DESC:The present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its pharmaceutically acceptable salt thereof combination with Metformin or its salt with stabilizing agent and one or more pharmaceutically acceptable excipients, where in the composition is used for the treatment of type-2 diabetes.

The present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its pharmaceutically acceptable salt thereof combination with Metformin or its salt, where in the Linagliptin is incorporated in to intragranular portion with stabilizing agent.

The present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its pharmaceutically acceptable salt thereof combination with Metformin or its pharmaceutically acceptable salt, where in the Metformin layer contain release rate polymer and one or more pharmaceutically acceptable excipients.

The present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its salt combination with Metformin or its salt, where in Metformin or its salt present in an amount of about 1% -90% w/w, Linagliptin or its pharmaceutical acceptable salt in an amount of about 5-15% based on the total weight of the composition.
The term "pharmaceutical acceptable excipient" as used herein refers to additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms which are suitable for administration to patients. Suitable excipients include diluents, binders, disintegrant, surfactants, lubricants, glidants, stabilizing agent and coloring agents and the like or mixture thereof and optionally a pharmaceutical acceptable excipient.

The term “composition” or “pharmaceutical composition” or “solid dosage forms” such as granules, pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term “pharmaceutically acceptable salts” as used herein refers to when the exemplary compounds contain an acidic group as well as a basic group, the compounds can form internal salts, which can also be used in the compositions and methods described herein. When an exemplary compound contains a hydrogen-donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the exemplary compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth, incorporated herein by reference. Physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term “Linagliptin” as used herein means Linagliptin or its pharmaceutically acceptable salts. Linagliptin may be in amorphous form, crystalline form, a mixture thereof or co-crystals with suitable co-formers. Preferably, Linagliptin base is in crystalline anhydrous form A.

The term “Metformin” as used herein means Metformin or its pharmaceutically acceptable salts. Metformin may be in amorphous form, crystalline form, a mixture thereof or co-crystals with suitable co-formers. Preferably, Metformin HCL.

Throughout this specification, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

The term “impurity” or “impurities,” as used herein, means those impurities specifically described herein, those derived from the process including reagents or solvents used in the process, intermediates used in the process or degradants including degradants of the compound synthesized in the process.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a tablet, capsule, syrups, suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising active ingredient and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The terms “treat” and “treating” as used herein refers are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising active ingredient or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

Suitable diluent may comprise but not limited to micro crystalline cellulose, starch, colloidal silicon dioxide, pregelatinized starch, calcium carbonate, dibasic, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, calcium phosphate, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, maltodextrin and mixtures thereof.

Suitable lubricants/glidants may comprise but not limited to magnesium stearate, colloidal silicon dioxide, aluminum silicate, sodium stearyl fumarate, colloidal silicon dioxide, stearic acid, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, starch, sodium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, fatty acid, fumaric acid, glyseryl palmito sulphate and/or combinations thereof. Further, the amount of lubricant is preferably in the range of 0.01% w/w to 20% w/w by weight of the composition.

Suitable binders include, but are not limited to acacia, alginic acid, agar, calcium carrageenan, dextrin, gelatin, liquid glucose, gum, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose (HPMC), ethyl cellulose, pectin, polyethylene glycol, povidone, Polysorbate 80, starch, pregelatinized starch and/or combinations thereof. Further, the amount of binder is preferably in the range of 0.5% w/w to 50% w/w by weight of the composition.

Suitable disintegrants/ Wetting agent include but are not limited to sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, Sorbitan monooleate, Span 80, Polysorbate, calcium and sodium carboxymethylcellulose, pregelatinized starch, magnesium trisilicate, cornstarch, potato starch and/or combinations thereof. Further, the amount of disintegrant is preferably in the range of 1% w/w to 25% w/w by weight of the composition.

Suitable surfactants include but are not limited to Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and mixtures thereof.

Suitable stabilizing agent include but are not limited to alkaline salts of metals which may be organic or inorganic source also includes basic amino acids and their derivatives more preferably L-arginine, L-lysine or L-histigine, Meglumine. A preferred stabilizing agent within the meaning of this invention is Meglumine.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its pharmaceutically acceptable salt thereof combination with Metformin or its salt with stabilizing agent and one or more pharmaceutically acceptable excipients, where in the composition is used for the treatment of type-2 diabetes.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its pharmaceutically acceptable salt thereof combination with Metformin or its salt, where in the Linagliptin is incorporated in to intragranular portion with stabilizing agent.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its pharmaceutically acceptable salt thereof combination with Metformin or its pharmaceutically acceptable salt, where in the Metformin layer contain release rate polymer and one or more pharmaceutically acceptable excipients.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition comprising Linagliptin or its salt combination with Metformin or its salt, where in Metformin or its salt present in an amount of about 1% -90% w/w, Linagliptin or its pharmaceutical acceptable salt in an amount of about 5-15% based on the total weight of the composition.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition comprising nucleophilic and/or basic agent, which is sufficient for stabilizing oral composition of Linagliptin, wherein the nucleophilic and/or basic agent are selected from the group L-arginine, Meglumine, L-lysine or L-histigine along with one or more pharmaceutically acceptable excipients.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition comprising the pharmaceutically acceptable excipients are selected from diluents, binders, disintegrant, surfactants, lubricants, glidants, stabilizing agent and coloring agents and the like or mixture thereof and optionally one or more pharmaceutical acceptable excipient.
In one of the embodiment of the present invention relates to an extended release pharmaceutical composition comprising the Linagliptin and Metformin or its pharmaceutically acceptable salts is prepared by granulation technique; preferably wet granulation, fluid bed technique.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition of Metformin or its salts and immediate release pharmaceutical composition of Linagliptin tablet dosage form.

In one of the embodiment of the present invention relates to an extended release pharmaceutical composition the excipients are selected from hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, micro crystalline cellulose, Meglumine, corn starch, mannitol, pre-gelatinized starch, magnesium stearate.

In one of the embodiment of the present invention relates to a pharmaceutical oral dosage form comprising Metformin or its salts and Linagliptin or its salts contain dissolution data shows 95% of drug release within 30-40 min for Linagliptin contain medium 0.1 N HCL, volume 900ml and RPM 50.

In one of the embodiment of the present invention is relating to preparation of oral pharmaceutical compositions, wherein the method of manufacturing comprises sift milled Metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and Microcrystalline cellulose by dry mix the above mixture and prepare the binder solution by dissolve polyvinyl pyrrolidone Isopropyl alcohol under stirring and granulate the above mixture in to this, prepare the Linagliptin layer by sift Linagliptin, Meglumine, and corn starch and prepare the binder solution by dissolve hydroxypropylmethyl cellulose in purified water and granulate the above step and sizing and milling the above mixture, perform blending and lubrication and compress the both Metformin and Linagliptin layer in to tablets.

Comparative multimedia dissolution profiles of reference product Vs test product:
Table 1: Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCL for Linagliptin.
Product name Reference product
Ondero Met (Linagliptin metformin HCl tablets) 2.5mg/1000mg Test product
Linagliptin metformin HCl tablets) 2.5mg/1000mg
Batch number 1080604 LIMT15-0169-005
Condition Time % Drug Release
Medium: 0.1N HCL 05 Min 39 46
10 Min 71 82
15 Min 94 93
20 Min 98 93
30 Min 98 93

Figure 1. Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCl for Linagliptin.

Table 2: Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCl for Metformin.
Product name Reference product
Ondero Met (Linagliptin metformin HCl tablets) 2.5mg/1000mg Test product
Linagliptin metformin HCl tablets) 2.5mg/1000mg
Batch number 1080604 LIMT15-0169-005
Condition Time % Drug Release
Medium: 0.1N HCl 05 Min 44 45
10 Min 78 83
15 Min 95 97
20 Min 101 98
30 Min 104 99
45 Min 108 100

Figure 2. Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCl for Metformin.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1:
Manufacturing Formula:
S.
No. Ingredients Qty. per Unit (mg) % w/w
2.5 mg / 1000 mg 5 mg / 1000 mg
Metformin Hydrochloride
Extended Release Layer
Intra granular agents
1. Metformin HCl 1000 1000 62.50
2. Hydroxypropylmethyl cellulose K100M CR 120 120 7.50
3. Hydroxypropylmethyl cellulose K200M CR 190 190 11.88
4. Polyvinyl pyrrolidone K-90 35 35 2.19
5. Micro Crystalline Cellulose 12 12 0.75
Binder solution
6. Polyvinyl pyrrolidone K-90 30 30 1.88
7. Iso Propyl Alcohol q.s. q.s.
Extra granular agents
8. Magnesium Stearate 13 13 0.81
Metformin Hydrochloride ER Tablet weight (mg) 1400 1400
Linagliptin Immediate Release layer
Intra granular agents
9. Linagliptin 2.5 5 0.16-0.31
10. Meglumine 10 20 0.63
11. Corn Starch 15 15 0.94
12. Mannitol 149.4 136.9 8.56-9.34
Binder solution
13. Hydroxypropylmethyl cellulose E3 6 6 0.38
14. Purified Water q.s. q.s. q.s.
Extra granular agents
15. Pregelatinised Starch 14 14 0.88
16. Sunset Yellow 0.1 - 0.01
17. Erythrosine Lake - 0.1 0.01
18. Magnesium Stearate 3 3 0.19
Linagliptin IR Tablet Weight (mg) 200 200 ---
Total core tablet weight (mg) 1600 1600 100.00
Film Coating $ (2.5% weight build up)
19. Opadry II Yellow 40 -- 2.50
20. Opadry II Pink -- 40 2.50
21. Purified water q.s. q.s. q.s.
Coated Tablet Weight (mg) 1640 1640 --

Brief Manufacturing Procedure:
Metformin HCl Layer:
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, Hydroxypropylmethyl cellulose K100M CR, Hydroxypropylmethyl cellulose K200M CR, Polyvinyl pyrrolidone K-90 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 Iso Propyl 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 following granulation parameters.
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 air dry the granules initially for 15 minutes at inlet temperature of 25°C ± 5°C and then dry at inlet temperature of 50°C ± 10°C until the LOD of the granules reaches 1.5 – 2.5 % 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 1.0 mm screen at medium speed and sift through sieve #20 ASTM. Continue this to mill the granules with 1.0 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, x and xi in blender and blend for 10 minutes at slow speed.
xiv. Load Magnesium Stearate of step-xii to the step xiii and blend for 5 minutes at slow speed and collect in double lined polybag.
Linagliptin Layer:
Milling & Sifting:
xv. Co-sift Linagliptin, Meglumine, and Corn Starch through sieve # 30 ASTM.
xvi. Co-sift contents of step xv with Mannitol through sieve # 30 ASTM.
Dry mixing
xvii. Load the sifted materials of step xvi in rapid mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Binder Preparation and Granulation:
xviii. Dissolve Hydroxypropylmethyl cellulose E3 in Purified Water under stirring and continue stirring until a clear solution is formed.
xix. Granulate step xvii dry mix with prepared binder solution of step no. xviii by the following granulation parameters.
Note: Granulation parameters may change accordingly with the batch size to equipment.
Wet milling:
xx. Unload the wet mass of step-xix from RMG and mill through co-mill fitted with 8.0 mm screen at high speed.
Drying
xxi. Load the contents of step xx in FBD and dry the granules at inlet temperature of 50°C ± 10°C until the LOD of the granules reaches 2.0 – 3.0 % w/w at 105°C (Auto mode) using IR moisture balance.

Sizing and Milling
xxii. Sift the dried granules of step xxi through sieve #30 ASTM and collect in double lined polybag.
xxiii. Mill the retentions of step-xxii by using co-mill fitted with 1.0 mm screen at medium speed and sift through sieve #30 ASTM. Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve #30 ASTM and collect in double lined polybag.
Sifting of extra-granular material
xxiv. Co-Sift Pre-gelatinized Starch and Sunset Yellow or Erythrosine Lake through sieve # 30 ASTM.
xxv. Sift Magnesium Stearate through sieve #60 ASTM.
Blending and Lubrication
xxvi. Load the sifted materials of step xxii, step xxiii and step xxiv in to blender and mix for 10 minutes at slow speed.
xxvii. Add step xxv of sifted Magnesium Stearate to step xxvi and mix for 5 minutes at slow speed and collect in doubled lined polybag.
Compression
xxviii. Compress the lubricated blend of step xv (Metformin Layer) and step xxvii (Linagliptin layer) with the suitable parameters.
Film Coating:
xxix. Weigh required quantity of purified water in a stainless steel vessel.
xxx. Disperse Opadry in step xxix (15% w/w solids) under stirring and continue stirring for 45 minutes to form uniform dispersion.
xxxi. Load the core tablets of step xxviii (Compressed tablets) in coating pan and pre-warm for 10 minutes at product temperature 30° - 50° C and check the pre warmed tablet weights.
Coat the tablets for 2.5 ± 1% w/w by using coating dispersion of step xxx, under continuous stirring with suitable coating parameters. After achieving the desired weight gain, dry the coated tablets for 10 minutes with product temperature of 30° - 50° C.
Example 2:
Manufacturing Formula:
S.
No. Ingredients Qty. per Unit (mg) % w/w
2.5 mg / 1000 mg 5 mg / 1000 mg
Metformin Hydrochloride Extended Release Layer
Intra granular agents
1. Metformin HCl 1000 1000 61.73
2. Hydroxypropylmethyl cellulose E5 25.7 25.7 1.59
Binder solution
3. Hydroxypropylmethyl cellulose E5 9.3 9.3 0.57
4. Purified Water q.s. q.s.
Extra granular agents
5. Poly Ethylene Oxide (Polyox WSR 303) 370 370 22.84
6. Magnesium Stearate 14 15 0.93
Metformin Hydrochloride ER Tablet weight (mg) 1420 1420
Linagliptin Immediate Release layer
Intra granular agents
7. Linagliptin 2.5 5 0.15-0.31
8. Meglumine 10 20 0.62
9. Corn Starch 15 15 0.93
10. Mannitol 149.4 136.9 8.45-9.22
Binder solution
11. Hydroxypropylmethyl cellulose E3 6 6 0.37
12. Purified Water q.s. q.s. q.s.
Extra granular agents
13. Pregelatinised Starch 14 14 0.86
14. Sunset Yellow 0.1 - 0.01
15. Erythrosine Lake - 0.1 0.01
16. Magnesium Stearate 3 3 0.19
Linagliptin IR Tablet Weight (mg) 200 200 ---
Total core tablet weight (mg) 1620 1620 100.00
Film Coating $ (2.5% weight build up)
17. Opadry II Yellow 40.5 -- 2.50
18. Opadry II Pink -- 40.5 2.50
19. Purified water q.s. q.s. q.s.
Coated Tablet Weight (mg) 1660.5 1660.5 --
Metformin HCl Layer:
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, Hydroxypropylmethyl cellulose E5 through sieve # 20 ASTM and collect in double lined polybag.
Dry Mixing:
iii. Load the sifted materials of step ii in Rapid Mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Binder Preparation and Granulation:
iv. Dissolve Hydroxypropylmethyl cellulose E5 in Purified Water under stirring and continue stirring until it forms clear solution.
v. Granulate step iii dry mix by using step iv binder solution with the following granulation parameters.
vi. Unload the wet mass through co-mill fitted with 8.0 mm screen at fast speed.
Drying
vii. Load the contents of step vi in FBD and air dry the granules initially for 15 minutes at inlet temperature of 25°C ± 5°C and then dry at inlet temperature of 50°C ± 10°C until the LOD of the granules reaches 1.5 – 2.5 % w/w at 105°C (Auto mode) using IR moisture balance.
Sizing, Milling and blending
viii. Sift the step vii dried granules through sieve #20 and collect the retains and undersize granules separately.
ix. Mill the retentions (oversized granules) of step viii using co-mill fitted with 2.0 mm screen at medium speed and sift through sieve #20 ASTM.
x. Mill the retentions of step ix by using co-mill fitted with 1.0 mm screen at medium speed and sift through sieve #20 ASTM. Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve #20 ASTM and collect in double lined polybag.
Sifting of extra-granular material
xi. Sift Poly Ethylene Oxide (Polyox WSR 303) through sieve #20 ASTM.
xii. Sift Magnesium Stearate through sieve #60 ASTM.
Blending and Lubrication
xiii. Load the granules of step viii, ix, x and xi in blender and blend for 10 minutes at slow speed.
xiv. Load Magnesium Stearate of step-xii to the step xiii and blend for 5 minutes at slow speed and collect in double lined polybag.
Linagliptin Layer:
Milling & Sifting:
xv. Co-sift Linagliptin, Meglumine, and Corn Starch through sieve # 30 ASTM.
xvi. Co-sift contents of step xv with Mannitol through sieve # 30 ASTM.
Dry mixing
xvii. Load the sifted materials of step xvi in rapid mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Binder Preparation and Granulation:
xviii. Dissolve Hydroxypropylmethyl cellulose E3 in Purified Water under stirring and continue stirring until a clear solution is formed.
xix. Granulate step xvii dry mix with prepared binder solution of step no. xviii by the following granulation parameters.
Note: Granulation parameters may change accordingly with the batch size to equipment.
Wet milling:
xx. Unload the wet mass of step-xix from RMG and mill through co-mill fitted with 8.0 mm screen at high speed.
Drying
xxi. Load the contents of step xx in FBD and dry the granules at inlet temperature of 50°C ± 10°C until the LOD of the granules reaches 2.0 – 3.0 % w/w at 105°C (Auto mode) using IR moisture balance.
Sizing and Milling
xxii. Sift the dried granules of step xxi through sieve #30 ASTM and collect in double lined polybag.
xxiii. Mill the retentions of step-xxii by using co-mill fitted with 1.0 mm screen at medium speed and sift through sieve #30 ASTM. Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve #30 ASTM and collect in double lined polybag.
Sifting of extra-granular material
xxiv. Co-Sift Pre gelatinized Starch and Sunset Yellow or Erythrosine Lake through sieve # 30 ASTM.
xxv. Sift Magnesium Stearate through sieve #60 ASTM.
Blending and Lubrication
xxvi. Load the sifted materials of step xxii, step xxiii and step xxiv in to blender and mix for 10 minutes at slow speed.
xxvii. Add step xxv of sifted Magnesium Stearate to step xxvi and mix for 5 minutes at slow speed and collect in doubled lined polybag.
Compression
xxviii. Compress the lubricated blend of step xv (Metformin Layer) and step xxvii (Linagliptin layer) with the suitable parameters.
Film Coating:
xxix. Weigh required quantity of purified water in a stainless steel vessel.
xxx. Disperse Opadry in step xxix (15% w/w solids) under stirring and continue stirring for 45 minutes to form uniform dispersion.
xxxi. Load the core tablets of step xxviii (Compressed tablets) in coating pan and pre-warm for 10 minutes at product temperature 30° - 50° C and check the pre warmed tablet weights.
,CLAIMS:1) An extended release pharmaceutical composition comprising Linagliptin or its salts in combination with Metformin or its salt with stabilizing agent and one or more pharmaceutically acceptable excipients.

2) The extended release pharmaceutical composition as claimed in claim 1, where in the Linagliptin is incorporated in to intra-granular portion with stabilizing agent.

3) The extended release pharmaceutical composition as claimed in claim 1, where in the Metformin layer comprises of release rate polymer and one or more pharmaceutically acceptable excipients.

4) The extended release pharmaceutical composition as claimed in claim 1, where in the Linagliptin is in the form of Immediate release dosage form and Metformin is in the form of Extended release dosage form.

5) The extended release pharmaceutical composition as claimed in claim 1, where in the Linagliptin or its pharmaceutical acceptable salt in an amount of about 5-15% w/w, Metformin or its pharmaceutical acceptable salt present in an amount of about 1% -90% w/w based on the total weight of the composition.

6) The extended release pharmaceutical composition as claimed in claim 1, where in the nucleophilic and/or basic agent are selected from the group L-arginine, meglumine, L-lysine or L-histigine along with one or more pharmaceutically acceptable excipients.

7) The extended release pharmaceutical composition as claimed in claim 1, where in the release rate polymer are selected from the group hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, hydroxyl propyl cellulose.

8) The extended release pharmaceutical composition as claimed in claim 1, where in the composition is prepared by granulation technique; preferably wet granulation, fluid bed technique.

9) The process for preparation of extended release pharmaceutical composition as claimed in claim 1, wherein the method of manufacturing comprises
a) sift milled Metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and Microcrystalline cellulose by dry mix the above mixture and prepare the binder solution by dissolve polyvinyl pyrrolidone Isopropyl alcohol under stirring and granulate the above mixture in to this,
b) prepare the Linagliptin layer by sift Linagliptin, meglumine, and corn starch and prepare the binder solution by dissolve hydroxypropylmethyl cellulose in purified water and granulate the above step and sizing and milling the above mixture,
c) perform blending and lubrication and compress the both Metformin and Linagliptin layer in to tablets with the suitable parameters.