DESC:FIELD OF THE INVENTION:
The present invention relates to layered tablet compositions comprising a dipeptidyl peptidase-4 (DPP-4) inhibitor such as teneligliptin, and a sodium glucose cotransporter (SGLT) inhibitor such as dapagliflozin. The invention further relates to a process for the preparation of the said compositions.

BACKGROUND OF THE INVENTION:
Type II diabetes is the most common form of diabetes accounting for 90% of diabetes cases. Oral therapeutic options for the treatment of type II diabetes mellitus include monotherapy using compounds belonging to classes such as biguanides, insulin, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, DPP-4 inhibitors, PPAR agonist, meglitinides, and SGLT inhibitors. Once monotherapy becomes inadequate, combination therapy is a rational course of action for treating hyperglycemia. Fixed dose combinations (FDC) are intended to improve patient compliance by providing two drugs with different modes of action in a single dosage form.

Dipeptidyl peptidase-4 (DPP-4) inhibitors is a class of anti-diabetic drugs that act by inhibiting the degradation of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Generically these compounds are termed as "gliptins”. DPP-4 inhibitors are commonly used in a combination therapy along with other antidiabetic drugs. Examples of DPP-4 inhibitor drugs include sitagliptin, teneligliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, dutogliptin, anagliptin, gemigliptin, trelagliptin, omarigliptin, evogliptin, and gosogliptin.

Teneligliptin is a DPP-4 inhibitor drug indicated for the treatment of type 2 diabetes mellitus, and is available in the form of 20 mg tablets in Japan by the trade name Tenelia®. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day.

SGLT Inhibitors act as a therapeutic agent for diabetes by suppressing an increase in blood glucose level by inhibiting sodium-dependent glucose cotransporter (SGLT1/SGLT2) and inhibiting/delaying the absorption of glucose and other sugars in the small intestine. Examples of SGLT inhibitor drugs include empagliflozin, canagliflozin, ertugliflozin, dapagliflozin, luseogliflozin, bexagliflozin, tofogliflozin, ipragliflozin, licogliflozin, mizagliflozin, and sotagliflozin.

Dapagliflozin, is a SGLT inhibitor indicated in the treatment of diabetes mellitus, as an adjunct to diet and exercise to improve glycemic control, and to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus. In the United States of America, it is available as immediate release tablets in dose strengths of 5 mg and 10 mg under the brand name FARXIGA®. The immediate release tablets are administered once daily. The active ingredient in FARXIGA® is a crystalline form of dapagliflozin propylene glycol hydrate.

Type 2 diabetes mellitus being a disease with multiple underlying pathophysiologic defects, monotherapy may be difficult to maintain glycemic control and may lead to treatment failure. In such cases, multi-drug therapy containing a combination of glucose-lowering agents having complementary mechanisms of action, which are well tolerated, would be beneficial. The combination should also provide conveniences for patients, such as oral dosing, single-pill formulations, and once-daily administration, potentially translating to improved patient compliance. Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter (SGLT) inhibitors are two such classes of drugs that can be used in multi-drug therapy.

In multi-drug therapy, different dosage forms each containing a single drug are administered together. This results in reduced patient compliance and errors in administering proper doses of each drug. It is therefore desirable to provide a single dosage form, combining two (or more) drugs, to ensure patient compliance.

Indian Patent Application 1696/KOLNP/2012 relates to teneligliptin containing solid preparation that caused less delay in a dissolution behaviour of teneligliptin, even after long-term preservation. Teneligliptin compositions, formulated as single layer tablets, showed adequate dissolution even on storage.

Indian Patent Application 693/MUMNP/2015 relates to teneligliptin and a process for preparation thereof. The application discloses pharmaceutical compositions comprising teneligliptin and at least one excipient, and compositions comprising a combination of teneligliptin and metformin. The compositions can be single layered or bilayered tablets.

PCT Publication No. WO2015/104658 discloses amorphous form of dapagliflozin, and amorphous solid dispersion of dapagliflozin with one or more pharmaceutically acceptable carriers, process for their preparation, and pharmaceutical composition thereof. The said carriers are selected from polyvinylpyrrolidones, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose acetate succinate.

U.S. Publication No. 2016/0256433 discloses an amorphous solid dispersion comprising dapagliflozin and at least one polymer, a pharmaceutical composition comprising said amorphous solid dispersion and the process for its preparation. These compositions of dapagliflozin under stress and accelerated storage conditions were found to be stable for a period of 3 months.

PCT Publication No. WO2015/128853 discloses pharmaceutical compositions comprising solid dispersion of dapagliflozin and one or more pharmaceutically acceptable excipients and the process for their preparation.

Indian Patent Application 201921037338 relates to fixed dose combination compositions of remogliflozin and teneligliptin, for the treatment of diabetes and associated complications. The compositions are in the form of a monolayer tablet or a bilayer tablet.

PCT Publication No. WO 20211/33023 relates to a combination preparation, containing sitagliptin and dapagliflozin, in the form of single layered tablets. The PCT publication teaches that use of lubricants like glyceryl monostearate, magnesium stearate, calcium stearate, and sucrose stearate increase related substances (impurities) of sitagliptin and dapagliflozin over time (Test Example 1 and Example 3 in WO 20211/33023). Hence the said compositions use sodium stearyl fumarate in a concentration of 3% to 8% by weight of the composition. The PCT publication further teaches that use of sodium stearyl fumarate at a concentration less than 3% by weight results in poor productivity, delayed discharge of granules during tabletting, impaired tablet compression, and poor content uniformity (Comparative Example 5 and Example 7 in WO 20211/33023). It further demonstrates that use of sodium stearyl fumarate at concentrations greater than 8% results in an increase in related substances (impurities), and a decreased dissolution rate of sitagliptin and dapaglilfozin (Comparative Examples 6 and 8 in WO 20211/33023).

In the present study, when single layered tablet dosage forms comprising a DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin, were developed with magnesium stearate as the lubricant, the said compositions did not demonstrate the desired stability and dissolution (Refer to Comparative Examples 1, 2A and 2B in the present study).

Comparative Example 1 in the present study demonstrates that a DPP-4 inhibitor drug such as teneligliptin and a SGLT inhibitor drug such as dapagliflozin, when formulated as single layered tablets, with magnesium stearate as the lubricant, the said tablets show impurity levels significantly higher than the acceptable limits (Refer to Comparative Example 1, Table 1, and Table 8 in the present study).

Further, Comparative Examples 2A and 2B in the present study demonstrate that even addition of antioxidant(s) to Comparative Example 1 does not result in impurity levels within the acceptable limits (Refer to Comparative Examples 2A and 2B, Table 2, and Table 8 in the present study).

This clearly demonstrates that the use of magnesium stearate in compositions containing a DPP-4 inhibitor drug, and a SGLT inhibitor drug, does not result in impurity levels within the acceptable limits, even when antioxidants are incorporated in the compositions.

It has surprisingly been found that a combination of DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin, when formulated as layered tablet compositions, exhibit the desired stability, processability, disintegration, and dissolution of teneligliptin and dapagliflozin, despite the use of magnesium stearate as the lubricant. Further, this is achieved with a lubricant concentration of not more than 2% by weight of the composition. This result is in distinct contrast to the teachings of prior art.

OBJECTS OF THE INVENTION
The object of present invention is to provide layered tablet compositions comprising a DPP-4 inhibitor drug such as teneligliptin and a SGLT inhibitor drug such as dapagliflozin, for oral administration.

Another object of the present invention is to provide layered tablet compositions comprising a DPP-4 inhibitor drug such as teneligliptin and a SGLT inhibitor drug such as dapagliflozin, wherein the compositions provide a dissolution of 75% to 110% of DPP-4 inhibitor drug at 30 minutes, and 75% to 110% of SGLT inhibitor drug at 30 minutes.

Yet another object of the present invention is to provide storage stable, layered tablet compositions comprising a DPP-4 inhibitor drug such as teneligliptin and a SGLT inhibitor drug such as dapagliflozin, wherein on storage the content of total impurities related to DPP-4 inhibitor drug is not more than 2% by weight, and the content of total impurities related to SGLT inhibitor drug is not more than 1% by weight.

Yet another object of the present invention is to provide a process for the preparation of layered compositions comprising a DPP-4 inhibitor drug such as teneligliptin and a SGLT inhibitor drug such as dapagliflozin.

SUMMARY OF THE INVENTION
The present invention relates to layered tablet compositions comprising a dipeptidyl peptidase-4 (DPP-4) inhibitor such as teneligliptin, and a sodium glucose cotransporter (SGLT) inhibitor such as dapagliflozin. The invention further relates to a process for the preparation of the said compositions.

DETAILED DESCRIPTION OF THE INVENTION
It has surprisingly been found that a combination of DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin, when formulated as layered tablet compositions, exhibit the desired stability, processability, disintegration, and dissolution of teneligliptin and dapagliflozin, despite the use of magnesium stearate as the lubricant. This result is in distinct contrast to the teachings of prior art.

In addition, in distinct contrast to the teachings of prior art, it has surprisingly been found that the said compositions exhibit the desired stability, processability, disintegration, and dissolution of teneligliptin and dapagliflozin, despite the use of lubricant in concentrations of less than 2% by weight of the composition.

The layered tablet compositions of the present invention, comprising a DPP-4 inhibitor drug, a SGLT inhibitor drug, and at least one lubricant, wherein the concentration of the lubricant is not more than 2% by weight of the composition, exhibit the desired processability, disintegration, dissolution and stability, of DPP-4 inhibitor drug and SGLT inhibitor drug.

In an embodiment, layered tablet compositions of the present invention comprise a DPP-4 inhibitor drug, a SGLT inhibitor drug, at least one lubricant, and at least one antioxidant, and exhibit the desired processability, disintegration, dissolution and stability of the drugs.

In another embodiment, the layered tablet compositions of the present invention comprise a DPP-4 inhibitor drug, a SGLT inhibitor drug, at least one lubricant at a concentration of not more than 2% by weight of the composition, and at least one antioxidant, and exhibit good processability, disintegration, dissolution, and stability of the drugs.

In an aspect of the embodiments, the lubricant is magnesium stearate.

The term “DPP-4 inhibitor drug” as used herein includes dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin, teneligliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, dutogliptin, anagliptin, gemigliptin, trelagliptin, melogliptin, denagliptin, omarigliptin, evogliptin, carmegliptin, and gosogliptin, and their pharmaceutically acceptable salts, hydrates, esters, derivatives, co-crystals, solvates, and polymorphs. One such example of DPP-4 inhibitor drug is teneligliptin hydrobromide hydrate.

The term “SGLT inhibitor drug” as used herein include sodium-dependent glucose cotransporter (sodium-glucose linked transporter/SGLT) inhibitors such as empagliflozin, canagliflozin, ertugliflozin, dapagliflozin, atigliflozin, sergliflozin, luseogliflozin, tofogliflozin, ipragliflozin, licogliflozin, mizagliflozin, and sotagliflozin, and their pharmaceutically acceptable salts, hydrates, esters, derivatives, co-crystals, solvates, and polymorphs. One such example of SGLT inhibitor drug is dapagliflozin which maybe in the form of dapagliflozin or dapagliflozin propane-diol solvate. The preferred SGLT inhibitor drug is amorphous dapagliflozin.

Layered tablet compositions, comprising a DPP-4 inhibitor drug such as teneligliptin and a SGLT inhibitor drug such as dapagliflozin, can be in the form of bi-layered, tri-layered, or multi-layered tablets. The compositions may further be coated with a film-coating.

Layered tablet compositions of the present invention, comprising a DPP-4 inhibitor drug such as teneligliptin and a SGLT inhibitor drug such as dapagliflozin, provide immediate release, extended-release, sustained-release, controlled-release, prolonged release, delayed-release, enteric-release, timed-release, pulsed-release, or a combination thereof, of the DPP-4 inhibitor drug and/or the SGLT inhibitor drug. In preferred compositions, the layered tablet compositions provide immediate release, extended-release, and/or delayed-release, and in more preferred compositions, the layered tablet compositions provide immediate release, of the DPP-4 inhibitor drug and/or the SGLT inhibitor drug.

DPP-4 inhibitor drug such as teneligliptin, used in the layered tablet compositions, has a particle size distribution wherein 90% by volume [d (0.9)] of DPP-4 inhibitor drug particles have a particle size ranging from 0.1 to 150 microns, or from 0.1 to 100 microns, or from 0.1 to 75 microns, or from 0.1 to 50 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

SGLT inhibitor drug such as dapagliflozin, used in the layered tablet compositions, has a particle size distribution wherein 90% by volume [d (0.9)] of SGLT inhibitor drug particles have a particle size ranging in the range of 0.5 microns to 250 microns, or from 0.5 microns to 200 microns, or from 0.5 microns to 150 microns, or from 1 micron to 100 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method. In an aspect the d (0.9) particle size of the SGLT inhibitor drug ranges from 0.5 microns to 50 microns.

SGLT inhibitor drug such as dapagliflozin, used in the layered tablet compositions, has a particle size distribution wherein 50% by volume [d (0.5)] of SGLT inhibitor drug particles have a particle size ranging from 0.5 microns to 100 microns, or from 0.5 micron to 90 microns, or from 5 microns to 80 microns, or from 10 microns to 70 microns, as determined by the laser diffraction method using the water dispersion method.

SGLT inhibitor drug such as dapagliflozin, used in the layered tablet compositions, has a particle size distribution wherein 10% by volume [d (0.1)] of SGLT inhibitor drug particles have a particle size ranging from 0.1 microns to 25 microns, or from 0.1 micron to 20 microns, or from 0.5 microns to 15 microns, or from 1 micron to 10 microns, as determined by the laser diffraction method using the water dispersion method.

Layered tablet compositions comprise DPP-4 inhibitor drug such as teneligliptin, in concentrations ranging from about 0.1% to about 25%, or from about 0.5% to about 25%, or from about 1% to about 20%, or from about 2.5% to about 20%, by weight of the composition.

Layered tablet compositions comprise SGLT inhibitor drug, such as dapagliflozin, in concentrations ranging from about 0.1% to about 25% by weight of the composition, or from about 0.5% to about 15%, or from about 1% to about 7.5%, or from about 2.5% to about 5% by weight of the composition.

In an aspect, solid oral compositions of the present invention comprise a DPP-4 inhibitor drug such as teneligliptin in concentrations ranging from about 1% to about 25% by weight of the composition, and a SGLT inhibitor drug such as dapagliflozin in concentrations ranging from about 1% to about 25% by weight of the composition.

In an embodiment, the layered tablet compositions comprise a DPP-4 inhibitor drug such as teneligliptin, a SGLT inhibitor drug such as dapagliflozin, and at least one lubricant, wherein the concentration of the lubricant is not more than 2% by weight of the said composition.

Lubricant(s) in the layered tablet compositions is selected from magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, palmitic acid, glyceryl monostearate, glyceryl behenate, and mixtures thereof. In a preferred aspect, the lubricant is magnesium stearate.

In another embodiment, the layered tablet compositions comprise a DPP-4 inhibitor drug such as teneligliptin, a SGLT inhibitor drug such as dapagliflozin, and at least one lubricant, wherein the concentration of the lubricant is about 0.01% to about 2%, preferably from about 0.01% to about 1.5%, more preferably from about 0.01% to about 1% and most preferably from about 0.05% to about 0.8%, by weight of the said composition.

In an embodiment, layered tablet compositions comprise teneligliptin, amorphous dapagliflozin, and at least one lubricant, the concentration of the lubricant in each layer is about 0.01% to about 2%, preferably from about 0.01% to about 1.5%, more preferably from 0.01% to 1% and most preferably from about 0.05% to about 0.8%, by weight of the said composition.

In another embodiment, the layered tablet compositions comprise a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium glucose cotransporter (SGLT) inhibitor in separate layers such that,
(i) a first layer comprises a DPP-4 inhibitor drug such as teneligliptin, one or more excipients, and at least one lubricant, and
(ii) a second layer comprises a SGLT inhibitor drug such as dapagliflozin, one or more excipients, and at least one lubricant.

In an aspect of the embodiment, the concentration of the lubricant in each layer is from about 0.01% to about 2%, or from about 0.01% to about 1.5%, or from about 0.01% to about 1% or from about 0.05% to about 0.8%, by weight of the said composition.

In another aspect of the embodiment, the concentration of the lubricant in each layer is from about 0.05% to about 0.7%, or from about 0.05% to about 0.6%, or from 0.05% to about 0.5%, by weight of the said composition.

Layered tablet compositions of the present invention comprise a DPP-4 inhibitor drug such as teneligliptin, a SGLT inhibitor drug such as dapagliflozin, one or more excipient(s), and at least one lubricant.

The excipient(s) in the layered tablet compositions is selected from a diluent, binder, disintegrating agent, antioxidant, surfactant, lubricant, extended-release agent, sustained-release agent, controlled-release agent, prolonged release agent, delayed-release agent, enteric-release agent, timed-release agent, pulsed-release agent, glidant, pigments, colouring agent, and mixtures thereof.

In preferred compositions, the one or more excipient(s) is selected from diluents, binders, disintegrating agents, antioxidants, pH modifying agents, surfactants, glidants, and mixtures thereof.

In an embodiment, the layered tablet compositions comprise a DPP-4 inhibitor drug such as teneligliptin, a SGLT inhibitor drug such as dapagliflozin, at least one lubricant, and at least one antioxidant.

In an embodiment, the layered tablet compositions comprise a DPP-4 inhibitor drug such as teneligliptin, a SGLT inhibitor drug such as dapagliflozin, at least one lubricant, and at least one antioxidant, wherein the concentration of the lubricant is not more than about 2%, preferably from about 0.01% to about 2%, preferably from about 0.01% to about 1.5%, more preferably from about 0.01% to about 1% and most preferably from about 0.05% to about 0.8%, by weight of the said composition.

Antioxidant(s) in the layered tablet compositions is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, sodium ascorbate, potassium sorbate, sorbic acid, sodium sulfite, tocopherol, vitamin E derivatives, citric acid, malic acid, ascorbic acid, and mixtures thereof.

Layered tablet compositions of the present invention comprise antioxidants in concentrations ranging from about 0.01% to about 4%, preferably from about 0.01% to about 2%, more preferably from about 0.01% to about 1%, and most preferably from about 0.05% to about 0.5% by weight of the composition.

In an embodiment, layered tablet compositions comprise teneligliptin, amorphous dapagliflozin, at least one lubricant, and at least one antioxidant, wherein the concentration of the lubricant in each layer is about 0.01% to about 2%, preferably from about 0.01% to about 1.5%, more preferably from 0.01% to 1% and most preferably from about 0.05% to about 0.8%, by weight of the said composition.

Diluent(s) in the layered tablet compositions is selected from cellulose derivatives (such as cellulose, microcrystalline cellulose, silicified microcrystalline cellulose), sugars (such as lactose, glucose, sucrose, fructose, dextrose), sugar alcohols (such as mannitol, sorbitol, xylitol, lactitol), starches, modified starches, inorganic salts, calcium sulfate, calcium silicate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium aluminometasilicate, dextran, maltodextrin, cetyl alcohol, stearyl alcohol, waxes, and mixtures thereof.

In an aspect, diluent(s) in the layered tablet compositions is selected from cellulose derivatives, sugars, sugar alcohols, starches, modified starches, and mixtures thereof, and is used in a concentration ranging from about 5% to about 90%, preferably from about 10% to about 85%, and more preferably from about 15% to about 80% by weight of the composition.

Binder(s) in the layered tablet compositions is selected from povidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methylcellulose (MC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, calcium carboxymethylcellulose, starch paste, ethylcellulose, polymethacrylates, gelatin, polyethylene oxide, gums (example xanthan gum, guar gum, acacia, locust bean gum or alginates), polyvinyl alcohol, and mixtures thereof, and is used in a concentration ranging from about 0.1% to about 35%, preferably from about 0.5% to about 20%, more preferably from about 1% to about 10%, and most preferably from about 2.5% to about 7.5 %, by weight of the composition.

Disintegrant(s) in the layered tablet compositions is selected from sodium starch glycolate, crospovidone, croscarmellose sodium, croscarmellose calcium, croscarmellose potassium, starch, starch 1500, modified starch, pregelatinized starch, crosslinked carboxymethyl starch, sodium hydrogen carbonate, sodium carbonate, low substituted hydroxypropyl cellulose, and mixtures thereof, and is used in a concentration ranging from about 0.1% to about 25%, preferably from about 0.5% to about 15%, more preferably from about 1% to about 10%, and most preferably from about 2.5% to about 7.5%, by weight of the composition.

Surfactant in the layered tablet compositions is selected from polysorbates (for example polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, micro-encapsulated polysorbate 80 such as SEPITRAP™ 80, micro-encapsulated polyoxyl 40 hydrogenated castor oil such as SEPITRAP™ 4000), polyoxyethylene castor oil derivatives polyoxyethylene hydrogenated castor oil (for example CREMOPHOR™), ethoxylated hydrogenated castor oil, phosphatidyl choline, phospholipids, medium chain triglycerides, docusate sodium, lecithin, glyceryl monostearate, sorbitan monostearate (SPAN™ 60), sorbitan monopalmitate (SPAN® 40), sorbitan monolaurate (SPAN™ 20), poloxamers (polyoxyethylene polyoxypropylene block copolymers), sodium lauryl sulfate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, sorbitan fatty acid esters, sucrose esters of fatty acids, PEG-8 Caprylic-capric glycerides, saturated polyglycolized glycerides, tocopherol PEG succinate, and mixtures thereof.

Surfactant is present in a concentration ranging from about 0.1% to about 25% by weight of the composition, preferably from about 0.5% to about 20%, more preferably from about 1% to about 15%, and most preferably from about 2.5% to about 10% by weight of the composition.

Glidant(s) is selected from suitable glidants known in the art. Examples of suitable pharmaceutically acceptable glidant are talc and colloidal silicon dioxide. The glidants may be present in a concentration ranging from about 0.1% to about 10% by weight of the composition.

Any suitable pharmaceutically acceptable natural, semi-synthetic, or synthetic colours, and flavours, such as titanium dioxide, iron oxide (e.g. iron oxide yellow, iron oxide red, iron oxide brown, iron oxide black or mixtures thereof) may be used. Preferred colours, and flavours are those listed in the handbook of excipients.

Layered tablet compositions of the present invention may optionally be coated with a film coating layer comprising film coating materials, and optionally plasticizers, colorants, pigments, lubricants, diluents and surfactants.

Film coating material(s) is selected from those known in the art such as hydroxypropyl methylcellulose, hydroxy propylcellulose, ethylcellulose, polymethacrylates, polyvinyl alcohol, Surelease™, Opadry™, Opadry™ AMB, Aquacoat™, polyvinyl acetate, and mixtures thereof. The film coating material is in the range of 0.1% to 20% by weight of the composition.

Plasticizer(s) is selected from propylene glycol, polyethylene glycol, triacetin, triethylcitrate, acetyl triethylcitrate, acetyltributylcitrate, diethyl phthalate, dibutyl phthalate, dibutylsebacate, miglyol, hydrogenated oils, and mixtures thereof. The plasticizer(s) in the coating layer is present in a concentration ranging from 2.5% to 30% by weight of the coating layer.

Coating layer may be deposited on the composition using a solvent selected from water, methanol, ethanol, isopropanol, acetone, dichloromethane, ethylacetate, and mixtures thereof.

Process for preparing layered tablet compositions of the present invention comprises one or more of steps selected from sifting, blending, granulation (wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or co-precipitation), milling, screening, drying, compression into tablets, or filling into capsules.

Layered tablet compositions of the present invention were evaluated for drug content, disintegration, dissolution, content of total impurities, and content uniformity.

DPP-4 inhibitor drug content (assay) or SGLT inhibitor drug content (assay), in the layered tablet compositions, as determined by liquid chromatography, ranges from about 90% to about 110%, preferably from about 92.5% to about 107.5%, and most preferably 95% to about 105% of the label claim.

Disintegration of the layered tablet compositions, as evaluated using ‘disintegration time’ test in accordance with the United States Pharmacopeia (USPNF-2021-Issue 1 <701> Disintegration), was not more than 30 minutes; preferably not more than 15 minutes, more preferably not more than 10 minutes and most preferably not more than 5 minutes.

In-vitro dissolution of DPP-4 inhibitor drug or SGLT inhibitor drug, from layered tablet compositions, was studied using at least one of the following dissolution conditions:
i. Condition 1: 900ml of 0.1N hydrochloric acid, USP Type II apparatus at 75 rpm
ii. Condition 2: 900ml of 0.1N hydrochloric acid, USP Type II apparatus at 50 rpm
iii. Condition 3: 900ml of acetate buffer pH 4.5, USP Type II apparatus at 50 rpm
iv. Condition 4: 900ml of phosphate buffer pH 6.8, USP Type II apparatus, 50 rpm
v. Condition 5: 900ml of purified water USP Type II apparatus at 50 rpm

Dissolution was calculated in terms of average cumulative percentage dissolution of DPP-4 inhibitor drug or average cumulative percentage dissolution of SGLT inhibitor drug, at various time-points.
In an aspect, the layered tablet compositions provide immediate release of DPP-4 inhibitor drug or SGLT inhibitor drug, when analysed in-vitro for dissolution under any one of the dissolution conditions 1-5.

In an embodiment, the dissolution of DPP-4 inhibitor drug or SGLT inhibitor drug, from the layered tablet compositions, in 30 minutes, is from 75% to 110%, or from 80% to 110%, or from 85% to 110%, or from 90% to 110%, or from 95% to 110%.

In yet another embodiment, the dissolution of DPP-4 inhibitor drug or SGLT inhibitor drug, from the layered tablet compositions, in 15 minutes, is from 75% to 110%, or from 80% to 110%, or from 85% to 110%, or from 90% to 110%, or from 95% to 110%.

In yet another embodiment, the dissolution of DPP-4 inhibitor drug or SGLT inhibitor drug, from the layered tablet compositions, in 10 minutes, is from 70% to 110%, or from 75% to 110%, or from 80% to 110%, or from 85% to 110%, or from 90% to 110%, or from 95% to 110%.

In yet another embodiment, the dissolution of DPP-4 inhibitor drug or SGLT inhibitor drug, from the layered tablet compositions, in 5 minutes, is from 70% to 110%.

Content Uniformity was conducted on the layered tablet compositions of the present invention. Acceptance criteria is that the average % DPP-4 inhibitor drug content or % SGLT inhibitor drug content, in the tablets, at each time-point is within 90%-110% of the target content, % DPP-4 inhibitor drug content or % SGLT inhibitor drug content, of individual tablet at each time-point is within 85%-115% of the target content, and the relative standard deviation (RSD) for all tablets is less than or equal to 4%.

Total impurities content (by weight) related to DPP-4 inhibitor drug or related to SGLT inhibitor drug, in the layered tablet compositions was determined by liquid chromatography.
The acceptable limits (acceptance criteria) of the content of total impurities related to DPP-4 inhibitor drug, in the layered tablet compositions, is not more than 2%, preferably not more than 1.8%, more preferably not more than 1.7%, and most preferably not more than 1.6%, by weight.

In an embodiment, the content of total impurities (by weight) related to DPP-4 inhibitor drug in the layered tablet compositions, is not more than 1.5%, preferably not more than 1.3%, more preferably not more than 1.2%, and most preferably not more than 1%.

The acceptable limits (acceptance criteria) of the content of total impurities related to SGLT inhibitor drug, in the layered tablet compositions, is not more than 1%, preferably not more than 0.8%, preferably not more than 0.6%, more preferably not more than 0.5%, and most preferably not more than 0.4%, by weight.

Storage stability of the layered tablet compositions was studied under at least one of the following storage conditions:
Accelerated storage conditions:
i) 600C ± 20C
ii) 400C ± 20C and 75% ± 5 % relative humidity (400C/75%RH)
Room-temperature storage conditions:
iii) 300C ± 20C and 75% ± 5 % relative humidity (300C/75%RH)
iv) 300C ± 20C and 65% ± 5 % relative humidity (300C/65%RH)
v) 250C ± 20C and 60% ± 5 % relative humidity (250C/60%RH)

After specific time-periods of storage, the solid oral compositions were analysed for % DPP-4 inhibitor drug content, % total impurities related to DPP-4 inhibitor drug, % SGLT inhibitor drug content, and/or % total impurities related to SGLT inhibitor drug.

The term “storage stable” or “storage stability” as used herein refers to the layered tablet compositions which comprise not more than 2% of total impurities content related to DPP-4 inhibitor drug, and not more than 1% of total impurities content related to SGLT inhibitor drug, after storage at 400C/75%RH for 6 months, or 250C/60%RH for 12 months, preferably 24 months.

The invention is now illustrated with non - limiting examples.

Comparative Example 1: Single Layer Tablet Composition
Single Layer Tablet composition of Comparative Example 1 was prepared in accordance with the composition details in Table 1. Teneligliptin hydrobromide hydrate, microcrystalline cellulose, Sepitrap™ 80, lactose, and low substituted hydroxy propyl cellulose were sifted through 40 mesh ASTM sieve. The sifted ingredients were blended together in rapid mixing granulator for about 15 minutes, and granulated with a solution of dapagliflozin in acetone. Granules were dried till it achieved a loss of drying of about not more than 3.0% w/w. The dried granules were passed through 30 mesh ASTM sieve. Colloidal silicon dioxide and low substituted hydroxy propyl cellulose were sifted through 40 mesh ASTM sieve, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (sifted through 40 mesh ASTM sieve) in the blender for about 5 minutes to provide dapagliflozin and teneligliptin lubricated granules. The granules were compressed using 10 mm round punches, and the compressed tablets coated with Opadry™ Yellow dispersion.

Table 1: Composition of Comparative Example 1
Ingredient % w/w of Tablet Composition
Granulation
Teneligliptin hydrobromide hydrate 8.26
Microcrystalline cellulose 29.692
Lactose 44.543
Sepitrap 80 4.90
Hydroxy propyl cellulose LH-11 3.92
Dapagliflozin 2.80
Lubrication
Hydroxy propyl cellulose LH-11 1.96
Colloidal silicon dioxide 0.98
Magnesium Stearate 0.98
Film Coating
Opadry II Yellow (85F520173) 1.96
Comparative Examples 2A and 2B: Single Layer Tablet Compositions
Single Layer Tablet composition of Comparative Example 2A and Comparative Example 2B was prepared in accordance to the composition details in Table 2, and the process similar to Comparative Example 1, with the exception that dry mix was granulated with a solution of dapagliflozin and propyl gallate in acetone. The granules were compressed using 9.5 mm round punches, and the compressed tablets coated with Opadry™ Yellow dispersion.

Table 2: Composition of Comparative Examples 2A and 2B
Ingredient % w/w of Tablet Composition
Comparative Ex. 2A Comparative Ex. 2B
Granulation
Teneligliptin hydrobromide hydrate 8.26 8.24
Microcrystalline cellulose 49.683 49.57
Lactose 24.51 24.45
Sepitrap 80 4.902 4.89
Hydroxy propyl cellulose LH-11 3.92 3.91
Dapagliflozin 2.80 2.79
Propyl Gallate 0.04 0.28
Lubrication
Hydroxy propyl cellulose LH-11 1.96 1.96
Colloidal silicon dioxide 0.98 0.98
Magnesium Stearate 0.98 0.98
Film Coating
Opadry II Yellow (85F520173) 1.96 1.96

Examples 3-6: Layered Tablet Compositions (Bilayered)
Composition details of Examples 3 to 6 in terms of percentage of ingredients by weight of composition are provided in Table 3, and in terms of percentage of ingredients by weight of their layer is provided in their respective procedures.

Table 3: Composition Details of Examples 3-6
Ingredients % Coated Tablet
Ex. 3 Ex. 4 Ex. 5 Ex. 6
Teneligliptin Layer
Teneligliptin hydrobromide hydrate 6.66 6.42 5.26 6.66
Mannitol 200 SD 26.97 25.8 -- 22.68
Microcrystalline cellulose (PH101) -- -- 41.02
Maize starch 5.93 5.73 8.20 5.93
Ferric oxide yellow 0.05 0.04 0.07 0.045
Hydroxyl propyl cellulose 0.90 0.87 1.25 0.45
Hydroxyl propyl cellulose (LH-22) -- -- -- 4.52
Propyl gallate -- 0.22 -- --
Butylated hydroxy anisole -- -- 0.18 0.226
Hydroxyl propyl cellulose (LH-11) 4.20 4.05 5.79 4.20
Colloidal silicon dioxide 0.226 0.22 0.31 0.226
Magnesium Stearate 0.226 0.22 0.31 0.23
Teneligliptin Layer 45.16 43.57 62.39 45.16
Dapagliflozin Layer
Microcrystalline cellulose (PH200) 40.61 25.38 16.76 16.22
Microcrystalline cellulose (PH101) -- -- -- 21.54
Lactose anhydrous -- 19.61 12.83 --
Sepitrap 80 2.82 2.72 1.78 2.82
Croscarmellose sodium 3.635
Hydroxyl propyl cellulose (LH-22) 4.16 -- -- 4.16
Hydroxyl propyl cellulose (LH-11) -- 3.27 2.14
Hypromellose (E3) 1.56 -- -- 0.78
Dapagliflozin 2.26 2.18 1.78 2.258
Colloidal silicon dioxide -- 0.76 0.18 --
Magnesium Stearate 0.52 0.55 0.18 0.52
Dapagliflozin Layer 51.93 54.47 35.65 51.93
Film-Coating
Opadry II Yellow (85F520173) 2.91 1.96 1.96 2.91

Example 3: Bi-layer tablet composition of teneligliptin and dapagliflozin
Procedure: Teneligliptin lubricated granules were prepared as follows (percentages are with respect to weight of teneligliptin lubricated granules / teneligliptin layer):
Teneligliptin hydrobromide hydrate (14.74% w/w) and mannitol (59.72%) w/w were co-sifted through 40 mesh ASTM sieve. Ferric oxide yellow (0.1% w/w) and maize starch (13.14% w/w) were co-sifted through 100 mesh ASTM sieve. The sifted powders were blended together for about 10 minutes in a rapid mixing granulator, and granulated using a solution of hydroxy propylcellulose (2.0% w/w) in water. Granules were dried till it achieved a loss of drying of about not more than 4% w/w. The dried granules were passed through 20 mesh ASTM sieve. Low substituted hydroxypropyl cellulose (9.3% w/w) and colloidal silicon dioxide (0.5% w/w) were sifted through 60 mesh ASTM sieve, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (0.5% w/w) (sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes to provide teneligliptin lubricated granules.

Dapagliflozin lubricated granules were prepared as follows (percentages are with respect to weight of dapagliflozin lubricated granules / dapagliflozin layer):
Microcrystalline cellulose PH 200 (70.39% w/w), Sepitrap™ 80 (5.43% w/w), and low-substituted hydroxypropyl cellulose LH-22 (4% w/w) were sifted through 40 mesh ASTM, and mixed for about 10 minutes in a rapid mixer granulator. The powder mixture was granulated using a solution of hydroxypropyl methylcellulose 3 cps (3% w/w) in water. Granules were dried till a loss of drying of not more than about 5% w/w was achieved. The granules were further granulated with a solution of dapagliflozin (4.35% w/w) in acetone. Granules were dried till a loss of drying of not more than about 3% w/w was achieved. The dried granules were passed through 30 mesh ASTM sieve. Microcrystalline cellulose PH 200 (7.83% w/w) and low-substituted hydroxypropyl cellulose LH-22 (4% w/w) were sifted through 40 mesh ASTM, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (1% w/w) ((sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes, to provide dapagliflozin lubricated granules.

Teneligliptin lubricated granules equivalent to 20 mg of teneligliptin and dapagliflozin lubricated granules equivalent to 10 mg of dapagliflozin were compressed as a bi-layered tablet using 10.5 mm round punch tooling. The resulting tablets were film coated with Opadry™ II yellow.

The coated tablet compositions were evaluated for disintegration time and dissolution of teneligliptin and dapagliflozin (using Condition 1), results of which are provided in Table 4.

Table 4: Disintegration and Dissolution of Layered Tablets of Example 3
Disintegration Time (minutes) 11 - 12
Average Cumulative % Dissolution at 15 minutes Teneligliptin 103%
Dapagliflozin 95%

Example 4: Bi-layer tablet composition of teneligliptin and dapagliflozin
Procedure: Teneligliptin lubricated granules were prepared as follows (percentages are with respect to weight of teneligliptin lubricated granules/teneligliptin layer):
Teneligliptin hydrobromide (14.74% w/w), mannitol (59.22% w/w), and hydroxypropyl cellulose (2% w/w) were co-sifted through 40 mesh ASTM sieve. Ferric oxide yellow (0.1% w/w) and maize starch (13.14% w/w) were co-sifted through 100 mesh ASTM sieve. The sifted powders were blended together for about 10 minutes in a rapid mixing granulator, and granulated using a solution of propyl gallate (0.5%w/w) in water. Granules were dried till it achieved a loss of drying of about not more than 4% w/w. The dried granules were passed through 20 mesh ASTM sieve. Low substituted hydroxypropyl cellulose (9.3% w/w) and colloidal silicon dioxide (0.5% w/w) were sifted through 60 mesh ASTM sieve, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (0.5% w/w) (sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes to provide teneligliptin lubricated granules.

Dapagliflozin lubricated granules were prepared as follows (percentages are with respect to weight of dapagliflozin lubricated granules / dapagliflozin layer):
Microcrystalline cellulose PH 200 (40% w/w), lactose monohydrate (36% w/w), Sepitrap™ 80 (5% w/w), and low-substituted hydroxypropyl cellulose LH-22 (4% w/w) were sifted through 40 mesh ASTM, and mixed for about 10 minutes in a rapid mixer granulator. The powder mixture was granulated using a solution of dapagliflozin (4% w/w) in acetone. Granules were dried till a loss of drying of not more than about 3% w/w was achieved. The dried granules were passed through 30 mesh ASTM sieve. Microcrystalline cellulose PH 200 (6.6% w/w) and low-substituted hydroxypropyl cellulose LH-11 (2% w/w) were sifted through 40 mesh ASTM, and colloidal silicon dioxide (1.4% w/w) was sifted through 60 mesh ASTM sieve, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (1% w/w) (sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes, to provide dapagliflozin lubricated granules.

Teneligliptin lubricated granules equivalent to 20mg of teneligliptin and dapagliflozin lubricated granules equivalent to 10mg of dapagliflozin were compressed as a bi-layered tablet using 12.5 mm round punch tooling. The resulting tablets were film coated with Opadry™ II yellow.

Tablet compositions were evaluated for disintegration time and dissolution of teneligliptin and dapagliflozin (using Condition 1), results of which are provided in Table 5.

Table 5: Disintegration and Dissolution of layered tablets of Example 4
Disintegration Time (minutes) 3 - 4
Average Cumulative % Dissolution at 45 minutes Teneligliptin 92%
Dapagliflozin 99%

Example 5: Bi-layer tablet composition of teneligliptin and dapagliflozin
Procedure: Teneligliptin lubricated granules were prepared as follows (percentages are with respect to weight of teneligliptin lubricated granules / teneligliptin layer):
Teneligliptin hydrobromide hydrate (8.42% w/w) and microcrystalline cellulose PH 101 (65.75% w/w) were co-sifted through 40 mesh ASTM sieve. Ferric oxide yellow (0.11% w/w) and maize starch (13.14% w/w) were co-sifted through 100 mesh ASTM sieve. Hydroxypropyl cellulose (2% w/w) was sifted through 40 mesh ASTM sieve. The sifted powders were blended together for about 10 minutes in a rapid mixing granulator, and granulated using a solution of butylated hydroxyanisole (0.29% w/w) in isopropyl alcohol. Granules were dried till it achieved a loss of drying of about not more than about 4% w/w. The dried granules were passed through 20 mesh ASTM sieve. Low substituted hydroxypropyl cellulose LH-11 (9.29% w/w) and colloidal silicon dioxide (0.5% w/w) were sifted through 60 mesh ASTM sieve, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (0.5% w/w) (sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes to provide teneligliptin lubricated granules.

Dapagliflozin lubricated granules were prepared as follows (percentages are with respect to weight of dapagliflozin lubricated granules / dapagliflozin layer):
Microcrystalline cellulose PH 200 (40.4% w/w), anhydrous lactose (36% w/w), Sepitrap™ 80 (5% w/w), and low-substituted hydroxypropyl cellulose LH-22 (4% w/w) were sifted through 40 mesh ASTM, and mixed for about 10 minutes in a rapid mixer granulator. The powder mixture was granulated using a solution of dapagliflozin (5% w/w) in acetone. Granules were dried till a loss of drying of not more than about 3% w/w was achieved. The dried granules were passed through 20 mesh ASTM sieve. Microcrystalline cellulose PH 200 (6.6% w/w), low-substituted hydroxypropyl cellulose LH-11 (2% w/w), and colloidal silicon dioxide (0.5% w/w) were sifted through 40 mesh ASTM, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (0.5% w/w) (sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes, to provide dapagliflozin lubricated granules.

Example 5A: Teneligliptin lubricated granules equivalent to 20mg of teneligliptin, and dapagliflozin lubricated granules equivalent to 10mg of dapagliflozin were compressed as a bi-layered tablet using 12.5 mm round punch tooling. The tablets were film coated with Opadry™ II yellow.

Example 5B: Teneligliptin lubricated granules equivalent to 20mg of teneligliptin, and dapagliflozin lubricated granules equivalent to 5mg of dapagliflozin were compressed as a bi-layered tablet using 10.5 mm round punch tooling. The tablets were film coated with Opadry™ II yellow.

Tablet compositions were evaluated for disintegration and dissolution of teneligliptin and dapagliflozin (using Conditions 1-4), and the results provided in Table 6.
Table 6: Disintegration and Dissolution of layered tablets of Example 4A
Disintegration Time (minutes) 3 - 4
Dissolution Condition Average Cumulative % Dissolution at 30 minutes
Teneligliptin Dapagliflozin
Condition 1 101% 104%
Condition 2 90% 89%
Condition 3 97% 79%
Condition 4 90% 80%

Example 6: Bi-layer tablet composition of teneligliptin and dapagliflozin
Procedure: Teneligliptin lubricated granules were prepared as follows (percentages are with respect to weight of teneligliptin lubricated granules / teneligliptin layer):
Teneligliptin hydrobromide hydrate (14.74% w/w) and mannitol (50.22% w/w) were co-sifted through 40 mesh ASTM sieve. Ferric oxide yellow (0.10% w/w) and maize starch (13.14% w/w) were co-sifted through 100 mesh ASTM sieve. Hydroxypropyl cellulose LH-22 (5% w/w) and hydroxypropyl cellulose (1% w/w) was sifted through 40 mesh ASTM sieve. The sifted powders were blended together for about 10 minutes in a rapid mixing granulator, and granulated using a solution of butylated hydroxyanisole (0.5% w/w) in isopropyl alcohol. Granules were dried till it achieved a loss of drying of about not more than about 4% w/w. The dried granules were passed through 20 mesh ASTM sieve. Low substituted hydroxypropyl cellulose LH-11 (9.30% w/w), hydroxypropyl cellulose LH-22 (5.0% w/w), and colloidal silicon dioxide (0.5% w/w) were sifted through 60 mesh ASTM sieve, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (0.5% w/w) (sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes to provide teneligliptin lubricated granules.

Dapagliflozin lubricated granules were prepared as follows (percentages are with respect to weight of dapagliflozin lubricated granules / dapagliflozin layer):
Microcrystalline cellulose PH 101 (41.48% w/w), microcrystalline cellulose PH 200 (23.41% w/w), Sepitrap™ 80 (5.43% w/w), croscarmellose sodium (3.5% w/w), low-substituted hydroxypropyl cellulose LH-22 (4% w/w), and hydroxypropyl methylcellulose E3 (1.5% w/w) were sifted through 40 mesh ASTM, and mixed for about 10 minutes in a rapid mixer granulator. The powder mixture was granulated using a solution of dapagliflozin (4.35% w/w) in acetone. Granules were dried till a loss of drying of about 2-4% w/w was achieved. The dried granules were passed through 20 mesh ASTM sieve. Microcrystalline cellulose PH 200 (7.83% w/w), croscarmellose sodium (3.5% w/w) and low-substituted hydroxypropyl cellulose LH-22 (4% w/w) were sifted through 40 mesh ASTM, and blended with the dried granules in a blender for about 10 minutes. The granules were further blended with magnesium stearate (1% w/w) (sifted through 60 mesh ASTM sieve) in the blender for about 5 minutes, to provide dapagliflozin lubricated granules.

Teneligliptin lubricated granules equivalent to 20mg of teneligliptin, and dapagliflozin lubricated granules equivalent to 10mg of dapagliflozin were compressed as a bi-layered tablet using 10.5 mm round punch tooling. The resulting tablets were film coated with Opadry™ II yellow.

Tablet compositions prepared in accordance to Example 6 were evaluated for disintegration, content uniformity and dissolution of teneligliptin and dapagliflozin (under dissolution conditions 1-5), results of which are provided in Table 7.

Table 7: Dissolution study of Example 6 under dissolution conditions 1-5
A. Disintegration Time (minutes) ? 4 – 5
B. Average Cumulative % Dissolution at 30 minutes ?
Dissolution Condition ? Teneligliptin Dapagliflozin
Condition 1 103% 103%
Condition 2 95% 100%
Condition 3 96% 91%
Condition 4 90% 91%
Condition 5 91% 97%
C. Content Uniformity ? Teneligliptin Dapagliflozin
RSD 2.5 1.7
Average % drug content 94.1 99.7

Storage Stability Studies
Solid oral compositions prepared in accordance with Comparative Examples 1-2, and Examples 3- 6 were packed in Alu-Alu blister packs, and subjected to various storage conditions. The compositions were withdrawn at specific time periods and analyzed for % teneligliptin content, % dapagliflozin content, and % total impurities. The results of storage stability study are provided in Tables 8 and 9.

Table 8: Storage stability Study at 600C ± 20C
Example No. ? % Total impurities related to teneligliptin % Total impurities related to dapagliflozin
Condition/Time Period ? Initial 600C/1M Initial 600C/1M
Comparative Example 1 1.20 18.72 0.51 2.15
Comparative Example 2A 1.00 11.45 0.36 2.08
Comparative Example 2B 1.00 11.32 0.36 1.85
Example 3 0.24 1.20 0.08 0.91
Example 4 0.36 1.21 0.25 0.74
Example 5A 0.34 1.63 0.04 0.39
Example 5B 0.27 1.27 0.04 0.39
Example 6 0.19 0.95 0.04 0.38

Table 9: Storage Stability study of Examples 5 and 6
Storage Condition / Time Period % teneligliptin content % dapagliflozin content % Total impurities related to teneligliptin % Total impurities related to dapagliflozin
Example 5A
Initial 104.2 102.8 0.39 0.18
400C/75%RH / 6M 99.1 101.5 0.98 0.38
250C/60%RH / 6M 102.2 102.1 0.56 0.26
250C/60%RH / 12M 101.9 101.7 0.77 0.25
300C/75%RH / 6M 101.5 102.2 0.71 0.25
300C/75%RH / 12M 101.8 102.6 0.79 0.32
300C/65%RH / 6M 100.7 102.9 0.65 0.27
300C/65%RH / 12M 102.7 102.5 0.59 0.32
Example 5B
Initial 103.1 96.6 0.27 0.28
400C/75%RH / 6M 100.8 96.6 0.64 0.40
250C/60%RH / 12M 102.5 98.3 0.58 0.31
300C/75%RH / 12M 102.7 96.9 0.64 0.33
300C/65%RH / 12M 102.6 97.4 0.65 0.32
Example 6
Initial 103.5 104.0 0.16 0.31
400C/75%RH / 3M 104.2 103.5 0.34 0.32
400C/75%RH / 6M 100.9 105.4 0.46 0.43
M = Month(s)

Comparative Example 1 and Table 8 show that a DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin, when formulated as single layered tablets, with magnesium stearate as the lubricant, show impurity levels significantly higher than the acceptable limits (not more than 2% by weight of DPP-4 related total impurities, not more than 1% by weight of SGLT related total impurities).

Comparative Examples 2A and 2B, and Table 8 demonstrate that even addition of antioxidant(s), to the layered compositions of a DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin, do not result in impurity levels within the acceptable limits.

Example 3 and Table 8 show that when DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin, when formulated as layered tablet compositions, exhibit the desired disintegration, dissolution, and stability, despite the use of magnesium stearate as the lubricant. The said compositions result in impurity levels within the acceptable limits.

Example 3 and Table 8 show that when DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin, when formulated as layered tablet compositions with a lubricant at a concentration of not more than 2% by weight of the composition, the said composition exhibits the desired stability, disintegration, and dissolution of teneligliptin and dapagliflozin. The said compositions result in impurity levels within the acceptable limits.

Examples 4-6, and Tables 8-9 show that addition of an antioxidant to the layered tablet compositions, further improves the stability of the compositions as the compositions result in impurity levels well within the limits at 600C, and after 6 months of storage stability studies at accelerated conditions and after 12 months at room-temperature conditions. The said compositions also show good processability (content uniformity), disintegration and dissolution of teneligliptin and dapagliflozin, and a total impurities content within acceptable limits for both DPP-4 related total impurities and SGLT related total impurities.

In conclusion,

i. Layered compositions comprising at least one lubricant at a concentration of not more than 2% by weight of the composition provides compositions with good processability, disintegration, and dissolution of a DPP-4 inhibitor drug such as teneligliptin, and a SGLT inhibitor drug such as dapagliflozin. The impurities related to the drug are also within the acceptable limits.

ii. Further addition of at least one antioxidant to the layered compositions provides compositions with good disintegration, and dissolution. The impurities related to the drugs are also well within the acceptable limits. ,CLAIMS:1. A storage-stable, layered tablet composition comprising a dipeptidyl peptidase-4 (DPP-4) inhibitor drug, a sodium glucose cotransporter (SGLT) inhibitor drug, one or more excipient(s), and at least one lubricant,
wherein the concentration of the lubricant(s) is 0.01% to 2% by weight of the composition, and
wherein the content of total impurities related to DPP-4 inhibitor drug, in the tablet composition, is not more than 2% by weight, and the content of total impurities related to SGLT inhibitor drug, in the tablet composition, is not more than 1% by weight.

2. The layered tablet composition as claimed in claim 1, wherein the concentration of the lubricant is 0.01% to 1% by weight of the composition.

3. The layered tablet composition as claimed in claim 1, wherein the tablet comprises
(i) a first layer comprising the DPP-4 inhibitor drug, one or more excipient(s), and at least one lubricant, and
(ii) a second layer comprising the SGLT inhibitor drug, one or more excipient(s), and at least one lubricant,
wherein the concentration of the lubricant in each layer is 0.01% to 1% by weight of the composition.

4. The layered tablet composition as claimed in claim 3, wherein the concentration of the lubricant in each layer is 0.05% to 0.6% by weight of the composition.

5. The layered tablet composition as claimed in claims 1 to 4, wherein the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, palmitic acid, glyceryl monostearate, and glyceryl behenate.

6. The layered tablet composition as claimed in claims 1 to 4, wherein the excipient(s) is selected from diluents, binders, disintegrants, antioxidants, pH modifying agents, surfactants, and glidants.

7. The layered tablet composition as claimed in claim 6, wherein the antioxidant is selected from butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium ascorbate, potassium sorbate, sorbic acid, sodium sulfite, tocopherol, vitamin E derivative, citric acid, malic acid, and ascorbic acid, and is used in a concentration of 0.01% to about 1% by weight of the composition.

8. The layered tablet composition as claimed in claim 1, wherein the layered tablet is a bi-layered tablet.

9. The layered tablet composition as claimed in claim 1, wherein
(i) the dipeptidyl peptidase-4 (DPP-4) inhibitor is teneligliptin or pharmaceutically acceptable salts, hydrates, esters, derivatives, co-crystals, solvates, and polymorphs thereof, and the particle size of teneligliptin used in the composition is in the range of 0.1 microns to 150 microns, and
(ii) the sodium glucose cotransporter (SGLT) inhibitor is dapagliflozin or pharmaceutically acceptable salts, hydrates, esters, derivatives, co-crystals, solvates, and polymorphs thereof, and the particle size of dapagliflozin used in the composition is in the range of 0.5 microns to 250 microns.

10. The layered tablet composition as claimed in claim 1, wherein on storage of the compositions at 400C/75%RH for 6 months or 250C/60%RH for 12 months, the content of total impurities related to DPP-4 inhibitor is not more than 1% by weight, and the content of total impurities related to SGLT inhibitor drug is not more than 0.5% by weight.