DESC:The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.

The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "controlled release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that Upadacitinib is released at a predetermined rate that is slower than the immediate release formulation. AUC, as used herein, refers to the area under the curve that represents changes in blood concentrations of Upadacitinib over time. Cmax, as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of Upadacitinib over time. Tmax, as used herein, refers to the time that it takes for Upadacitinib blood concentration to reach the maximum value. T 1/2, as used in this disclosure, refers to the time that it takes for Upadacitinib blood concentration to decline to one-half of the maximum level. Collectively AUC, Cmax, Tmax, and T1/2 are the principle pharmacokinetic parameters that characterize the pharmacokinetic responses of a particular drug product such as Upadacitinib in an animal or human subject.

The term Empagliflozin as employed herein refers is used in broad sense to include not only “Empagliflozin its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

The term Sitagliptin as employed herein refers is used in broad sense to include not only “Sitagliptin its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

The term Metformin as employed herein refers is used in broad sense to include not only “Sitagliptin its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

The term "salt" as used herein, refers to salts derived from inorganic or organic acids. Examples of suitable salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, fumarate, hydrochloride, carbonates, bicarbonates, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, salicylate, succinate, sulfate, nitrates, tartrate, sulfonates, thiocyanate, tosylate, mesylate, and undecanoate.

As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the composition” includes reference to one or more compositions (or to a plurality of compositions) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus in some embodiments, The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of’ or “consist essentially of’ the described features.

“Pharmaceutically acceptable salt” as used herein includes both acid and base addition salts. In some embodiments, the pharmaceutically acceptable salt of any one of the compounds described herein is the form approved for use by the US Food and Drug Administration. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et ah, “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66: 1-19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

As used herein, “treatment” or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to anti-diabetic effect, therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” or “anti-diabetic effect” is meant eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder (e.g., an improvement in: hyperglycemia, polyuria, polydipsia, polyphagia, diabetic dermadromes etc.) such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the complications associated with the underlying disorder (e.g., cardiovascular disease). For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

The terms “diabetes” and “diabetes mellitus” are used interchangeably herein. These terms refer to type 1 diabetes mellitus, type 2 diabetes mellitus, complications of diabetes mellitus, and of neighboring disease states. As used herein, diabetes or diabetes mellitus (DM) refers to a group of metabolic disorders in which there are high blood sugar levels over a prolonged period.

The extended-release compositions of the present invention comprise along with Metformin comprises of at least one release controlling agent. The term "release controlling agent" as used herein means any excipient that can retard the release of active agent and includes, but is not limited to, polymeric release controlling agent, non-polymeric release controlling agent or combinations thereof.

Suitable polymeric release controlling agent may be employed in the compositions of the present invention. In an embodiment, the polymeric release controlling agent employed in the compositions of the present invention may be swelling or non-swelling. The release controlling agent can be incorporated as polymer matrix or as a rate controlling polymer coating. In a further embodiment, polymeric release controlling agents that may be employed in the compositions of the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers, acrylic acid derivatives or the like or any combinations thereof. Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carb oxy methyl ethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof.

Saccharides or polysaccharides include, but are not limited to, guar gum, xanthan gum, gum arabic, tragacanth or combinations thereof. Vinyl derivatives, polymers and copolymers thereof include, but are not limited to, polyvinylacetate aqueous dispersion (Kollicoat® SR 30D, copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol, mixture of polyvinyl acetate and polyvinylpyrrolidone (e.g. Kollidon® SR), polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP), or combinations thereof. Polyalkylene oxides and derivatives thereof include, but are not limited to, polyethylene oxide and the like or any combinations thereof. The term "polyethylene oxide polymer" or "PEO" as used herein includes all forms and MWs of PEO polymers. Sources of PEO polymers include, e.g., Polyox WSR-303™. Acrylic acid derivatives include, but are not limited to, methacrylic acids, poiymethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butylmethacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit ® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethyl acrylate methymethacrylate copolymer), Eudragit® L 100 and Eudragit® S (methacrylic acid'methyl methacrylate copolymer), Eudragit® L 100-55 (methacrylic acid'ethyl acrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof. Maleic copolymer based polymeric release controlling agent includes, but is not limited to, vinylacetate maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and the like, or combinations thereof. In one embodiment, polymers with low viscosity are employed in the compositions of the present invention as release controlling agent such as, but not limited to, Methocel K4M, and the like or combinations.

In addition to the above discussed excipients, the controlled release compositions of the present invention comprise at least one pharmaceutically acceptable excipients, such as, but not limited to diluents, glidants, lubricants, disintegrants, binders, stabilizers, pH modifier, release controlling agent, preservatives, colorants and the like or combinations thereof.

Diluents are inert ingredients sometimes used as bulking agents in order to decrease the concentration of the active ingredient in the final formulation. Suitable diluents used in the present invention are selected from, not limited to, sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, ethyl cellulose.

Suitable glidants included in the present formulation can be selected from the group consisting of silica, fumed silica, silicified cellulose, sodium stearate, magnesium aluminum silicate, pyrogenic silica, hydrated sodium silio-aluminate, cellulose, calcium phosphate, sodium lauryl sulfate, pregelatinized starch, talc, Colloidal silicon dioxide and physical or co-processed combinations thereof. The glidant can be silica, and can be a hydrophilic fumed silica (colloidal silicon dioxide).

Examples of suitable lubricants include, but are not limited to, polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and the like. In one embodiment, the lubricant is magnesium stearate.

Examples of suitable pH modifiers include, but are not limited to, organic acids, such as tartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate; magnesium or calcium carbonate or bicarbonate; and combinations thereof. In one embodiment, the pH modifier is tartaric acid. In one embodiment, the pharmaceutical composition comprises from about 10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof. In other embodiments, the formulation comprises from about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about 30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %, about 15 w/w.%, about 20 w/w %, about 25 w/w % or about 30 w/w % pH modifier. In one embodiment, the pH modifier is tartaric acid.

Suitable disintegrants be employed in the formulations of the present invention include croscarmellose sodium, crospovidone, sodium starch glycolate, starch or combinations thereof.

As discussed herein, sustained peak plasma concentrations can theoretically be achieved by means of sustained release matrix systems. However, when such systems are made of hydrophilic polymers, such as HPMC, they seldom provide pH independent drug release of pH-dependent soluble drugs, and they are normally incapable of attaining zero-order release except for practically insoluble drugs. Unexpectedly, is has now been discovered that when a pH modifier, such as tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof, is used in a hydrophilic sustained release matrix system, it allows Compound 1 or a pharmaceutically acceptable salt or solid state form thereof to be released at a steady rate regardless of the pH of the environment. In an unexpected finding, it was discovered that as a tablet containing the hydrophilic polymer matrix system erodes.

In embodiments the present invention relates to a pharmaceutical composition comprising of SLGT2 inhibitor or its pharmaceutically acceptable salts in combination with DPP-IV inhibitor and one or more excipients.

In one of the embodiments the present invention relates to a pharmaceutical composition comprising a combination of Sitagliptin or its pharmaceutically acceptable salts, Empagliflozin or its pharmaceutically acceptable salts and Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts in combination with Sitagliptin and Metformin one or more pharmaceutically acceptable excipients where in the pharmaceutical composition is multilayer tablet dosage form preferably bilayer tablet dosage form.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts in combination with Sitagliptin and Metformin one or more pharmaceutically acceptable excipients, where in the said formulation has no or minimum drug-drug interaction, maximum stability along with optimal bioavailability.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts in combination with Sitagliptin and Metformin one or more pharmaceutically acceptable excipients like diluent, binder, glidant, lubricant, solubilizer, disintegrant and colorant.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Sitagliptin or its pharmaceutically acceptable salts and Empagliflozin or its pharmaceutically acceptable salts and one or more excipients.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts combination with Sitagliptin and Metformin, wherein the oral pharmaceutical composition is a bilayer tablet composition.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin, Sitagliptin and Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where in the Empagliflozin and Sitagliptin is present in the one layer (Immediate release layer), Metformin is present in the another layer (Extended release layer).

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin, Sitagliptin and Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where in the formulation is prepared by wet granulation method.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin, Sitagliptin and Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, process for the preparation of such composition.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising of SLGT2 inhibitor or its pharmaceutically acceptable salts and one or more excipients in combination with DPP-IV inhibitor further comprising of any other anti-diabetic agent or its pharmaceutically acceptable salts.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising DPP-IV inhibitor is Sitagliptin or its pharmaceutically acceptable salts and SGLT2 inhibitor is Empagliflozin or its pharmaceutically acceptable salts and one or more excipients, other anti-diabetic agent is Metformin or its pharmaceutically acceptable salts and one or more excipients.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts combination with Sitagliptin and Metformin one or more pharmaceutically acceptable excipients where in the pharmaceutical composition is multilayer tablet dosage form preferably bilayer tablet dosage form.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts combination with Sitagliptin and Metformin one or more pharmaceutically acceptable excipients, where in the said formulation has no or minimum drug-drug interaction, maximum stability along with optimal bioavailability.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts combination with Sitagliptin and Metformin one or more pharmaceutically acceptable excipients like diluent, binder, glidant, lubricant, solubilizer, disintegrant and colorant.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising DPP-IV inhibitor is Sitagliptin or its pharmaceutically acceptable salts and SGLT2 inhibitor is Empagliflozin or its pharmaceutically acceptable salts and one or more excipients.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salts combination with Sitagliptin and Metformin, wherein the oral pharmaceutical composition is a bilayer tablet composition.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin, Sitagliptin and Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where in the Empagliflozin and Sitagliptin is present in the one layer (Immediate release layer), Metformin is present in the another layer (Extended release layer).

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin, Sitagliptin and Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where in the formulation is prepared by wet granulation method.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Empagliflozin, Sitagliptin and Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, process for the preparation of such composition.

Examples:

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1:

S. No Ingredients 10 mg / 100 mg / 1000 mg 25 mg / 100 mg / 1000 mg
Quantity in (mg) % w/w Quantity in (mg) % w/w
Empagliflozin and Sitagliptin Portion
1. Empagliflozin 10.00 4.00 25.00 10.00
2. Sitagliptin Phosphate Monohydrate 128.50 51.40 128.50 51.40
3. Microcrystalline Cellulose PH 101 39.47 15.79 24.47 9.79
4. Crospovidone XL 5.00 2.00 5.00 2.00
5. Sun set yellow lake 0.03 0.01 - -
6. Lake of Erythrocin - -l 0.03 0.01
Granulating Fluid
7. Hydroxypropylcellulose 9.00 3.60 9.00 3.60
8. Purified water Q.s - Q.s -
Extra granular portion
9. Crospovidone XL 5.00 2.00 5.00 2.00
10. Microcrystalline Cellulose PH 102 50.00 20.00 50.00 20.00
11. Magnesium stearate 3.00 1.20 3.00 1.20
Empagliflozin and Sitagliptin Portion Weight 250.00 100.00 250.00 100.00
Metformin Hydrochloride (Extended Release) Portion
12. Metformin Hydrochloride 1000.00 71.42 1000.00 71.42
13. Hydroxy Propyl Methyl Cellulose K100 M 120.00 8.89 120.00 8.89
14. Hydroxy Propyl Methyl Cellulose K200 M 190.00 14.07 190.00 14.07
15. Microcrystalline Cellulose 12.00 0.89 12.00 0.89
Granulating Fluid
16. Povidone K- 90 21.25 1.57 21.25 1.57
17. Isopropyl Alcohol q. s. -- q. s. --
Extra granular portion
18. Magnesium stearate 6.75 0.50 6.75 0.50
Metformin Hydrochloride (Extended Release) Portion Weight 1350.00 100.00 100.00
Bilayer Tablet Core weight 1600.00 -- 1600.00 --
Film Coating
19. Opadry Yellow 48.00 3.00 -- --
20. Opadry Red -- -- 48.00 3.00
21. Purified Water q.s. -- q.s. --
Total Tablet weight 1648.00 1648.00

Brief Manufacturing Procedure (Wet granulation):

Layer – I:

Manufacturing Process for Empagliflozin and Sitagliptin:

Sifting:
i. Co-sift Empagliflozin, Sitagliptin phosphate monohydrate, Microcrystalline Cellulose PH 101, Crospovidone XL and Coloring agent through sieve # 40 ASTM.
Dry mixing and Granulation:
ii. Load the sifted materials of step - i in Rapid Mixer Granulator and mix for 10 minutes using impeller at slow speed and chopper off.
Binder Solution Preparation:
iii. Dispensed required quantity of purified water shall be divided in to two parts. Part-I contains 80% of total water and Part-II contains remaining water.
iv. Dissolve Hydroxypropylcellulose in purified water (Part-I from step iii) under stirring and stirring was continuous for up to clear solution obtained.
v. Granulate step-ii dry mix by using step-iv binder solution and with Part-II water in step-iii rinse the binder solution vessel and add to the wet mass by the following granulation parameters.

Drying
vi. Unload the wet mass from RMG and mill through co-mill fitted with suitable screen at slow speed.
vii. Dry the granules at inlet temperature of 55°C ± 10°C in FBD until the required LOD achived.
Sizing and Milling
viii. Sift the step-vii dried granules through sieve #30 ASTM (600µm).
ix. Mill the retentions of step-viii by using co-mill fitted with 1.0 mm screen at slow to medium speed and sift through sieve #30 ASTM (600µm). Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve # 30 ASTM (600 µm).
Sifting of extra-granular material
x. Sift Crospovidone XL and Microcrystalline cellulose 102 through sieve #40 ASTM (420 µm).
xi. Sift Magnesium stearate through sieve #60 ASTM (250 µm).
Blending and Lubrication
xii. Load the granules of step-ix and step-x materials in blender and mix for 10 minutes at slow speed.
xiii. Add pre sifted magnesium stearate of step-xi to above step xii material and mix for 5 minutes at slow speed.
Layer – II:
Manufacturing Process for Metformin Hydrochloride (Extended Release) Portion:
Milling & Sifting:
i. Mill the Metformin Hydrochloride through multi-mill with 2.0 mm screen at fast speed with impact forward and sift the material through sieve # 20 ASTM.
ii. Co-sift Metformin Hydrochloride, Hydroxypropyl Methyl cellulose K100M CR, Hydroxypropyl Methyl cellulose K200M CR and Microcrystalline cellulose through sieve # 20 ASTM and collect in double lined polybag.
iii. Again co-sift materials of step-ii through sieve # 20 ASTM and collect in double lined polybag.
Dry Mixing:
iv. Load the sifted materials of step-iii in Rapid Mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Binder Preparation and Granulation:
v. Dissolve Polyvinyl pyrrolidone K-90 in Isopropyl Alcohol under stirring and continue stirring until it forms clear solution.
vi. Granulate step-iv dry mix by using step-v binder solution with the suitable granulation parameters.
Milling
vii. Unload the wet mass through co-mill fitted with 8.0 mm screen at fast speed.
Drying
viii. Load the contents of step-vii in FBD and dry the granules initially for 15 minutes at inlet temperature of 25°C ± 5°C and then at inlet temperature of 50°C ± 10°C until the LOD of the granules reaches less than 1.5 % w/w at 105°C (Auto mode) using IR moisture balance.
Sizing, Milling and Blending
ix. Sift the step-viii dried granules through sieve #20 and collect the retains and undersize granules separately.
x. Mill the retentions (oversized granules) of step ix using co-mill fitted with 2.0 mm screen at medium speed and sift through sieve #20 ASTM.
xi. Mill the retentions of step-x by using co-mill fitted with 2.0 mm screen at medium speed and sift through sieve #20 ASTM. Continue this to mill the granules with 2.0 mm screen until all the material passes through sieve #20 ASTM and collect in double lined polybag.
Sifting of extra-granular material
xii. Sift Magnesium stearate through sieve #60 ASTM.
Blending and Lubrication
xiii. Load the granules of step-ix, step-x, step-xi and step-xii in blender and blend for 5 minutes at slow speed.
Bilayer Compression
i. Compress the lubricated blend of Layer-II (Metformin Portion) and lubricated blend of Layer - I (Empagliflozin and Sitagliptin Portion) into bilayer tablets with suitable punches and Parameters.

Example 2:

S.No. Ingredients Qty per Unit (mg)
10 mg / 100 mg % w/w 25 mg / 100 mg % w/w
1. Empagliflozin 10.00 3.33 25.00 8.33
2. Sitagliptin Phosphate monohydrate 128.50 42.83 128.50 42.83
3. Micro Crystalline Cellulose PH 101 69.50 23.17 54.50 16.17
4. Croscarmellose Sodium 12.00 4.00 12.00 4.00
Binder Solution
5. Copovidone 12.00 4.00 12.00 4.00
7. Purified water Qs -- Qs --
Extra granular
8. Croscarmellose sodium 12.00 4.00 12.00 4.00
9. Micro Crystalline Cellulose PH 102 50.00 16.67 50.00 16.67
10. Magnesium stearate 6.00 2.00 6.00 2.00
Core Tablet Weight (mg) 300.00 100.00 300.00 100.00
Film Coating
11. Opadry yellow 9.00 3.00 -- --
12. Opadry Pink -- -- 9.00 3.00
13. Purified water Qs -- Qs --
Coated Tablet Weight (mg) 309.00 -- 309.00

Manufacturing Procedure (Wet granulation):

Sifting
i. Co-sift Empagliflozin, Sitagliptin phosphate monohydrate, Microcrystalline Cellulose PH 101, Croscarmellose sodium through sieve # 40 ASTM.
Dry mixing and Granulation
ii. Load the sifted materials of step-i in Rapid Mixer Granulator and mix for 10 minutes using impeller at slow speed and chopper off.

Binder Solution Preparation
iii. Dispensed required quantity of purified water shall be divided in to two parts. Part-I contains 80% of total water and Part-II contains remaining water.
iv. Dissolve Copovidone in purified water (Part-I from step iii) under stirring and stirring was continuous for up to clear solution obtained.
v. Granulate step-ii dry mix by using step-iv binder solution and with Part-II water in step-iii rinse the binder solution vessel and add to the wet mass by the following granulation parameters.

Drying

vi. Unload the wet mass from RMG and mill through co-mill fitted with suitable screen at slow speed.
vii. Dry the granules at inlet temperature of 55°C ± 10°C in FBD until the required LOD achived.
Sizing and Milling

viii. Sift the step-vii dried granules through sieve #30 ASTM (600 µm).
ix. Mill the retentions of step-viii by using co-mill fitted with 1.0 mm screen at slow to medium speed and sift through sieve #30 ASTM (600µm). Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve # 30 ASTM (600 µm).
Sifting of extra-granular material

x. Sift Croscarmellose sodium and Microcrystalline cellulose 102 through sieve #40 ASTM (420 µm).
xi. Sift Magnesium stearate through sieve #60 ASTM (250 µm).
Blending and Lubrication

xii. Load the granules of step-ix and step-x materials in blender and mix for 10 minutes at slow speed.
xiii. Add pre sifted magnesium stearate of step-xi to above step xii material and mix for 5 minutes at slow speed.
Compression

xiv. Compress the above blend with suitable tooling.

Film Coating

Coat the tablets of step 10 with film coating material.
,CLAIMS:1) A bilayer tablet composition comprising a combination of SLGT2 inhibitor or its salts, DPP-IV inhibitor or its salts optionally comprising of any other anti-diabetic agent or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

2) The bilayer tablet composition as claimed in claim 1, where in the SGLT2 inhibitor is Empagliflozin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

3) The bilayer tablet composition as claimed in claim 1, where in the DPP-IV inhibitor is Dapagliflozin or Sitagliptin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

4) The bilayer tablet composition as claimed in claim 1, where in another diabetic agent is Metformin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

5) The bilayer tablet composition as claimed in claim 1, where in Empagliflozin is present in the composition from 02-25% from the total weight of the composition.

6) The bilayer tablet composition as claimed in claim 1, where in Sitagliptin is present in the composition from 30-75% from the total weight of the composition.

7) The bilayer tablet composition as claimed in claim 1, where in Metformin is present in the composition from 50-85% from the total weight of the composition.

8) The bilayer tablet composition as claimed in claim 1, wherein Empagliflozin and Sitagliptin are present in the immediate-release layer and Metformin is present in the extended-release layer.

9) The bilayer tablet composition as claimed in claim 1, wherein the formulation is prepared by wet granulation method.