmaceutically acceptable excipients and other layer is having pharmaceutically acceptable excipients. Alternatively, both layer of bilayer tablet may contain active ingredients.
The invention composition can be made by different manufacturing processes such as by direct compression and by wet granulation. Wet granulation involves formation of

granules using active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients and this portion can be termed as intra-granular portion. These granules are then lubricated with blend of excipients comprising lubricant and this lubricant blend then compressed to form a tablet. The portion outside the granules can be referred as extra-granular portion. Direct compression on the other hand requires only that the active ingredient is blended with one or more pharmaceutically acceptable excipients before compression and then compressed into tablet. The prefered way for making the invention composition is wet granulation.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof, vildagliptin or salt thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with aqueous seal coat.
In yet another embodiment, there is disclosed a process of preparing a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof, vildagliptin or salt thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with aqueous seal coat, wherein said processs comprises steps of: (a) preparing a granule comprising remogliflozin or salt or ester thereof, vildagliptin or salt thereof and and one or more pharmaceutically acceptable excipients, (b) lubricating the granules of step (a) using lubricating agents, (c) compressing the lubricated granules of step (b) to obtain uncoated tablets, and optionally (d) coating the tablets by using an aqueous film coating layer to obtain final composition.

The tablet prepared using above process is having monolithic matrix or monolayer of active ingredient and pharmaceutical excipients.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof, vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin etabonate, vildagliptin and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises 50mg or 100mg or 250mg of remogliflozin etabonate, 25mg or 50mg or 100mg of vildagliptin and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.

In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises 50mg or 100mg or 250mg of remogliflozin etabonate, 25mg or 50mg or 100mg of vildagliptin and one or more pharmaceutically acceptable excipients such as crosscarmellose sodium, microcrystalline cellulose, and povidone, and the extra-granular portion comprises one or more pharmaceutically acceptable excipients such as crosscarmellose sodium, microcrystalline cellulose, and magnesium stearate; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof and a pharamceutically acceptable excipient, and the extra-granular portion comprises vildagliptin or salt thereof and a pharamceutically acceptable excipient; wherein the said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a process of preparing a fixed dose pharmaceutical composition comprising comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof and a pharamceutically acceptable excipient, and the extra-granular portion comprises vildagliptin or salt thereof and a pharamceutically acceptable excipient; wherein the said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat, wherein said processs comprises steps of: (a) preparing a granule comprising remogliflozin or salt or ester thereof and and one or more pharmaceutically acceptable excipients, (b) lubricating the

granules of step (a) using lubricating agents, (c) mixing with lubricated granules of step (b), vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients to obtain a blend, (d) compressing the blend of step (c) to obtain uncoated tablets, and optionally (e) coating the tablets by using the aqueous film coating layer to obtain final composition.
The tablet prepared using above process is having monolithic matrix or monolayer of active ingredient and pharmaceutical excipients.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein the said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin etabonate and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises vildagliptin and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein the said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a fixed dose pharmaceutical composition comprising a combination of remogliflozin etabonate and vildagliptin for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-

granular portion, wherein the intra-granular portion comprises 50mg or 100mg or 250mg of remogliflozin etabonate and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises 25mg or 50mg or 100mg of vildagliptin and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein the said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is coated with an aqueous seal coat.
In yet another embodiment, there is disclosed a pharmaceutical composition comprising a fixed dose combination of remogliflozin etabonate and vildagliptin for treatment of diabetes, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises 50mg or 100mg or 250mg of remogliflozin etabonate and one or more pharmaceutically acceptable excipients such as crosscarmellose sodium, microcrystalline cellulose, and povidone, and the extra-granular portion comprises 25mg or 50mg or 100mg of vildagliptin and one or more pharmaceutically acceptable excipients such as crosscarmellose sodium, microcrystalline cellulose and magnesium stearate; wherein said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is coated with an aqueous seal coat.
In yet another embodiment, disclosed is a stable pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein said portions are compressed together to obtain a tablet dosage form. In yet another embodiment, the pharmaceutical composition of the invention is in the form of monolayer tablet or bilayer tablet. The prefered form is a bilayer tablet. In yet another embodiment, the pharmaceutical composition of the invention is further coated with an aqueous or non-aqueous film coat. The prefered film coat is non-aqueous coat. In yet another embodiment, the invention composition is manufactured using a wet granulation or direct compaction method. The composition portion having remogliflozin or salt or ester thereof is manufactured using a wet granulation method. The composition portion having vildagliptin is manufactured using direct compaction (roller compaction) method. In yet another embodiment, the pharmaceutical composition of the invention is packed in

Alu-Alu blister or dessicant Alu-Alu blister pack. In yet another embodiment, the pharmaceutical composition of the invention when stored under RT or accerlarated stability studies at 400C/75% RH; has not more than 2% of total impurity, or not more than 1% of impurity A and B or not more than 0.5% of single maximum impurity.
In yet another embodiment, there is disclosed a stable pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a tablet dosage form which is coated with an aquous seal coat.
In yet another embodiment, there is disclosed a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, said second portion comprises granules of vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a tablet dosage form which is coated with aquous seal coat; wherein the tablet is having monolithic matrix or monolayer of active ingredient and pharmaceutical excipients.
In yet another embodiment, there is disclosed a process of preparing a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a tablet dosage form which is coated with aquous seal coat, wherein said process

comprises steps of: (a) preparing granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients using wet granulation, (b) preparing granules of vildagliptin or salt thereof are prepared by roller compaction, (c) compressing the granules of step (a) and (b) together to obtain a tablet and (d) coating the tablets by using an aqueous film coating layer to obatin final composition.
In yet another embodiment, there is disclosed a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a bilayer tablet dosage form which is coated with aquous seal coat.
In yet another embodimeny, disclosed is a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, said second portion comprises granules of vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a bilayer tablet dosage form which is coated with aquous seal coat.
In yet another embodiment, disclosed is a process of preparing a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a bilayer tablet dosage form which is coated with aquous seal coat, wherein said

process comprises steps of: (a) preparing granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients using wet granulation, (b) preparing granules of vildagliptin or salt thereof are prepared by roller compaction, (c) compressing the granules of step (a) and (b) together to obtain a bilayer tablet and (d) coating the tablets by using an aqueous film coating layer to obatin final composition.
In yet another embodiment, disclosed is a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a tablet dosage form which is coated with non-aquous seal coat.
In yet another embodiment, disclosed is a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, said second portion comprises granules of vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a tablet dosage form which is coated with non-aquous seal coat; wherein the tablet is having monolithic matrix or monolayer of active ingredient and pharmaceutical excipients.
In yet another embodiment, disclosed is a process of preparing a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together

to obtain a tablet dosage form which is coated with non-aquous seal coat, wherein said process comprises steps of: (a) preparing granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients using wet granulation, (b) preparing granules of vildagliptin or salt thereof are prepared by roller compaction, (c) compressing the granules of step (a) and (b) together to obtain a tablet and (d) coating the tablets by using an non-aqueous film coating layer to obatin final composition.
In still another and prefered embodiment, disclosed is a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a bilayer tablet dosage form which is coated with non-aquous seal coat.
In still another embodiment, disclosed is a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, said second portion comprises granules of vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together to obtain a bilayer tablet dosage form which is coated with non-aquous seal coat.
In still another embodiment, disclosed is a process of preparing a pharmaceutical composition comprising a first portion and a second portion, wherein said first portion comprises granules of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, said second portion comprises granules of vildagliptin or salt thereof and a pharmaceutically acceptable excipient; wherein granules of remogliflozin or salt or ester thereof are preapred by wet granulation and granules of vildagliptin or salt thereof are prepared by roller compaction; wherein said portions are compressed together

to obtain a bilayer tablet dosage form which is coated with non-aquous seal coat, wherein said process comprises steps of: (a) preparing granules of remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients using wet granulation, (b) preparing granules of vildagliptin or salt thereof are prepared by roller compaction, (c) compressing the granules of step (a) and (b) together to obtain a bilayer tablet and (d) coating the tablets by using an non-aqueous film coating layer to obatin final composition. In another embodiment, the composition is packed in Alu-Alu blister or dessicant Alu-Alu blister pack. In yet another embodiment, the composition is stable when stored under RT or accerlarated stability studies at 400C/75% RH and has not more than 2% of total impurity, not more than 1% of impurity A and B and not more than 0.5% of single maximum impurity.
The impurities A and B are known and are described as below:
Chemical Name Structure
Impurity A : L-Prolinamide, N-(3- rT rhydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl- JOWY
H^
Impurity B : (2S,2'S)-1,1'-[[(3-hydroxytricyclo[3.3.1.1(3,7)]dec-1- "^P
yl)imino]bis( 1 -oxo-2,1 -ethanediyl)]di(2- ^.-CV
pyrrolidinecarbonitrile) —^^ c "7—%

Chemical Name I Structure
Impurity A : L-Prolinamide, N-(3- /v 7^
hydroxytricyclo[3.3.1.13,7]dec-1- /~7 ^ H )
yl)glycyl- HD'^/'rtH jf Y
Impurity B : (2S,2'S)-1,1'-[[(3-
hydroxytricyclo[3.3.1.1(3,7)]dec-1- ^P^
yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2- ^-.--Co ^^°
pyrrolidinecarbonitrile) >^„ ^^ ^
The single maximum impurity is unknown.
In another embodiment of invention, there is provided a use of a pharmaceutical composition according to any of the embodiment, for prevention, treatment or prophylaxis of diabetes.

In another embodiment of invention, there is provided a use of kit comprising a pharmaceutical composition according to any of the embodiment, for treatment or prophylaxis of diabetes.
In still another aspect, the pharmaceutical composition of the present invention on administration reduces Hb1Ac level and body weight of patient without causing hypoglycemia. Further the composition of the present invention complies with the in-vitro parameters and in-vivo parameters shown by the individual drugs.

Sr.No
Ingredients % w/w
I Intra-granular
1 Remogliflozin Etabonate 31.86 (100mg or 250mg)
2 Vildagliptin 6.27 (50mg)
3 Crosscarmellose sodium 1.50
4 Microcrystalline cellulose 6.46
II Binder
5 Povidone K30 2.08
6 Purified Water
III Extra-granular
7 Crosscarmellose sodium 2.10
8 Microcrystalline cellulose 48.83
9 Magnesium Stearate 0.90
Total 100.0
IV Aquoes coating
10 Opadry Yellow (03B520003) 3.0
11 Purified water q.s.
Total

7.2. The diminuted granules from step 6 were loaded and sifted excipients blend from
step 7.1 in blender.
7.3 The blend is mixed in blender.
8. Lubrication:
8.1 The magnesium stearate was sifted through 60#sieve.
8.2 The sifted magnesium stearate was added in mixer and mixed.
II) Compression:
The granules were compressed in to the tablets using below parameteres.
Punch details: 19 × 8 mm Average weight: 800.0 mg
III) Coating:
1. Preparation of coating dispersion: Opadry was dispersed in purified water and mixed by stirring, filter through 100 mesh.
2. Th tablets were coated by spraying coating dispersion.
EXAMPLE 2: A tablet composition of remoliflozin etabonate in intra-granular portion and vildagliptin in extra-granular portion.
Sr.No Ingredient % w/w
I Intra-granular
1 Remogliflozin Etabonate 31.95 (100mg or 250mg)
2 Crosscarmellose sodium 1.50
3 Microcrystalline cellulose 6.46 (50mg)
Binder
4 Povidone k30 2.08
5 Purified Water q.s
II Extra-granular
6 Vildagliptin 6.27
7 Crosscarmellose sodium 2.10
8 Microcrystalline cellulose 48.74
9 Magnesium Stearate 0.90
Total 100.0
III Film coating
10 Opadry Yellow (03B520003) 3.0
11 Purified water q.s.
Total -
Sr.No Ingredient % w/w
I Intra-granular
1 Remogliflozin Etabonate 31.95 (100mg or
250mg)
2 Crosscarmellose sodium 1.50
3 Microcrystalline cellulose 6.46 (50mg)
Binder
4 Povidone k30 2.08
5 Purified Water q.s
II Extra-granular
6 Vildagliptin 6.27
7 Crosscarmellose sodium 2.10
8 Microcrystalline cellulose 48.74
9 Magnesium Stearate 0.90 Total 100.0
III Film coating
10 Opadry Yellow (03B520003) 3.0
11 Purified water q.s. Total -
Manufacturing process:

1. Microcrystalline cellulose and crosscarmellose sodium were sifted through mesh 30#.
2. Remogliflozin etabonate was mixed with step 1 and sift through 20#.
3. In rapid mixer granulator (RMG) step 2 mix was transfered and perform drymix.
4. Binder was prepared by addition povidone in water and granulated using binder solution.
5. After granulation, the mixture of step 4 was wet sifted through 12#.
6. After wet sifting the granules were dried in fluidized bed dryer.
7. After drying the granules were passed through 30#.
8. Vildagliptin was weighed and extra-granular part sifted through 30#.
9. Mixed step 9 with step 8 and blend for 8 min.
10. The step 9 mix was lubricated with magnesium stearate for 3 min.
11. Final blend of step 10 was compressed in to tablet composition followed by coating.
12. The core tablets were coated using a coating till required weight gain is achieved.
EXAMPLE 3: Synergistic effect of a combination of remogliflozin etabonate and vildagliptin on blood glucose.
Methodology: Oral glucose tolerance test (OGTT) was performed in healthy male Sprague Dawley rats (6 to 8 weeks old). Rats were divided into different treatment groups based on overnight-fasting whole-blood-glucose (WBG). Rats in control groups were orally dosed with glucose, whereas the treatment groups received a dose of glucose as well as respective treatment. After glucose challenge, WBG was measured at 15, 30, 60 and 120 minutes by tail-snip method using glucose meter [Journal of Endocrinology (2014) 222, G13–G25. European Journal of Pharmacology 729 (2014) 59–66].
Results:
Figure 1: Remogliflozin etabonate 1mg/kg decreased blood glucose AUC by 7%.
Vildagliptin 1mg/kg decreased blood glucose AUC by 6%. The combination of
remogliflozin etabonate and vildagliptin synergistically decreased blood glucose AUC by
22%.

Thereofore, remogliflozin etabonate in combination with vildagliptin showed marked synergistic effect in decreasing blood glucose AUC compared to their individual effects.
EXAMPLE 4: A Protocol for a randomised, double-blind, double-dummy, parallel-group, multi-centre, active-controlled study to evaluate efficacy and safety of fixed dose combination of remogliflozin etabonate and vildagliptin in subjects with type-II diabetes mellitus.
Protocol Full A randomised, double-blind, double-dummy, parallel-group,
Title: multi-centre, active-controlled study to evaluate efficacy and
safety of fixed dose combination of remogliflozin etabonate and
vildagliptin in subjects with type II diabetes mellitus.
Protocol Number: GPL/CT/2019/006/III
Study Acronym FOREVER (Fdc Of REmogliflozin and Vildagliptin Efficacy and
toleRability study)
Phase of Phase 3
Development:
Indication: Type II Diabetes Mellitus
Name of FDC of Remogliflozin etabonate 100 mg/ Vildagliptin 50 mg
Investigational Tablets
Product/Code or

Study Drug
Study Rationale: Metformin is the first line pharmacotherapy for patients with type
II diabetes mellitus (T2DM). Still many patients are not able to
achieve glycaemic control with metformin monotherapy.
Guidelines by American Diabetes Association recommend use of
additional glucose-lowering therapies without preference to any
particular class of glucose-lowering agents (ADA Pharmacologic
approaches, Diabetes Care 2019). Patients who do not achieve
glycaemic control with metformin and other glucose lowering
drug are required to take additional third glucose lowering
therapy. Sodium-glucose co-transporter-2 inhibitors (SGLT2i)
and dipeptidyl peptidase-4 inhibitors (DPP-4i) have different and
mutually independent mechanisms of action and compliment the
action of metformin. As a result, many patients require a
combination of SGLT2i and DDP4i in addition to metformin for
the treatment of T2DM.
Remogliflozin and vildagliptin are twice daily SGLT2i and DPP4i
respectively, approved in India for the treatment of diabetes as
monotherapy and add-on therapy with metformin. A fixed dose
combination of Remogliflozin and Vildagliptin will reduce the
pill burden and help improve treatment compliance.
Protocol Full A randomised, double-blind, double-dummy, parallel-group,
Title: multi-centre, active-controlled study to evaluate efficacy and
safety of fixed dose combination of remogliflozin etabonate and vildagliptin in subjects with type II diabetes mellitus.
Protocol Number: GPL/CT/2019/006/III
Study Acronym FOREVER (Fdc Of REmogliflozin and Vildagliptin Efficacy and
toleRability study)
Phase of Phase 3
Development:
Indication: Type II Diabetes Mellitus
Name of
FDC of Remogliflozin etabonate 100 mg/ Vildagliptin 50 mg
Investigational
Tablets Product/Code or
Study Drug
Study Rationale:
Metformin is the first line pharmacotherapy for patients with type
II diabetes mellitus (T2DM). Still many patients are not able to
achieve glycaemic control with metformin monotherapy.
Guidelines by American Diabetes Association recommend use of
additional glucose-lowering therapies without preference to any
particular class of glucose-lowering agents (ADA Pharmacologic
approaches, Diabetes Care 2019). Patients who do not achieve
glycaemic control with metformin and other glucose lowering
drug are required to take additional third glucose lowering
therapy. Sodium-glucose co-transporter-2 inhibitors (SGLT2i)
and dipeptidyl peptidase-4 inhibitors (DPP-4i) have different and
mutually independent mechanisms of action and compliment the
action of metformin. As a result, many patients require a
combination of SGLT2i and DDP4i in addition to metformin for
the treatment of T2DM.
Remogliflozin and vildagliptin are twice daily SGLT2i and DPP4i respectively, approved in India for the treatment of diabetes as monotherapy and add-on therapy with metformin. A fixed dose combination of Remogliflozin and Vildagliptin will reduce the pill burden and help improve treatment compliance.

Remogliflozin acts by preventing renal re-absorption of glucose
and promoting excretion of glucose in the urine. This leads to a
reduction in plasma glucose levels in an insulin-independent
manner. Vildagliptin reduces blood glucose by preventing
degradation of incretin peptides such as glucagon-like peptide 1
(GLP-1), stimulating insulin release and inhibiting glucagon
secretion. A combination of SGLT2i and DPP4i has been
demonstrated to have superior glucose lowering efficacy
compared to SGLT2i or DPP4i given alone.
This study is intended to compare the dual addition of
remogliflozin plus vildagliptin versus empagliflozin plus
linagliptin as a 2nd-line add-on therapy in subjects with T2DM
who are inadequately controlled on metformin therapy. A fixed-
dose combination of empagliflozin and linagliptin is approved in
India for treatment of type II diabetes and will be used as
comparator drug in the study.
Rationale for Dose Selection for Phase 3 Study
The doses used in the combination are same as the approved doses
of monocomponent products. Remogliflozin is approved as 100
mg twice daily and Vildagliptin is approved as 50 mg BID. In 24-
week phase III study efficacy and safety of Remogliflozin 100 mg
BID was demonstrated with predictable and consistent
improvement in glycemic control (HbA1c, fasting plasma glucose
and post prandial plasma glucose). Similarly, efficacy and safety
of Vildagliptin 50 mg BID has been demonstrated in phase III
clinical trial.
The proposed phase 3 clinical study will evaluate the efficacy and
safety of FDC of remogliflozin etabonate 100 mg and vildagliptin
50 mg administered twice daily in background therapy of
metformin in comparison to empagliflozin 25 mg and linagliptin 5
mg QD in the subjects who have inadequately controlled T2DM
with stable dose of metformin. FDC of empagliflozin and
linagliptin is selected as an active comparator as it is approved
therapy and has shown significant glycemic efficacy and safety in
clinical trials. HbA1c is an accepted surrogate for assessment of
short-term clinical consequences of hyperglycemia, as well as the
long-term microvascular complications of diabetes mellitus and
will be evaluated as the primary efficacy endpoint in this study.

Study Objectives:
Primary Objective
To evaluate the efficacy of concurrent administration of FDC of remogliflozin etabonate and vildagliptin with metformin in comparison with concurrent administration of FDC of empagliflozin and linagliptin with metformin in change from baseline in glycosylated haemoglobin (HbA1c) after 16 weeks of double-blind treatment in subjects with type II diabetes mellitus.
Secondary Objectives
• To evaluate the efficacy of concurrent administration of FDC of remogliflozin etabonate and vildagliptin with metformin in comparison with concurrent administration of FDC of empagliflozin and linagliptin with metformin in:
• change from baseline in fasting plasma glucose and
• change from baseline in post-prandial plasma glucose
• change from baseline in Body weight
• proportion of patients achieving therapeutic glycaemic response defined as HbA1c <7%
• proportion of subj ects requiring rescue medication
• To evaluate the safety and tolerability of concurrent administration of FDC of remogliflozin and vildagliptin with metformin in comparison with concurrent administration of FDC of empagliflozin and linagliptin with metformin over 16 weeks of double-blind treatment
Study Population: Subjects with T2DM receiving stable doses of metformin as monotherapy for at least 10 weeks prior to screening at a dose of ≥1500 mg per day and have inadequate glycemic control (i.e. HbA1c ≥ 8% and ≤ 11% at screening).
Study Design: This is a randomized, double-blind, double-dummy, active-controlled, two-arm, parallel-group, multi-center study to evaluate the efficacy and safety of concurrent administration of FDC of remogliflozin etabonate and vildagliptin with metformin in comparison with concurrent administration of FDC of empagliflozin and linagliptin with metformin in subjects with T2DM who have inadequate glycemic control with stable dose of metformin as monotherapy.
Subjects with HbA1c ≥8% and ≤11% at Screening will be considered eligible for randomization, on fulfilling other study inclusion criteria. For each subject, the study will begin when the ICF is signed. At run-in visit (-2 weeks), subjects will be switched to nearest multiple of metformin 500 mg IR tablets.
Eligible subjects will be randomized to receive one of the following treatments in a double blind, double dummy design. Matching placebo(s) will be used to blind the two treatment arms

and every subject will receive a total of 2 tablets twice daily
including one of the following active study drugs along with
matching placebo(s):
Arm 1: Remogliflozin etabonate 100 mg and vildagliptin 50 mg
administered as 1 tablet BID. Subjects randomized to Arm 1 will
receive double-blind matching placebo Empagliflozin/Linagliptin
once daily
Arm 2: Empagliflozin 25 mg and linagliptin 5 mg FDC,
administered as 1 tablet QD in morning. Subjects randomized to
Arm 2 will receive double-blind matching placebo of
Remogliflozin/Vildagliptin twice daily
All subjects will receive 2 tablets in the morning and 1 in the
evening.
In addition, subjects will continue to receive metformin at stable
doses of >1500 mg per day, throughout the study period in an
open label manner. Metformin will be administered in the
multiples of 500 mg IR tablet.
Balanced randomization will be planned in the Arm 1 and Arm 2.
Randomization will be stratified for
• HbA1c level (HbA1c 8-8.9%, 9-9.9% and 10-11%) at
screening
Each subject will undergo screening assessments at Screening
Visit. The screening period will span over a maximum of 3 weeks
duration and will include 2 weeks run-in period. Screening will be
completed within 1 week after consent and eligible subjects will
attend the run-in visit. At screening, run-in and all treatment
visits, standard consultation for dietary and exercise modification
will be provided to all subjects in accordance with the applicable
national/international guidelines (eg. American Diabetes
Association. Standards of medical care in diabetes—2016, ICMR
guidelines for management of type II diabetes – 2005). At run-in
visit, background metformin will be switched to nearest multiple
of metformin 500 mg IR tablets. Subjects will be provided with
diary at the time of run-in visit along with glucometer to record
details about study drug administration and for self-measurement
of blood glucose.
Double-blind study treatment will be administered daily in
randomized subjects for 16 weeks. Subjects will be required to
visit the site at weeks 6, 12 and 16 after randomization. An
additional visit for a safety follow up will be required 2 weeks
after successful completion of the double-blind study treatment.
Subjects will be provided with diary at the time of randomization
along with glucometer to record details about study drug
administration, adverse events and self-monitored blood glucose
levels. Subject will be required to bring completed diary at each
visit.

Study Endpoints: Efficacy
Primary Endpoint
• Mean change from baseline in HbA1c levels at end of
treatment
Secondary Endpoints
• Mean change from baseline in HbA1c levels at week 12
• Mean change from baseline in fasting plasma glucose
(FPG) levels at end of treatment
• Mean change from baseline in post-prandial plasma
glucose (PPG) at end of treatment
• Mean change from baseline in body weight at end of
treatment
• Proportion of subj ects achieving a therapeutic glycaemic
response, defined as HbA1c <7%, end of treatment
• Proportion of subj ects requiring rescue medication for
hyperglycaemia during study treatment
Safety
• Treatment Emergent Adverse Events (TEAEs), AEs
of special interest: hypoglycaemia, urinary tract infections
and genital fungal infections; lipid profile and other
laboratory tests; vital signs
Planned Number A total of 400 subjects with T2DM will be enrolled (randomized)
of Subjects: in the study.
Planned Duration The anticipated maximum total study duration for each subject is
of Study approximately 21 weeks. This will consist of the screening period
Participation: of up to 3 weeks (including 2-week open label run-in period), the
treatment period of up to 16 weeks, and the follow-up period of 2
weeks after the last dose of study drug.
Planned Duration 16 Weeks
of Treatment:

Inclusion Criteria: Inclusion Criteria
Each subject must meet all of the following criteria to be
randomized in the study:
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 ≥8% to ≤11%.
4. Willing and able to comply with all aspects of the protocol.
5. Must be willing to use a highly effective form of contraception (with pearl index < 1%) e.g. double barrier method, for the duration of the study. Methods like periodic abstinence, post ovulation procedures and withdrawal are not considered adequate. Oral contraceptive pills are not allowed due to potential of drug interaction with investigational product. If the subject is a female of childbearing potential, the result of a urine pregnancy test at screening must be negative. Each female will be considered to have childbearing potential unless surgically sterilized by hysterectomy or has been post-menopausal for at least 2 years.
Exclusion Criteria: Exclusion Criteria
A subject who meets any of the following criteria must not be
randomized in the study:
1. History of Type 1 diabetes mellitus or secondary diabetes mellitus or diabetes insipidus
2. History of metabolic acidosis or diabetic ketoacidosis
3. FPG >270 mg/dL at screening.
If FPG is >270 mg/dL at screening, FPG will be repeated within 1 week. If repeat FPG is >270 mg/dL, subject will be excluded from the study.
4. BMI ≥45.0 kg/m2 at screening
5. Subjects with elevated thyroid stimulating hormone (TSH) level at screening with or without thyroid hormone replacement therapy
6. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation or serum creatinine level of > 1.5 mg/dL for male subjects and > 1.4 mg/dL for female subjects, at screening
7. Severe hepatic insufficiency and/or significant abnormal liver

function defined as aspartate aminotransferase (AST) and/or
alanine aminotransferase (ALT) > 3X 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 revascularization (coronary angioplasty or bypass
grafts), or cerebrovascular accident.
10. Subjects with uncontrolled hypertension with sitting systolic
BP ≥160 mmHg and/or diastolic BP ≥ 100 mmHg at
screening. Note: Subjects with SBP ≥ 160mmHg and <
180mmHg or a DBP ≥ 100 mmHg and < 110mmHg will be
able to enter the run-in period, provided their hypertension
treatment is adjusted as deemed appropriate by the
investigator. These subjects can not be randomized if they
meet the blood pressure exclusion criterion of SBP ≥ 160
mmHg or DBP ≥ 100 mmHg measured at randomization visit.
11. Any abnormality on 12-lead ECG at screening that in the
opinion of the investigator is clinically significant and is
judged as potential risk for subject’s participation in the study.
For male subjects with mean QTcB ≥450 msec or female
subjects with mean QTcB ≥470 msec, triplicate ECG will be
performed. If mean QTcB is ≥450 msec in males or mean
QTcB is ≥470 msec in females on triplicate ECG, subject will
be excluded from the study.
12. History of anaemia or haemoglobinopathy and/or serum
haemoglobin <10 g/dL (<100 g/L) for men; haemoglobin <9
g/dL (<90 g/L) for women at screening
13. Donation or transfusion of blood, plasma, or platelets within
the past 3 months prior to enrolment
14. History of malignancy within the last 5 years prior to
enrolment, excluding non-melanoma skin cancer (e.g. basal or
squamous cell skin carcinoma) or treated carcinoma-in-situ of
cervix
15. Intolerance, contraindication or potential
allergy/hypersensitivity to any of the ingredients of study
medication or any other SGLT2 inhibitors or DPP4 inhibitors
16. Subjects with symptomatic diarrhoea or any other medical
condition which the investigators may judge to be a risk for
dehydration and hypovolemia
17. Subjects with symptomatic urinary tract infection or mycotic
genital infection at screening or history of a recent

symptomatic infection within 4 weeks prior to screening

18. Subject with a positive result for hepatitis B surface antigen or hepatitis C antibody at screening.
19. Subject is known to be seropositive for human immunodeficiency virus (HIV).
20. Subject not willing to comply with dietary and exercise plan provided at screening.
21. Subject with any condition 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.
22. Employee of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
23. Concurrent enrollment in another interventional clinical study.
24. Previous participation in another interventional clinical study within 3 months prior to screening or within 5 half-lives of the previous study drug.
25. Pregnant or breastfeeding women
26. 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.

Study-Specific
Criteria for Discontinuation of Subjects from Treatment
Discontinuation/
Withdrawal
Criteria: Subjects must discontinue investigational product (and noninvestigational product at the discretion of the investigator) for any of the following reasons:
• Withdrawal of informed consent (subject’s decision to withdraw for any reason)
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the opinion of the investigator, indicates that continued participation in the study is not in the best interest of the subject
• Pregnancy
• Termination of the study by Glenmark
• eGFR <60 mL/min/1.73m2 for sustained period of time (12 weeks)
SGLT2 inhibitors including Remoglifozin based on their mechanism of action have been shown to reduce eGFR by up to 10% with initiation of therapy; however this has in general been reversible and eGFR values returned to baseline within 12 - 24 weeks of continued therapy.
Lifestyle and/or
Dietary
Restrictions: • Subjects must be in a fasting state at least 10 hours prior to study visit (however, drinking water is allowed). Permitted medications may be taken with water only.

• Subjects must abstain from tobacco for 12 hours prior to all study visits.
• Subjects must make every attempt to adhere to the dietary and physical activity changes and goals as discussed with the Investigator(s).
• Women of child-bearing potential must immediately contact the Investigator if pregnancy is suspected or known and if there is change or plan to change birth control method.
• The subjects should not take investigational product on the morning of the clinic visit (IP will be administered at the investigator site)
Study Drug, Dose, and Mode of Administration Investigational Product:
Name of Investigational Product: FDC of remogliflozin etabonate and vildagliptin (or Matching Placebo)
Dosage Form: Tablet
Dose: remogliflozin etabonate 100 mg and vildagliptin 50 mg
Dosage Frequency: Twice daily
Mode of Administration: Twice daily with food preferably at similar time of the day
Comparator

Name of Comparator: FDC of empagliflozin and linagliptin
(GlyxambiTM (or Matching Placebo)
Dosage Form: Tablet
Dose: empagliflozin 25 mg and linagliptin 5 mg
Dosage Frequency: Once daily
Mode of Administration: Once daily in the morning with food
preferably at similar time of the day
Prior and Permitted Medications
Concomitant Other chronic medications such as lipid lowering agents or oral
anti-hypertensives (except loop or potassium sparing diuretics or
beta-blockers) may be allowed provided the choice of drug(s) and
dose(s) remain stable for at least 1 month prior to and throughout
the study period, unless a dose adjustment is medically necessary
to manage the subject during the trial.
• Topical, inhaled and intranasal corticosteroids are
allowed. Oral corticosteroids may be allowed provided
the daily dose is less than 20 mg of prednisone or
equivalent and has remained stable for at least 3 months
prior to screening and throughout the treatment period.
Rescue Medication
• Subj ects meeting pre-specified glycaemic criteria (see
Table below), based upon central laboratory HbA1c or
FPG and repeat, confirmatory HbA1c or FPG, during the
double-blind treatment period, starting at Week 6, and up
to Week 16 visits, will be eligibile for open label rescue
medication. Subjects with a central laboratory HbA1c or
FPG value meeting the lack of glycemic control criterion
at a pre-specified visit will be scheduled for a follow-up
visit (within 3 - 5 days) to obtain a second central
laboratory HbA1c or FPG value and review the subject’s
glucose meter readings. If the repeat central laboratory
HbA1c or FPG value still meets the criterion, the subject
must be rescued.

Lack of Glycaemic Control Criteria for Initiation of Rescue
Medication

Visit Central Laboratory FPG

Week 6 (including follow-up for week 6) FPG >270 mg/dL

After Week 6 (excluding follow-up for week 6) to Week 12 FPG >240 mg/dL

Week 12 to Week 16 HbA1c >9 percent or FPG >200 mg/dL

Subjects who meet rescue criteria must first complete the visit
procedures before receiving open-label rescue medication.
Rescue medication given will be open label anti-diabetic agent
except GLP-1 analogs, other DPP4 inhibitors or SGLT2 inhibitors
or their combinations. The dose of ongoing open label metformin
will not be changed and study drug will be continued. Choice of
rescue medication (other than those mentioned above) and dose
will be as per investigator’s discretion and will be administered as
locally approved prescribing information.
Note: Rescue medication will not be provided by the sponsor in
this study.

Excluded concomitant medications: Time prior to
The following medications are prohibited throughout the entire study and for the indicated time prior to screening: Screening:
• Any anti-diabetic medications (including oral anti-diabetic agents, insulin and alternative medicine/herbal medications) except for metformin in subjects already receiving stable doses. 12 Weeks
• Weight loss medication, including but not limited to mazindol, sibutramine, phentermine, orlistat, rimonabant, benzphetamine, diethylpropion, methamphetamine, and/or phendimetrazine 1 month
• Oral hormonal contraceptive pills 1 month
• Immunosuppressant medications that are known to increase the risk of infections 1 month
• Medications that are expected to 1 month or 5-half
interfere with blood glucose levels including but not limited to loop or potassium sparing diuretics, monoamine oxidase inhibitors, tricyclic amines, beta-blockers etc. lives
• Potent inducers of CYP3A4, 1 month or 5-half
including rifabutin, rifampin, pioglitazone, efavirenz, carbamazepine, dexamethasone, barbiturates, phenytoin and oxcarbazepine lives

Efficacy Assessments: Primary efficacy assessment will be HbA1c as per the schedule of assessments (Table 2). Other efficacy assessments include fasting plasma glucose, post-prandial plasma glucose and total body weight (Table 2).
Pharmacokinetic/
Pharmacodynami
c/Biomarker/Phar
macog-enomic
Assessments: Not applicable
Safety Assessments: The safety evaluations will include analyses of treatment emergent AEs (including AEs of special interest such as hypoglycemic events, urinary tract infection and genital fungal infection), vital signs (pulse and BP), physical examination, laboratory parameters, ECG, and eGFR
Data Safety Monitoring Board: Not applicable
STATISTICAL METHODS:
Study Analysis Sets
Populations: Analysis of the primary endpoint will be conducted using the modified ITT (mITT) analysis set. In addition, a supportive analysis will be performed for the primary efficacy endpoint using the Per Protocol Set (PPS).
mITT analysis set
The mITT analysis set will include all randomised subjects who received at least one dose of study medication, who have a non-missing baseline measurement and at least one post-baseline efficacy measurement for primary efficacy variable.
Per protocol analysis set
The per protocol analysis set (PPS) will include all subjects who are randomized, received at least one dose of study medication, completed the study and do not have any major protocol deviations. Major protocol deviations will be defined in the statistical analysis plan (SAP).
Safety analysis set
The Safety analysis set (SAS) will include all subjects who are randomized and received at least one dose of study medication. All safety endpoints will use the safety analysis set unless otherwise specified.
Determination of The total sample size for the study would be 400 subjects. The

Sample Size:
details of the sample size assumptions are provided below.
A total of 160 evaluable subjects in each treatment group is
estimated to provide a power of 90% at one sided significance
level of 2.5% (2 sided 5%), with assumed standard deviation of
1.1% of HbA1c, to demonstrate non-inferiority of FDC of
remogliflozin and vildagliptin in comparison with FDC of
empagliflozin and linagliptin, in HbA1c change from baseline at
week 16, with a non-inferiority (NI) margin of 0.40. Assuming
that 20% of randomized subjects will not be included in the per-
protocol set, 400 subjects (roughly 200 subjects per group) will be
randomized in the study. NI margin of 0.40 was selected based on
the effect size of the active comparator (i.e. FDC of empagliflozin
25 mg and linagliptin 5 mg) in placebo controlled studies and is
compliant with the international guidelines for development of
anti-diabetic agents.
Efficacy Analysis of Primary Efficacy Endpoint
Analyses: The comparison of FDC of remogliflozin and vildagliptin versus
FDC of empagliflozin and linagliptin in change in HbA1c from
baseline to week 16 will be analysed using a Mixed Model
Repeated Measure (MMRM) method. The null hypotheses is that
FDC of remogliflozin etabonate 100 mg and vildagliptin 50 mg is
inferior to FDC of empagliflozin 25 mg and linagliptin 5 mg in
change from baseline in HbA1c, and the alternative hypotheses is
that FDC of remogliflozin etabonate 100 mg and vildagliptin 50
mg is non-inferior to FDC of empagliflozin 25 mg and linagliptin
5 mg based on the non-inferiority margin of 0.40. The MMRM
model will include data from all visits until week 16 and the
following covariates: treatment, visit, HbA1c baseline, centre, and
treatment by visit interaction; unstructured covariance matrix will
be used, thus allowing adjustment for correlations between the
time points within subjects.The differences between the FDC of
remogliflozin and vildagliptin, and FDC of empagliflozin and
linagliptin will be compared based on the above MMRM model,
and p-values from non-inferiority and superiority testing will be
provided.
The statistical methods, including methods for handling missing
data, will be fully described in the SAP
Analysis of key Secondary Efficacy Endpoints
Mean change from baseline to specified timepoints for the fasting
plasma glucose, fasting lipids and body weight endpoints will be
summarized and analysed using MMRM model.
Proportion of subjects achieving therapeutic glycemic response
(HbA1c < 7%) and proportion of subjects discontinuing for
Hyperglycaemia will be summarized by treatment arm and
compared using chi-square test.

Pharmacokinetic/ Not applicable
Pharmacodynami
c/ Biomarker/
Pharmacogenomi
c Analyses:
Safety Analyses: The analysis of safety and tolerability will be based on the safety
analysis set. Safety data during the 16-week double-blind
treatment period and the 2-week safety follow-up period will be
evaluated and summarized descriptively. Adverse events will be
summarized by system organ class and preferred term. Subjects
will be counted only once for each preferred term, system organ
class, and by the highest severity of an event. Laboratory
evaluations will be summarized with descriptive statistics at each
visit, and change from baseline summarized for each post-
randomization visit. Laboratory measurements will also be
summarized based on the number and percentage of subjects
above or below a pre-specified threshold. ECG, vital signs (pulse
and BP), hypoglycemic events, eGFR and physical examination
will be summarized. Details will be presented in the SAP
Interim Analyses: Not applicable
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. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

CLAIMS We Claim:
1. A fixed dose pharmaceutical composition comprising combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof in a weight ratio of 1:0.1 to 1:10 for the treatment of diabetes.
2. A fixed dose pharmaceutical composition of claim 1, wherein remogliflozin is present as remogliflozin etabonate.

3. A fixed dose pharmaceutical composition of claim 1, wherein vildagliptin is present as vildagliptin base.
4. A fixed dose pharmaceutical composition of claim 1, wherein the weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.2 to 1:5.
5. A fixed dose pharmaceutical composition of claim 1, wherein the weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof is 1:0.5.
6. A fixed dose pharmaceutical composition of claim 1, wherein the weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof is 1:0.2.

7. A fixed dose pharmaceutical composition claim 1, wherein said composition further comprises a pharmaceutically acceptable excipients.
8. A fixed dose pharmaceutical composition of claim1, wherein remogliflozin or salt or ester thereof is present in an amount of 0.5 mg to 500 mg.
9. A fixed dose pharmaceutical composition of claim 1, wherein remogliflozin or salt or ester thereof is present in an amount of 50mg or 100mg or 250mg.
10. A fixed dose pharmaceutical composition of claim 1, wherein vildagliptin or salt thereof is present in an amount of 5mg to 500mg.

11. A fixed dose pharmaceutical composition of claim 1, wherein vildagliptin or salt thereof is present in an amount of 25mg or 50mg or 100mg.
12. A fixed dose pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable excipients are one or more of 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 and chelating agents.
13. A fixed dose pharmaceutical composition of claim 1, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof, vildagliptin or salt thereof and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient; wherein the said intra-granular and extra-granular portions are compressed together to obtain a tablet dosage form which is optinally coated with an aqueous seal coat.
14. A fixed dose pharmaceutical composition of claim 1, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof and a pharamceutically acceptable excipient, and the extra-granular portion comprises vildagliptin or salt thereof and a pharamceutically acceptable excipient; wherein the portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.
15. A fixed dose pharmaceutical composition of claim 1, wherein the composition comprises an intra-granular portion and an extra-granular portion,

wherein the intra-granular portion comprises remogliflozin or salt or ester thereof, vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, the extra-granular portion comprises one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein the portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat. 16. A fixed dose pharmaceutical composition of claim 1, wherein the composition comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises remogliflozin or salt or ester thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, and a binder, and the extra-granular portion comprises vildagliptin or salt thereof and one or more pharmaceutically acceptable excipients such as a disintegrant, a diluent, lubricant, and a binder; wherein said portions are compressed together to obtain a tablet dosage form which is optionally coated with an aqueous seal coat.