OR SALT THEREOF

CASE REFERENCE

The present application has been made combining two Indian Application Nos. 201721012521 dated April 7, 2017 and 201721012522 dated April 7, 2017.

FIELD OF THE INVENTION

The present invention relates to effervescent compositions comprising Saxagliptin or salt thereof optionally in combination with metformin for the treatment of type 2 diabetes.

BACKGROUND OF THE INVENTION

Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar level. Common symptoms include increased thirst, frequent urination, increased hunger, feeling tired and sores that do not heal.

Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure and poor blood flow in the limbs which may lead to amputations.

Type 2 diabetes primarily occurs as a result of obesity and lack of exercise. Some people are more genetically at risk than others. Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to diabetes mellitus type 1 and gestational diabetes. Type 2 diabetes is typically a chronic disease associated with a ten-year-shorter life expectancy.

Blood sugars levels in Type 2 diabetes can be controlled by proper exercise and nutrition. If blood sugar level not controlled on exercise and nutrition, there are several anti-diabetic medications available. The anti-diabetic agent includes dipeptidyl peptidase 4 inhibitors, non-sulfonylureas, alpha-glucosidase inhibitors, amylin analogs, incretin mimetics, insulin, meglitinides, SGLT-2 inhibitors and thiazolidinediones.

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of oral drugs for the treatment of type 2 diabetes. They inhibit the breakdown of glucagon-like peptide- 1 (GLP- 1) and increase the incretin effect in patients with type 2 diabetes. In clinical practice they are associated with significant reductions in HbAi _c (glycated haemoglobin), no weight gain and a low risk of hypoglycemia.

The different dipeptidyl peptidase-4 (DPP-4) inhibitors are saxagliptin, sitagliptin, linagliptin, alogliptin and like.

Saxagliptin is anti-diabetic drug of dipeptidyl peptidase-4 inhibitor class. Chemically Saxagliptin is (l S,3S,5S)-2- ((2S)-2-Amino-2-(3-hydroxyadamantan- l-yl) acetyl)-2- azabicyclo [3.1.0] hexane-3-carbonitrile and its molecular weight is 315.41. Its empirical formula is C18H25 3O2. Saxagli tin is represented by compound of structural formula I

Formula I

Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in ethanol, acetonitrile, isopropyl alcohol, methanol, acetone and polyethylene glycol 400. The non-sulfonylureas (Biguanides) are anti-hyperglycemic agent used in the treatment of type 2 diabetes. Different biguanides include metformin, phenformin and buformin. Buformin and Phenformin both are withdrawn from the market due to toxic effects. Metformin is widely used in the treatment of diabetes mellitus type 2.

Metformin hydrochloride is a biguanide anti-hyperglycemic agent used for treating non- insulin-dependent diabetes mellitus. Chemically Metformin hydrochloride is N, N- dimethylimidodicarbonimidic diamide hydrochloride and its molecular weight is 165.63. Its empirical formula is C4H11N5 · HC1. Metformin hydrochloride is represented by compound of structural formula II

Νγ ^Ν γ ^ΝΗ ί

NH M

Formula II

Metformin hydrochloride is a white to off-white crystalline powder. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol and is practically insoluble in ether, acetone and chloroform.

Saxagliptin hydrochloride tablets has been approved in USA as on July 31 , 2009 under the trade name Onglyza ^® and is available in the strength of 2.5mg and 5mg. The product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.

Combination of Saxagliptin hydrochloride and metformin hydrochloride extended release tablet has been approved in USA as on Nov 5, 2010 under the trade name Kombiglyze ^® XR and is available in the strength of 5mg;500mg; 5mg;lgm and 2.5mg; lgm. The product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both Saxagliptin and metformin is appropriate. The Chinese Patent Publication No. CN102379869A discloses novel oral formulation of Saxagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said oral formulation is a tablet, capsule, dispersible tablets, chewable tablets, pills, granules, dry suspension, orally disintegrating tablets, soft capsules, buccal tablets, effervescent tablets, oral solutions, oral suspensions, drops, sustained release formulations or controlled release formulations, for the treatment of diabetes or related diseases. The invention of this Chinese Patent Publication CN102379869A was particularly directed towards dispersible composition of Saxagliptin or salt thereof. This patent publication generically discloses wide variety of dosage forms including effervescent tablets; however, it does not teach about technology, composition, method of manufacturing or need of developing the effervescent composition of Saxagliptin or salt thereof.

The PCT Publication No. WO2015040460 discloses stable effervescent tablet, granule or powder composition free from sodium introduced by the effervescing couple, comprising an effective amount of antidiabetic compound metformin.

The PCT Publication No. WO2014191806 discloses delayed-release pharmaceutical composition, comprising: an effervescent tablet, granule, or powder and effective amount of metformin as active ingredient.

The PCT Publication No. WO20131 15745 discloses effervescent composition comprising Voglibose and metformin hydrochloride.

Currently, the commercially marketed product of Saxagliptin for the treatment of type 2 diabetes is available in the form of conventional immediate release tablet. The commercially marketed product of Saxagliptin or salt thereof as well as products known in the prior art suffer from several drawbacks in terms of bioavailability and in terms of release of active ingredient from the dosage form. Also, they have several adverse effects such as upper respiratory tract infection, urinary tract infection, headache, hypersensitivity reactions including anaphylaxis, angioedema and exfoliative skin conditions, acute pancreatitis, Severe and disabling arthralgia.

According to the Biopharmaceutical Classification System (BCS), Saxagliptin is classified as BCS Class 3 drug which is high soluble and low permeable. The intrinsic membrane permeability of Saxagliptin is very low; therefore, absorption is limited by the permeation rate. Due to its low permeability 75% of Saxagliptin is absorbed and the oral systemic bioavailability is only 50% compared to intravenous administration.

Thus, there is an unmet need in the art to provide a composition which provides more permeation of Saxagliptin through gastrointestinal membrane and efficient release of Saxagliptin through the dosage form.

OBJECTS OF THE INVENTION

Accordingly, it is an object of the present invention to provide effervescent compositions comprising Saxagliptin or salt thereof which allow more permeation of Saxagliptin through gastrointestinal membrane and efficient release of Saxagliptin or salt thereof through the dosage form.

It is another object of the present invention to provide effervescent compositions which results in better patient compliance in the treatment of type 2 diabetes with less adverse effects.

It is a further object of the present invention to provide effervescent compositions comprising Saxagliptin or salt thereof, optionally in combination with metformin in the treatment of type 2 diabetes patient whose diabetes is not controlled on Saxagliptin monotherapy. It is yet another object of the present invention to provide a method for treating type 2 diabetes involving administration of the effervescent compositions comprising Saxagliptin or salt thereof. It is yet a further object of the present invention to provide a method for treating type 2 diabetes involving administration of the effervescent compositions comprising Saxagliptin or salt thereof and metformin whose diabetes is not controlled on Saxagliptin monotherapy. SUMMARY OF THE INVENTION

A first aspect of the present invention is to provide effervescent compositions comprising Saxagliptin or salt thereof.

In another aspect of the present invention is to provide effervescent compositions comprising Saxagliptin or salt thereof along with one or more pharmaceutically acceptable excipient.

In another aspect of the present invention is to provide effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet of Saxagliptin or salt thereof.

In another aspect of the present invention is to provide effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet of Saxagliptin or salt thereof comprising one or more pharmaceutically acceptable excipient.

In another aspect of the present invention is to provide process of manufacturing the effervescent compositions comprising Saxagliptin or salt thereof. In another aspect of the present invention is to provide effervescent compositions comprising Saxagliptin or salt thereof optionally in combination with metformin or salt thereof. In another aspect of the present invention is to provide method of treating type 2 diabetes by administering effervescent composition comprising Saxagliptin or salt thereof. In another aspect of the present invention is to provide method of treating type 2 diabetes by administering effervescent composition comprising Saxagliptin or salt thereof optionally in combination with metformin or salt thereof.

DETAIL DESCRIPTION OF THE INVENTION

The present invention relates to effervescent compositions comprising Saxagliptin or salt thereof.

The effervescent compositions of the present invention may be in the form of composition which is meant to be administered directly in to the gastrointestinal tract via oral route. The effervescent compositions of the present invention may float in the gastrointestinal tract.

The effervescent compositions of the present invention may be in the form of composition which is meant to be added into the glass of water just before administration and the drug solution or dispersion is to be consumed immediately.

The term effervescent composition according to present invention means the composition of Saxagliptin or salt thereof which upon contact with aqueous media produces carbon dioxide.

The term effervescent composition according to present invention also means the composition of Saxagliptin or salt thereof which comprises acidic agent and basic agent.

Conventional solid delivery systems of Saxagliptin or salt thereof such as tablet must be ingested with water to disintegrate the dosage form, inside the stomach it has to disintegrate into small particles and the active ingredient has to be solubilized such that it can be absorbed into the blood plasma of the patient. The disintegration and solubilization processes for solid dosage forms delay the bioavailability of the active ingredient.

The effervescent compositions of the present invention offer enhanced dissolution and absorption of saxagliptin or salt thereof resulting in increased bioavailability. According to present invention Saxagliptin or salt thereof are absorbed better from effervescent formulations as compared to dry, solid tablet formulations.

The effervescent compositions of the present invention provide quick dissolution upon contact with aqueous media, clear aqueous composition after dissolution, pleasant taste and enhanced absorption.

The effervescent compositions comprising Saxagliptin or salt thereof of the present invention may be in the form of effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet.

The effervescent compositions comprising Saxagliptin or salt thereof may contain one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, lubricant, glidant and coloring agents.

The examples of diluents include but not limited to mannitol, sorbitol, xylitol, cellulose derivatives, starch, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide or mixture thereof.

The examples of acidic agents include but not limited to citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof. Typically, the acid agent is present in the effervescent composition in an amount of about 3% to about 75% based on the total weight of the composition; preferably in an amount of about 5% to about 40%; more preferably in an amount of about 5% to about 15%. The examples of basic agents include but not limited to sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate or mixture thereof. Typically, the basic agent is present in the effervescent composition in an amount of about 5% to about 80% based on the total weight of the composition; preferably in an amount of about 20% to about 50%.

The examples of binders include but not limited to, ethyl cellulose, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch or mixture thereof. Typically, the binder is present in the effervescent composition in an amount of about 0.5% to about 30% based on the total weight of the composition; preferably in an amount of about 1% to about 10% The examples of disintegrants include but not limited to croscarmellose sodium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate or mixture thereof. Typically, the disintegrant is present in the effervescent composition in an amount of about 1% to about 20% based on the weight of the composition.

The examples of solubilizing agent or surfactant include but not limited to polyethylene glycol, polyvinylpyrrolidone, dextran, polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol or mixture thereof. Typically, the solubilizing agent is present in the effervescent composition in an amount of about 0.1% to about 20% based on the total weight of the composition.

The examples of sweeteners include but not limited to acesulfame potassium, sodium saccharin, cyclamates, sucralose or mixture thereof. Typically, sweetener is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.1% to about 2% The examples of flavor include but not limited to fruit flavor, peppermint flavor or mixture thereof. Typically, the flavor is present in the effervescent composition in an amount of about 0% to about 10% based on the total weight of the composition; preferably in an amount of about 2% to about 6%

The examples of pH regulating agent include but not limited to fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid salts or mixture thereof.

The examples of stabilizing agent include but not limited to tocopherol, cyclodextrin, tetrasodium edetate, nicotinamide or mixture thereof.

The examples of lubricant include but not limited to calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or mixture thereof. Typically, the lubricant is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.2 to about 4%

The examples of glidant include but not limited to silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate or mixture thereof. Typically, the glidant is present in the effervescent composition in an amount of about 0.1% to about 20% based on the total weight of the composition.

The examples of coloring agents include but not limited to titanium dioxide and dye suitable for food such as those known as F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika or mixture thereof. Typically, the coloring agent is present in the effervescent composition in an amount of about 0.1% to about 3.5% based on the total weight of the composition.

In another aspect of the present invention is to provide process of manufacturing the effervescent compositions comprising Saxagliptin or salt thereof. The effervescent compositions comprising Saxagliptin or salt thereof of the present invention can be manufactured by process such as direct compression, dry granulation (slugging), wet granulation, heat fusion, roller compaction and hot melt extrusion. The process of manufacturing effervescent composition comprising admixture of Saxagliptin or salt thereof, acidic agent, basic agent optionally along with one or more pharmaceutically acceptable excipient; wherein said admixture can be either filled in to the capsule, sachet; or compressed in to the unit dosage form. The compressed unit dosage form may be tablet, caplet and like.

The effervescent composition can comprise any suitable amount of the Saxagliptin or salt thereof in order to produce an effective blood level of the Saxagliptin in the type 2 diabetic patient. The weight percentage of Saxagliptin or salt thereof can be 0.05% to 90%, preferably 0.5 to 70% based on the total weight of composition. The amount of Saxagliptin or salt thereof may ranges from 0.5mg to 50mg, preferably 0.5 to 20mg, more preferably 1.25mg, 2.5mg, 5mg, 7.5mg and lOmg.

The effervescent composition of the present invention may comprise Saxagliptin base or its salt like hydrochloride, bromide, nitrate, fumarate, sulfate, maleate, citrate, trifluoroacetic acid salt, benzoate, methanesulfonate, benzene sulfonate, butenedioate, P- toluenesulfonate, phosphate, aspartate, glycinates, malonates, succinate, acetate, hemifumarate, perchlorates, arginine. The effervescent composition of the present invention preferably contains hydrochloride salt of saxagliptin. According to present invention not only the choice of acidic and basic agent affect performance but the ratio of acid to base also affects the performance of the effervescent composition of Saxagliptin or salt thereof. The ratio of acidic to basic agent according to present invention may ranges between 1 :3 to 3: 1. The acidic agents may be like citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof; more preferably acidic agents. More preferably acidic agents may be citric acid. The basic agents may be like sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate. More preferably basic agent may be sodium bicarbonate.

Acidic agent and basic agent present in the effervescent composition reacts with aqueous media; wherein acid neutralizes base with the liberation of carbon dioxide and formation of acid salt and water

The effervescent compositions comprising Saxagliptin or salt thereof of the present invention reacts with aqueous media and produces carbon dioxide by effervescent reaction. The carbon dioxide produced by effervescent reaction allows enhanced permeability of Saxagliptin or salt thereof due to an alteration of the paracellular as well as transcellular pathway. The paracellular pathway is the primary route of absorption for active ingredients in which solutes diffuse into the intercellular space between epithelial cells. The carbon dioxide produced by effervescent alters (widens) the intercellular space between cells, which leads to greater absorption of active ingredients. The effervescent compositions comprising Saxagliptin or salt thereof of the present invention also promote transcellular absorption by inducing a change in the cell membrane structure.

The effervescent compositions comprising Saxagliptin or salt thereof of the present invention shows quick disintegration and dissolution upon contact with water. The effervescent composition of the present invention when formulated as tablet has a disintegration time of about 300 seconds or less. Preferably, the disintegration time of the effervescent tablet is about 180 seconds or less and more preferably about 90 seconds or less. The disintegration time is measured in 200 ml of water at room temperature of about 25°C±5°C.

The effervescent compositions comprising Saxagliptin or salt thereof of the present invention upon dissolution has pH ranges from 3 to 6.5. The pH is measured in 200 ml of water at room temperature of about 25°C±5°C. The effervescent compositions comprising Saxagliptin or salt thereof of the present invention has pleasant taste which allows patient acceptability and better compliance in the treatment of type 2 diabetes. The effervescent compositions comprising Saxagliptin or salt thereof of the present invention can be made up of any weight with suitable quantities of Saxagliptin or salt thereof and pharmaceutically acceptable excipient.

The other physical parameters of effervescent compositions of present invention like appearance, thickness, weight variation, hardness, friability, smell, taste, after taste were found to be satisfactory.

The effervescent compositions comprising Saxagliptin or salt thereof of the present invention may contain optionally one or more therapeutic agent selected from the group consisting of analgesics, antipyretics, antihistamines, anorexics, antiasthmatics, antiflatulents, antimigraine agents, antispasmodics, decongestants, antiallergic agents, anxiolytic, hypnotics, stimulants, antibiotics, antidiabetic agents, oncolytic agents, expectorants, electrolyte preparations, laxatives, vitamins, phytopharmaceuticals, pulmonary drugs, antihypertensives, antiemetics, anti-inflammatory drugs, renal drugs, steroids, drugs for neurological disorders, anti-psychotic drugs, drugs for treating endocrine disorders, drugs for promoting immunology, drugs for treating osteoarthritis, drugs for treating glaucoma, drugs for treating allergic rhinitis, drugs for treating anemias and other hematological disorders, drugs for treating infectious diseases, drugs for insomnia, cardiovascular agents, antidiarrhoeal agents, diuretics and agents for stimulating blood flow.

Preferably one or more therapeutic agent selected from the group consisting of antidiabetic agent, wherein anti-diabetic agent is selected from the group consisting of like biguanides, insulin, long and short acting insulin analogues, sulfonylureas, DPP-IV inhibitors, SGLT2 inhibitors, 1 lbeta-hydroxysteroid dehydrogenase inhibitors, glucokinase activators, AMPK activators, alpha-glucosidase inhibitors, Glp- 1 receptor agonists, G1P receptor agonists, a glycogen phosphorylase inhibitor, an inhibitor of fatty acid binding protein, DGAT inhibitors, PPAR gamma agonists, PPAR delta agonists, and other antidiabetics derived from thiazolidinediones.

More preferably the antidiabetic agent is biguanide wherein the biguanide is a metformin or salt thereof.

Therefore, in another aspect of the present invention is to provide effervescent compositions comprising Saxagliptin or salt thereof, optionally in combination with metformin in the treatment of type 2 diabetes patient.

The high sugar levels of many type 2 diabetic patients are not controlled on saxagliptin alone; therefore, effervescent compositions comprising Saxagliptin or salt thereof in combination with metformin provides better patient compliance for patients whose diabetes is not controlled on Saxagliptin monotherapy.

The effervescent composition can comprise any suitable amount of the Saxagliptin or salt thereof or metformin or salt thereof in order to produce an effective blood level of the Saxagliptin in the type 2 diabetic patient with less adverse effect such as upper respiratory tract infection, urinary tract infection, headache, hypersensitivity reactions including anaphylaxis, angioedema and exfoliative skin conditions, acute pancreatitis, severe and disabling arthralgia.

The effervescent composition can comprise any suitable amount of the Saxagliptin or salt thereof or metformin or salt thereof; the amount of metformin or salt thereof ranges from 200mg to 2gm; preferably 250mg to 1.5gm. The amount of Saxagliptin or salt thereof ranges from 0.5mg to 50mg, preferably 0.5 to 20mg, more preferably 1.25mg, 2.5mg, 5mg, 7.5mg and lOmg.

The effervescent compositions comprising Saxagliptin or salt thereof optionally in combination with metformin or salt thereof of the present invention can be packaged in suitable air tight containers and moisture proof packs. EXAMPLES:

In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example 1:

Manufacturing Process:

1. Saxagliptin hydrochloride, citric acid, sodium bicarbonate, sodium citrate, mannitol, sucralose, polyvinyl pyrrolidone, cherry flavor and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #40.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablet using tablet compression machine. Example 2:

Manufacturing Process:

1. Saxagliptin hydrochloride, citric acid, sodium bicarbonate, sodium citrate, mannitol, sucralose, polyvinyl pyrrolidone, cherry flavor and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablet using tablet compression machine.

Example 3:

4. Sodium citrate 595

5. Mannitol 772

6. Sucralose 12.5

7. Polyvinyl pyrrolidone 62.5

8. Cherry flavor 4

9. Colloidal silicon dioxide 20

10. Magnesium stearate 19

Tablet weight 2500

Manufacturing Process:

1. Saxagliptin hydrochloride, citric acid, sodium bicarbonate, sodium citrate, mannitol, sucralose, polyvinyl pyrrolidone, cherry flavor and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #40.

3. The blend of step 1 was lubricated with part quantity magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablets at lower hardness using tablet compression machine.

5. Obtained soft tablets were milled using co-mill fitted with suitable screen.

6. Milled granules of step-5 were lubricated by mixing with remaining quantity of magnesium stearate of step -2.

7. The blend of step 6 was compressed using suitable tooling fitted to compression machine.

Example 4:

4. Sodium citrate 594

5. Mannitol 774

6. Sucralose 12.5

7. Polyvinyl pyrrolidone 62.5

8. Cherry flavor 4

9. Colloidal silicon dioxide 20

10. Magnesium stearate 19

1 1. Purified water Qs.

Tablet weight 2500

Manufacturing Process:

1. Saxagliptin hydrochloride and mannitol were sifted through ASTM #40 and mixed in a granulator.

2. Polyvinyl Pyrrolidone was dissolved in purified water to prepare a binder solution.

3. Materials from Step -1 were granulated using binder of step -2 and obtained granules were dried and milled.

4. Milled granules were mixed with citric acid, sodium citrate, sodium bicarbonate, sucralose, cherry flavor and colloidal silicon dioxide.

5. Magnesium stearate was sifted through ASTM #60.

6. The blend of step 4 was lubricated with magnesium stearate of step 5.

7. The blend of step 6 was compressed into tablet using tablet compression machine.

Example 5:

5. Sodium citrate 275

6. Mannitol 587

7. Sucralose 1 1

8. Polyvinyl pyrrolidone 37

9. Forest fruit flavor 3

10. Colloidal silicon dioxide 12

1 1. Magnesium stearate 10

Tablet weight 2000

Manufacturing Process:

1. Saxagliptin hydrochloride, Metformin hydrochloride, sodium bicarbonate, Mannitol, Sucralose, Polyvinyl pyrrolidone, forest fruit flavor and colloidal silicon dioxide were sifted through ASTM #40. Citric acid and Sodium citrate were sifted through 20# and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablet using tablet compression machine.

Example 6:

9. Forest Fruit Flavor 4

10. Colloidal Silicon Dioxide 20

11. Magnesium stearate 19

Tablet weight 2500

Manufacturing Process:

1. Metformin Hydrochloride, Saxagliptin hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinyl Pyrrolidone, Forest Fruit Flavor and colloidal silicon dioxide were sifted through ASTM #40. Citric acid and Sodium citrate were sifted through 20 # and mixed in blender.

2. Magnesium stearate was sifted through ASTM #40.

3. The blend of step 1 was lubricated with part quantity magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablets at lower hardness using tablet compression machine.

5. Obtained soft tablets were milled using co-mill fitted with suitable screen.

6. Milled granules of step-5 were lubricated by mixing with remaining quantity of magnesium stearate of step -2.

7. The blend of step 6 was compressed using suitable tooling fitted to compression machine.

Example 7:

7. Sucralose 12.5

8. Polyvinyl pyrrolidone 17

9. Forest fruit Flavor 4

10. Colloidal silicon dioxide 20

1 1. Magnesium stearate 19

12. Purified water QS

Tablet weight 2500

Manufacturing Process:

1. Metformin Hydrochloride, Saxagliptin hydrochloride and mannitol were sifted through ASTM #40 and mixed in a granulator.

2. Polyvinyl Pyrrolidone was dissolved in purified water to prepare a binder solution.

3. Materials from Step - 1 were granulated using binder of step -2 and obtained granules were dried and milled.

4. Milled granules were mixed with sifted citric acid, sodium citrate, sodium bicarbonate, sucralose, forest fruit flavour and colloidal silicon dioxide.

5. Magnesium stearate was sifted through ASTM #60.

6. The blend of step 4 was lubricated with magnesium stearate of step 5.

7. The blend of step 6 was compressed into tablet using tablet compression machine.

Example 8:

8. Polyvinyl pyrrolidone 62.5

9. Forest fruit flavor 4

10. Colloidal silicon dioxide 20

1 1. Magnesium stearate 19

Tablet weight 2500

Manufacturing Process:

1. Saxagliptin hydrochloride, Metformin Hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinyl pyrrolidone, Forest fruit flavor and colloidal silicon dioxide were sifted through ASTM #40, citric acid were sifted through 20# and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablets using tablet compression machine.

Example 9:

Manufacturing Process:

1. Saxagliptin hydrochloride, Metformin Hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinyl pyrrolidone, Forest fruit flavor and colloidal silicon dioxide were sifted through ASTM #40, citric acid were sifted through 20# and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablet using tablet compression machine. Example 10:

Manufacturing Process:

1. Metformin Hydrochloride, Saxagliptin hydrochloride, sodium bicarbonate, mannitol, sucralose, polyvinyl pyrrolidone, Forest fruit flavor and colloidal silicon dioxide were sifted through ASTM #40. Citric acid and Sodium citrate were sifted through 20 # and mixed in blender.

Sodium Benzoate was sifted through ASTM #60.

The blend of step 1 was lubricated with sodium benzoate of step 2.

The blend of step 3 was compressed into tablet using tablet compression machine

Example 11:

Manufacturing Process:

1. Saxagliptin hydrochloride, Metformin Hydrochloride, sodium bicarbonate, mannitol, sucralose, polyvinyl pyrrolidone, Forest fruit flavor and colloidal silicon dioxide were sifted through ASTM #40, citric acid were sifted through 20# and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablet using tablet compression machine. Example: 12

Manufacturing Process:

1. Saxagliptin hydrochloride dihydrate, Metformin hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinyl pyrrolidone, Forest fruit flavor and

Colloidal silicon dioxide were sifted through ASTM #40, Tartaric acid was sifted through #20 and mixed.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablets using tablet compression machine. Example: 13

Manufacturing Process:

1. Metformin hydrochloride, Saxagliptin hydrochloride dihydrate, Sodium bicarbonate, Mannitol, Sucralose, Polyvinyl pyrrolidone, Forest fruit flavor and

Colloidal silicon dioxide were sifted through ASTM #40. Citric acid and Sodium citrate were sifted through #20 and mixed.

2. Sodium stearyl fumarate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with Sodium benzoate of step 2.

4. The blend of step 3 was compressed into tablet using tablet compression machine.