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:
PHARMACEUTICAL COMPOSITION COMPRISING OF REMOGLIFLOZIN OR
SALT OR ESTER THEREOF AND VILDAGLIPTIN OR SALT THEREOF

TECHNICAL FIELD OF THE INVENTION
The invention relates to a stable 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 stable 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 stable pharmaceutical composition having a fixed dose combination of remogliflozin or salt thereof and vildagliptin or salt thereof for treatment of diabetes and associated complications.
SUMMARY OF INVENTION
In one embodiment, the invention composition comprises a fixed dose combination of remogliflozin etabonate and vildagliptin for treatment of diabetes, wherein the composition produces synergistic effect in reducing the blood glucose levels when compared to composition having only one active agent.
In one 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.
In another embodiment, the stable pharmaceutical composition is forumlated as a tablet dosage form. In still 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 another embodiment, the pharmaceutical composition comprises remogliflozin which is present as remogliflozin etabonate and the vildagliptin or salt thereof is present as vildagliptin base.
In still another embodiment, the pharmaceutical composition comprises remogliflozin etabonate in an amount of 0.5 mg to 500 mg. Alternatively, remogliflozin etabonate is present in an amount of 50mg or 100mg or 250mg.
In still another embodiment, the pharmaceutical composition comprises vildagliptin which is present in an amount of 5mg to 500mg. Alternatively, the concentration of vildagliptin or salt thereof is 25mg or 50mg or 100mg.
In still another embodiment, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof ranges from 1:0.1 to 1:15. In still another embodiment, 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, a weight ratio of remogliflozin or salt or ester thereof and vildagliptin or salt thereof is 1: 0.5 or 1: 0.2.
The pharmaceutical composition comprises the pharmaceutically acceptable excipients which 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.
In yet another embodiment, the stable 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 remogliflozin etabonate and vildagliptin 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, 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, disclosed is 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 bilayer tablet dosage form which is coated with non-aquous 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 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 yet another embodiment, disclosed is a process of preparing 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, 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 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.
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. One way ANOVA followed by Dunnet’s Multiple comparison test.
DETAIL DESCRIPTION OF INVENTION
There is provided a pharmaceutical composition comprising a fixed dose combination of remogliflozin or salt thereof and DPP-IV inhibitor or salt thereof.
In particular, there is provided a stable tpharmaceutical composition comprising a fixed dose 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.
The term “Portion” used throughout the specification refers to a compartment or layer of active pharmaceutical agent (Remogliflozin or vildagliptin) and a pharmaceutically acceptable excipient or a compartment or layer of a pharmaceutically acceptable excipient. The first and second portions are distinct and separated from each other physically.
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 composition is administered once a daily or twice a daily.
In still another embodiment, the remogliflozin etabonate and vildagliptin 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, crosscarmellose sodium, 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 aspect 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 aspect, 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. In some embodiments, remogliflozin etabonate is present in first layer or portion and vildagliptin is present in second layer or portion.
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 some embodiments, the composition portion having remogliflozin is prepared by wet granulation. In some embodiments, the composition portion having vildagliptin is prepared by direct compaction or roller compaction.

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.
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- <—-XV
pyrrolidinecarbonitrile) "~ ^%. d> ^

The impurities A and B are known and are described as below:
Chemical Name I Structure
Impurity A : L-Prolinamide, N-(3- /v T^
hydroxytricyclo[3.3.1.13,7]dec-1- /~7 U~)
yl)glycyl- HO^^/^ jf Y
Impurity B : (2S,2'S)-1,1'-[[(3-
hydroxytricyclo[3.3.1.1(3,7)]dec-1- ^T^
yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2- <^-.--Ce, ^T"
pyrrolidinecarbonitrile) >^„ C^^i
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, 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¬vito parameters and in-vivo parameters shown by the individual drugs.

EXAMPLE 1:

Sr.No Ingredients % w/w
I Intragranular
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 Extragranular
7 Crosscarmellose sodium 2.10
8 Microcrystalline cellulose 48.83
9 Magnesium Stearate 0.90
Total 100.0
IV Aqueous coating
10 Opadry Yellow (03B520003) 3.0
11 Purified water q.s.
Total
Manufacturing process: I) Granulation:
1. Sifting: Remogliflozin Etabonate 20# sieve, Vildagliptin, Crosscarmellose sodium and microcrystalline cellulose were sifted through 40#sieve.
2. Dry mixing: The above mixture was dry mixed in Rapid Mixer Granulator.
3. Binder Preparation: Povidone K30 was dissolved in purified water untill clear solution was obtained.
4. Wet Mixing: The dry mix blend of step 2 is granulated using binder solution of step 3
5. Drying: The granules were dried in dryer till required LOD is achieved.
6. Diminution: The dried granules were sifted through sieve 30# sieve.
7. Blending:

7.1. Crosscarmellose sodium and Microcrystalline cellulose were sifted through 30# sieve.
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.
IV) Analytical results:
ASSAY: (LIMIT: 90.0% to 110.0% of labelled amount)

Weight of Average Weight (mg) Assay/Results Water content
10 Tablets (gm)
Remogliflozin Etabonate Vildagliptin

8.20641 820.64 Spl-1: 99.9 Spl-2: 98.6 Avg.: 99.3 Spl-1: 98.4 Spl-2: 97.1 Avg.: 97.8 5.62
RELATED SUBSTANCES:- Initial results

Remogliflozin Etabonate Vildagliptin
Impurity-A Unknown single max impurity Total Impurities Impurity-A Impurity-B Unknown single max impurity Total Impurities
Limit NMT 1.0% NMT 0.5% NMT 3.0% NMT 1.0% NMT 1.0% NMT 0.5% NMT 2.0%
Spl-1 0.15 0.29 0.65 0.22 ND 0.78 1.22
Spl-2 0.14 0.28 0.64 0.22 ND 0.77 1.16
Avg. 0.15 0.29 0.65 0.22 ND 0.78 1.19

EXAMPLE 2:

Sr.No Ingredient % w/w
I Intragranular
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 Extragranular
6 Vildagliptin 6.27
7 Crosscarmellose sodium 2.10
8 Microcrystalline cellulose 48.74
9 Magnesium Stearate 0.90
Total 100.0
III Aqueous Film coating
10 Opadry Yellow (03B520003) 3.0
11 Purified water q.s.
Total -
Manufacturing process: As described in Example 1. Analytical results:

Storage condition 250C ± 20C &
60% RH ± 5 %
RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Test Specification Initial 1M 6M 1M 6M 1M 2M 6M
Avg. weight 820 mg ± 3 % 799.30 822.08 812.34 819.00 822.64 828.48 823.88 823.52
RS for
Vildagliptin
i) Impurity-A NMT 1.0% 0.02 0.05 0.22 0.05 0.20 0.30 0.70 2.02
ii) Impurity-B NMT 1.0% ND ND ND ND ND ND ND ND
iii) Single Max NMT 0.5% 0.13 0.16 0.25 0.15 0.25 0.41 0.35 1.84
iv) Total impurities NMT 2.0% 0.38 0.40 1.01 0.41 0.92 0.89 1.10 4.61
Assay Vildagliptin 90.0 % to 110.0 % LA 97.2 99.7 NP 102.7 NP 100.5 NP NP

Sr.No Ingredient % w/w mg/tab
I Wet granulation
1 Remogliflozin Etabonate 31.86 254.860
2 Crosscarmellose sodium 1.50 12.000
3 Microcrystalline cellulose 6.46 51.670
Binder
4 Povidone K30 2.08 16.663
5 Purified Water q.s
Extragranular
7 Crosscarmellose sodium 2.10 16.800
8 Microcrystalline cellulose 55.23 441.807
II Roller compaction
9 Vildagliptin 25.08 50.160
10 Lactose Anhydrous ( Supertab 21 AN) 23.91 47.820
11 Microcrystalline cellulose 40.51 81.020
12 Sodium Starch glycollate 10.00 20.000
13 Total
Extragranular
14 Magnesium Stearate 3.60 7.200
Total 100.0 1000
III Aqueous Film coating
15 Opadry Yellow (03B520003) 3.0 30.0
16 Purified water q.s. q.s.
Manufacturing Procedure:
I) Remogliflozin etabonate Granulation:
1. Sifting : Remogliflozin Etabonate was sifter through 20# sieve, Crosscarmellose
sodium and Microcrystalline cellulose sifted through 40# sieve .
2. Dry mixing : Above blend was dry mixed in Rapid Mixer Granulator.
3. Binder Preparation: Povidone K30 was dissolved in purified water till clear solution was obtained.
4. Wet Mixing : The drymix blend of step 2 was granulated using binder solution of step 3
5. Drying : The granules were dried in dryer till required LOD is achieved.
6. Diminution: The dried granuleswere sifted through 30# sieve.
7. Blending:

7.1. Crosscarmellose sodium and Microcrystalline cellulose were sifted through 40# sieve and
7.2 The diminuted granules from step 6 were loaded and sifted excipients blend from step
7.3 The blend was mixed in blender. 8. Lubrication:

8.1 Magnesium stearate was sifted through 60# sieve.
8.2 Sifted magnesium stearate was added in blender and mixed.
II) Vildagliptin Roll compaction:
1. Sifting : Vildagliptin, Lactose Anhydrous ( Supertab 21 AN ), Sodium Starch
glycollate and Microcrystalline cellulose were sifted through 30# sieve .
2. Blending: The blend was mixed for 15 minutes in blender.
3. Roll compaction & Sizing: The blend was roll compacted and passed the granules
through comill and sifted through #30 sieve. Repeated the roll compaction cycle till %
ratio of granules through #30 and fines on 60# mesh is 70:30.
4. Lubrication:
4.1 Magnesium stearate was sifted through 60# sieve.
4.2 Sifted magnesium stearate was added in blender and Mix.
II) Compression:
Compressed the granules in tablets.
III) Coating:
1. Preparation of coating dispersion: Opadry was dispersed in purified water and mix by stirring, filter through 100 mesh.
2. Coated the tablets by spraying coating dispersion.
IV) Analytical results:

Storage condition 250C ± 20C & 60% RH ± 5 % RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Specification Initial 1M 2M 1M 2M 1M 2M
1020 mg ± 3 % 1028.70 1015.56 NP 1019.48 NP 1014.70 1018.32
Vildagliptin RS
NMT 1.0% 0.01 0.05 NP 0.04 NP 0.18 0.39
NMT 1.0% ND ND NP ND NP ND ND
NMT 0.5% 0.15 0.27 NP 0.27 NP 0.55 0.60
NMT 2.0% 0.28 0.62 NP 0.53 NP 1.02 1.06
Assay/Vildagliptin
90.0 % to 110.0 %
LA 98.1 101.4 NP 101.0 NP 100.9 NP

EXAMPLE 4:

Sr.No Ingredients % w/w mg/tab
I Wet granulation
1 Remogliflozin Etabonate 31.86 254.860
2 Crosscarmellose sodium 1.50 12.000
3 Avicel Ph 101 6.46 51.670
Binder
4 Povidone k29/32 2.08 16.663
5 Purified Water q.s
Extragranular
6 Crosscarmellose sodium 2.10 16.800
7 Avicel Ph 102 55.10 440.807
8 Magnesium Stearate 0.90 7.200
Total 100.00 800.000
II Roller compaction
9 Vildagliptin 25.08 50.160
10 Lactose Anhydrous 21 AN 23.91 47.820
11 Microcrystalline cellulose 102 40.50 81.000
12 Sodium Starch glycollate 10.00 20.000
13 Ferric oxide red 0.01 0.020
14 Magnesium Stearate 0.50 1.000
Total 100 200
III Film coating
15 Opadry (03B520003) 3.0 30.0
16 Purified water q.s. q.s.
Total - 1030.0
Manufacturing Process: As described in Example 3. IV) Analytical results:

Storage condition 250C ± 20C & 60% RH 300C ± 20C & 75% RH 400C ± 20C & 75%
Test Specificat ion Initial 1M 2M 3M 1M 2M 3M 1M 2M 3M
Avg. weight 1020 mg ± 3 % 1017.54 1017.26 NP 1014.63 1015.41 NP 1019.53 1015.58 NP 1020.62
RS for Vildagliptin i) Impurity-A NMT 1.0% 0.00 0.05 NP 0.10 0.05 NP 0.09 0.20 0.37 0.53
ii) Impurity-B NMT 1.0% ND ND NP ND ND NP ND ND ND ND
iii) Single Max NMT 0.5% 0.12 0.21 NP 0.26 0.21 NP 0.24 0.34 0.26 0.34
iv) Total impurities NMT 2.0% 0.26 0.51 NP 0.54 0.49 NP 0.52 0.81 0.71 1.43
Assay Vildagliptin 90.0 % to
110.0 %
LA 97.4 96.4 NP 98.8 96.1 NP 99.2 95.8 NP 98.6

EXAMPLE 5:

Sr.No Ingredient % w/w mg/tab
1 Remogliflozin Etabonate 31.95 102.240
2 Crosscarmellose sodium 1.50 4.800
3 Avicel PH 101 6.46 20.672
Binder
4 Povidone k29/32 2.08 6.656
5 Purified Water q.s q.s
Extragranular
7 Crosscarmellose sodium 2.10 6.720
8 Avicel PH 102 55.01 176.032
Vilda by roller compaction
9 Vildagliptin 25.08 50.160
10 Lactose Anhydrous 21 AN 23.91 47.820
11 Microcrystalline cellulose 102 40.51 81.020
12 Sodium Starch glycollate 10.00 20.000
13 Magnesium Stearate 0.5 1
Extragranular
14 Magnesium Stearate 0.90 2.880
Total 520
15 Opadry yellow 2.0 10.4
16 Purified water qs qs
Total 530.4
Manufacturing Process: As described in Example 3. IV) Analytical results:

Storage condition 250C ± 20C & 60% RH ± 5 % RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Test Specification Initial 1M 6M 1M 6M 1M 6M
Avg. weight 530 mg ± 3 % 531.36 528.32 527.45 528.12 528.14 524.88 526.82
RS for Vildagliptin i) Impurity-A NMT 1.0% 0.01 0.03 0.17 0.03 0.15 0.18 1.16
ii) Impurity-B NMT 1.0% ND ND ND ND ND ND ND
iii) Single Max NMT 0.5% 0.08 0.17 0.40 0.17 0.60 0.45 0.76
iv) Total impurities NMT 2.0% 0.19 0.31 0.69 0.33 1.22 0.77 2.48
Assay Vildagliptin 90.0 % to 110.0 % LA 97.2 97.3 NP 97.3 NP 93.1 NP

EXAMPLE 6:

Sr.No Ingredient % w/w mg/tab
1 Remogliflozin Etabonate 31.95 102.240
2 Crosscarmellose sodium 1.50 4.800
3 Avicel PH 101 5.76 18.424
Binder
4 Povidone k29/32 2.08 6.665
5 Purified Water q.s q.s
Vilda by roller compaction
6 Vildagliptin 25.09 50.180
7 Lactose Anhydrous 21 AN 24.0 48.000
8 Microcrystalline cellulose 102 40.1 80.22
9 Sodium Starch glycollate 10.0 20.000
10 Ferric oxide yellow 0.10 0.200
11 Magnesium Stearate 0.70 1.4
Extragranular
12 Crosscarmellose sodium 2.10 6.720
14 Avicel PH 102 55.71 178.280
15 Magnesium Stearate 0.90 2.880
16 (YS-1-18202-A) 3.0 15.6
17 Methylene chloride qs 207.48
18 Iso propyl alcohol qs 88.92
Manufacturing Process: As described in Example 3. IV) Analytical results:

Storage condition 250C ± 20C & 60% RH ± 5 % RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Test Specification Initial 1M 2M 3M 1M 2M 3M 1M 2M 3M 6M
Avg. weight 530 mg ± 3 % 537.94 533.60 535.60 537.41 535.75 534.32 537.14 536.49 534.49 534.64 536.47
RS for Vildagliptin i) Impurity-A NMT 1.0% 0.01 0.02 0.04 0.06 0.02 0.04 0.05 0.11 0.35 0.44 NP
ii) Impurity-B NMT 1.0% ND ND ND ND ND ND ND ND ND ND NP
iii) Single Max NMT 0.5% 0.03 0.10 0.12 0.24 0.10 0.12 0.23 0.37 0.37 0.49 NP
iv) Total impurities NMT 2.0% 0.10 0.17 0.24 0.33 0.18 0.22 0.31 0.66 1.01 1.35 NP
Assay Vildagliptin 90.0 % to 110.0 % LA 99.8 98.5 97.1 NP 98.6 97.8 NP 99.5 98.1 NP 99.8

EXAMPLE 7, 8 and 9:

Sr.No Ingredients Qty/Tab (in mg) Qty/Tab (in mg)

For 100+50 mg tablets For 50+50 mg tablets
Remogliflozin Etabonate Granulation:
1 Remogliflozin etabonate 100 50
2 Croscarmellose sodium 4.8 2.4
3 Microcrystalline Cellulose 20.668 10.334
4 Povidone K 30 6.665 3.333
5 Purified water Qs ----
Lubrication:
6 Crosscarmellose Sodium 6.72 3.36
7 Microcrystalline Cellulose (Avicel PH102) 178.267 89.133
8 Magnesium Stearate 2.88 1.44
Total Core weight 320.0 160.0
Vildagliptin Granulation:
9 Vildagliptin 50 50
10 Lactose anhydrous 21AN 48 48
11 Microcrystalline Cellulose 80.38 80.38
12 Sodium starch glycollate 20 20
13 Ferric oxide yellow 0.22 0.22
14 Magnesium Stearate 1.4 1.4
Total Core weight 200.0 200.0
Film coating:
15 Opadry White YS-1-18202A 20.0 14.0
16 Methylene Dichloride Qs Qs
17 Iso propyl alcohol Qs Qs
Manufacturing process: As described in Example 3.
In Example 8 and 9, the tablets are packed in Alu-Alu blister and dessicant in Alu-Alu blister respectively.

IV) Analytical results for Example 7:

Storage condition 250C ± 20C & 60% RH ± 5 % RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Test Specificati on Initi al 1M 2M 3M 4M 6M 1M 2M 3M 4M 6M 1M 2M 3M 4M 5M 6M
Avg. weight 530 mg ± 3
% 543. 13 538. 52 533. 97 536. 15 533. 31 539. 16 539. 29 537. 45 535. 68 537. 90 539. 90 537. 20 539. 68 536. 99 535. 09 538. 98 535.0 8
RS for
Vildaglipti
n
i)
Impurity-A NMT 1.0% 0.01 0.02 0.06 0.08 0.08 0.18 0.04 0.05 0.07 0.08 0.16 0.16 0.28 0.45 0.56 NP 0.79
ii) Impurity-B NMT 1.0% ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND NP ND
iii) Single Max NMT 0.5% 0.03 0.10 0.21 0.21 0.17 0.21 0.12 0.09 0.18 0.19 0.23 0.24 0.17 0.27 0.30 NP 0.44
iv) Total impurities NMT 2.0% 0.08 0.19 0.27 0.35 0.28 0.48 0.23 0.21 0.30 0.30 0.49 0.54 0.72 1.00 1.11 NP 1.44
Assay
Vildaglipti
n 90.0 % to
110.0 %
LA 100. 5 98.2 97.4 95.7 NP 97.9 98.3 99.2 96.7 NP 97.9 96.1 96.0 95.5 NP 100. 4 97.2
Analytical results for Example 8:

Pack ( Alu-Alu blister)
Storage condition 250C ± 20C & 60% RH ± 5 % RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Test Specification Initia l 1M 2M 3M 1M 2M 3M 1M 2M 3M
Appearanc e Should Comply Complies
Avg. weight 370 mg ± 5 % 370.7 2 373. 20 375. 75 371. 87 376. 50 372. 90 375.3 4 373. 79 373. 47 375.4 8
RS for Vildaglipti n
i) Impurity-A NMT 1.0% 0.02 0.01 0.05 0.07 0.02 0.06 0.09 0.16 0.31 0.50
ii) Impurity-B NMT 1.0% ND ND ND ND ND ND ND ND ND ND
iii) Single Max NMT 0.5% 0.02 0.04 0.14 0.18 0.05 0.16 0.18 0.12 0.26 0.23
iv) Total impurities NMT 2.0% 0.04 0.05 0.19 0.27 0.11 0.22 0.30 0.31 0.69 0.90
Assay Vildaglipti n 90.0 % to 110.0 % LA 97.2 98.6 99.0 99.0 101. 5 98.4 100.3 104. 3 99.1 101.1

Analytical results for Example 9:

Pack (Desiccant Alu-Alu blister)
Storage condition 250C ± 20C & 60% RH ± 5 % RH 300C ± 20C & 75 % RH ± 5 % RH 400C ± 20C & 75 % RH ± 5 % RH
Test Specifica tion Initia l 1M 2M 3M 1M 2M 3M 1M 2M 3M
Appearance Should Comply Complies
Avg. weight 370 mg ± 5 % 370. 72 366. 61 372. 55 367.4 7 370. 82 369. 47 370.3 7 371. 32 371. 24 364.7 7
Dissolution
a)
Remogliflozin NLT
75% of
the L.A
dissolved
in 45
min. 100. 2 NP NP NP 99.4 NP NP 98.9 NP NP
b) Vildagliptin NLT
75% of
the L.A
dissolved
in 45
min. 98.6 NP NP NP 99.7 NP NP 99.5 NP NP
RS Remogliflozin i) Impurity A NMT 1.0% 0.05 0.05 0.06 0.06 0.05 0.06 0.05 0.07 0.06 0.06
ii) Single Max. NMT 0.5% 0.26 0.36 0.13 0.13 0.38 0.13 0.12 0.38 0.12 0.13
iii)Total Imp NMT 2.0% 0.48 0.62 0.29 0.32 0.58 0.33 0.31 0.60 0.32 0.34
RS forVildagliptin i) Impurity-A NMT 1.0% 0.02 0.04 0.04 0.05 0.03 0.05 0.05 0.04 0.16 0.19
ii) Impurity-B NMT 1.0% ND ND ND ND ND ND ND ND ND ND
iii) Single Max NMT 0.5% 0.02 0.04 0.11 0.13 0.05 0.13 0.12 0.09 0.19 0.17
iv) Total impurities NMT 2.0% 0.04 0.11 0.15 0.17 0.11 0.18 0.18 0.20 0.41 0.42
Assay
a)
Remogliflozin 90.0 % to
110.0 %
LA 97.6 96.9 99.1 99.2 100. 1 98.0 100.2 100. 5 99.1 98.9
b) Vildagliptin 90.0 % to
110.0 %
LA 97.2 99.6 100. 6 102.4 100. 1 98.7 101.3 101. 5 98.3 100.2
Water Content For
Informati
on 4.00 NP 5.14 NP NP 5.16 NP NP 5.80 NP

EXAMPLE 10: Comparsion of Impurity data of all examples of the specification.

Examples Analysis Period Vildagliptin Impurity results (400C ± 20C & 75 % RH ± 5 % RH) Remarks

Impurity
A
(1.0%) Single
Max
(0.5%) Total (2.0%)
Example -1 Initial 0.22 0.78 1.19 Higher impurity levels observed.
Example -2 1 Month 0.30 0.41 0.89 Substantial increase in impurity levels from one month to six

6 Month 2.02 1.84 4.61 month is observed.
Example -3 1 Month 0.18 0.55 1.02 By minimizing the contact of Vildagliptin with water, reduced level of impurity A is observed.
Example -4 3 Month 0.53 0.34 1.43 By preparing bilayer tablets contact between two actives part is reduced and impurity levels are considerably reduced.
Example -5 6 Month 1.16 0.76 2.48 Formulation with dry granulation of vildagliptin is not sufficient to control the impurity levels impurities are observed on higher side.
Example -6 3 Month 0.44 0.49 1.35 Impurity levels are controlled by avoiding water in coating.
Example -7 6 Month 0.79 0.44 1.44 Stabilized formulation contact. between two active parts is minimized , use of water is avoided in vildagliptin part and coating part
Example -8 3 Month 0.50 0.23 0.90 Stabilized formulation in alu alu pack.
Example -9 3 Month 0.19 0.17 0.42 Stabilized formulation in desiccants alu pack , water permeation is reduced. Impurity levels are better controlled.
It is noted from the above table that generation of single max impurity was more for example 1 to 6 and but was lower for example 7 to 9.

EXAMPLE 11: 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.
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 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.
2. The stable pharmaceutical composition of claim 1, wherein the composition is a tablet.
3. The stable pharmaceutical composition of claim 1, wherein the remogliflozin is present as remogliflozin etabonate.
4. The stable pharmaceutical composition of claim 1, wherein the vildagliptin or salt thereof is present as vildagliptin base.
5. The stable pharmaceutical composition of claim 3, wherein the remogliflozin etabonate is present in an amount of 0.5 mg to 500 mg.
6. The stable pharmaceutical composition of claim 5, wherein the remogliflozin etabonate is present in an amount of 50 mg or 100mg or 250mg.
7. The stable pharmaceutical composition of claim 4, wherein the vildagliptin is present in an amount of 5 mg to 500 mg.
8. The stable pharmaceutical composition of claim 4, wherein the amount of Vildagliptin or salt thereof is 25mg or 50mg or 100mg.
9. The stable pharmaceutical composition of claim 1, wherein a weight ratio of remogliflozin or salt thereof and vildagliptin or salt thereof ranges from about 1: 0.1 to about 1:15.
10. The stable pharmaceutical composition of claim 9, wherein the weight ratio of remogliflozin or salt thereof and vildagliptin or salt thereof ranges from about 1: 0.5.
11. The stable pharmaceutical composition of claim 9, wherein a weight ratio of remogliflozin or salt thereof and vildagliptin or salt thereof ranges from about 1: 0.2.
12. The stable pharmaceutical composition of claim 1, 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, chelating agents.
13. The stable pharmaceutical composition of claim 2, wherein the composition is in the form of monolayer tablet or bilayer tablet.
14. The stable pharmaceutical composition of claim 1, wherein the composition is further coated with an aqueous or non-aqueous film coat.
15. The stable pharmaceutical composition of claim 13, wherein the composition is coated a non-aqueous film coat.
16. The stable pharmaceutical composition of claim 1, 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.
17. The stable pharmaceutical composition of claim 1, 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.
18. The process of preparing composition of claim 16, 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.

19. The pharmaceutical composition of claim 16 , wherein the composition is packed in Alu-Alu blister or dessicant Alu-Alu blister pack.
20. The pharmaceutical composition of claim 16, wherein the composition 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.