DESC:According to the embodiments of the present invention relates to the oral pharmaceutical compositions comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, with one or more pharmaceutically acceptable excipients.
The present invention relates to the oral pharmaceutical compositions comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, wherein the Metformin is in the form of immediate release or extended release dosage form.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Linagliptin is incorporated in to the binder solution with binder and stabilizing agent and one are more pharmaceutically acceptable salts.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, one or more pharmaceutically acceptable excipients is free of magnesium stearate.

The present invention relates to a solid oral pharmaceutical composition comprising the pharmaceutically acceptable excipients is selected from diluents, binders, disintegrant, surfactants, lubricants, glidants and coloring agents and the like or mixture thereof and optionally a pharmaceutical acceptable excipient.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Metformin is in the form of immediate release or extended release, where in the lubricant is Calcium Stearate.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the composition is in the form of immediate release or extended release oral dosage form.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Linagliptin may be incorporated in to binder solution.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Linagliptin may be incorporated in to coating layer.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the intragranular portion contain Metformin alone devoid of any other pharmaceutically acceptable excipients.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the pharmaceutical composition is a bilayer tablet composition.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the pharmaceutical composition is a mono layer tablet composition.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the formulation is prepared by wet granulation fluid bed process.
The present invention relates to a solid oral pharmaceutical composition is in the form of immediate release tablet dosage form.

The present invention relates to a solid oral pharmaceutical composition is in the form of extended release tablet dosage form.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Dapagliflozin is used in the percentage from 0.1-90%, specifically 0.1-70% and more specifically 0.1-25% from total weight of the concentration.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Linagliptin is used in the percentage from 0.1-90%, specifically 0.1-70% and more specifically 0.1-25% from total weight of the concentration.

The present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Metformin is used in the percentage from 20-95%, specifically 40-95% and more specifically 60-95% from total weight of the concentration.

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 and coloring agents. Other pharmaceutically acceptable excipients can also be included.

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

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 in amorphous or crystalline form.

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.

According to the embodiments of the present invention diluent are selected from the group comprising of, Micro crystalline cellulose, starch, 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.

According to the embodiment of the present invention suitable binders used according to the present invention are selected from the group comprising of hydroxypropylmethylcellulose, maize starch, povidone, co-povidone hydroxypropylcellulose, pregelatinized starch and the like or combination thereof.

According to the embodiments of the present invention disintegrant are selected from the group comprising of starches, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, corn starch, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low-substituted hydroxypropylcellulose, crospovidone and mixtures thereof.
According to the embodiments of the present invention suitable surfactants are selected from 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.

According to the embodiments of the present invention 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.

According to the embodiments of the present invention suitable film coating polymers used according to the present invention are selected from polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), Hypromellose, Lactose, Triacetin, Talc, Titanium oxide and iron oxide and the like or mixtures thereof.

According to the embodiments of the present invention suitable stabilizing agent used according to the present invention is Meglumine.

According to an embodiment of the present invention composition will provide stable product, as well as improved dissolution profile and bioavailability.

According to an embodiment of the present invention relates to the oral pharmaceutical compositions comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, with one or more pharmaceutically acceptable excipients.
According to an embodiment of the present invention relates to the oral pharmaceutical compositions comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, with one or more pharmaceutically acceptable excipients, wherein the Metformin is in the form of immediate release or extended release dosage form.

According to an embodiment of the present invention relates to the oral pharmaceutical compositions comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Linagliptin is incorporated in to the binder solution with binder and stabilizing agent and one are more pharmaceutically acceptable salts.

According to an embodiment of the present invention relates to the oral pharmaceutical compositions comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, one or more pharmaceutically acceptable excipients is free of magnesium stearate.

According to an embodiment of the present invention relates to a solid oral pharmaceutical composition comprising the pharmaceutically acceptable excipients is selected from diluents, binders, disintegrant, surfactants, lubricants, glidants and coloring agents and the like or mixture thereof and optionally a pharmaceutical acceptable excipient.

According to an embodiment of the present invention relates to process for preparing oral pharmaceutical compositions comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Metformin is in the form of immediate release or extended release, where in the lubricant is calcium stearate.

According to an embodiment of the present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Linagliptin may be incorporated in to binder solution.

According to an embodiment of the present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the Linagliptin is incorporated in to coating layer.

According to an embodiment of the present invention relates to a solid oral pharmaceutical composition comprising Dapagliflozin; Linagliptin and Metformin or its pharmaceutically acceptable salts, where in the intragranular portion contain Metformin alone devoid of any other pharmaceutically acceptable excipients.

According to an embodiment of the present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the pharmaceutical composition is a bilayer tablet composition.

According to an embodiment of the present invention relates to a solid oral pharmaceutical composition comprising combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its salts, where in the formulation is prepared by wet granulation fluid bed process.

According to an embodiment of the present invention to provide a particle size distribution of the drug may have particle size (D90) is less than 500 µm, preferably less than 200 µm, and more preferably less than100 µm are combination thereof.

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.
Examples:
Example-1:
S. No. Ingredients Qty mg/Tablet
5 mg/2.5 mg /500 mg % w/w 5 mg/2.5 mg /1000 mg % w/w
Intragranular Part
1 Metformin HCl 500.00 86.96 1000.00 86.96
Binder Solution
2 Linagliptin 2.50 0.43 2.50 0.22
3 Co-povidone 47.50 8.26 95.00 8.26
4 Meglumine 6.00 1.04 12.00 1.04
5 Purified Water q.s -- q.s --
Extra granular Part
6 Corn starch 12.50 2.17 27.50 2.39
7 Colloidal silicon dioxide 1.50 0.26 3.00 0.26
8 Calcium stearate 5.00 0.87 10.00 0.87
Total weight of Linagliptin and Metformin Layer 575.00 100.00 1150.00 100.00
Brief Manufacturing Procedure
Sifting and milling:
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.
Dry mixing and Granulation
ii. Load the sifted materials of step-i in fluid bed processor.
Drug Solution Preparation
iii. Disperse the weighed quantity of Linagliptin API in purified water (17% to total dry mix weight) under stirring and continue stirring until it forms a uniform dispersion. To this add weighed quantity of Co-povidone under stirring and continue stirring till a uniform dispersion forms. To this add weighed quantity of Meglumine under stirring and continue stirring till a uniform dispersion forms. Keep the dispersion stirring while spraying.
iv. Granulate step-ii by using step-iii drug solution at 60°C ± 10°C inlet temperature with product temperature at 40°± 10° C and with optimum air flow, spray rate and atomization pressure. Rinse the containers with purified water (3% to total dry mix weight) and spray the solution.
Note: If required, add extra water not be more than 5% of total dry mix weight.
Drying
v. Dry the wet mass in Fluid Bed Processor at inlet 50°C ± 10°C till LOD reaches 1.0 % to 3.0 % w/w at 105°C using suitable moisture analyser.
Sizing, Milling and blending
vi. Pass the materials of step v through sieve #20 ASTM.
vii. Mill the retentions of step-vi by using Co-mill fitted with 1.5 mm screen at slow to medium speed and sift through sieve #20 ASTM.
viii. Mill the retentions of step-vii by using co-mill fitted with 1.0 mm screen at medium to fast speed and sift through sieve #20 ASTM.
ix. Blend the under size granules of step vii and step-viii in blender and blend for 5 minutes at slow speed.
Sifting of extra-granular material
x. Sift maize starch and colloidal silicon dioxide through sieve #40 ASTM.
xi. Sift Magnesium Stearate through sieve #60 ASTM.
Blending and Lubrication
xii. Load the granules of step-ix into blender and add step-x and blend for 10 minutes at slow speed.
xiii. Add magnesium stearate of step-xi to the step-xii and blend for 5 minutes at slow speed.
Layer II - Dapagliflozin Part – Wet Granulation Process:
S. No. Ingredients Qty mg/Tablet
5 mg/2.5 mg /500 mg % w/w 5 mg/2.5 mg /1000 mg % w/w
Intragranular Part
1 Microcrystalline Cellulose (Hicel 50 M) 95.00 47.50 95.00 47.50
2 Lactose Anhydrous (Super tab 21 AN) 36.15 18.08 36.15 18.08
3 Croscarmellose sodium 5.00 2.50 5.00 2.50
4 HPMC E5 6.00 3.00 6.00 3.00
Binder Solution
5 Dapagliflozin Propanediol monohydrate 6.15 3.08 6.15 3.08
6 Isopropyl alcohol + Purified water (60 : 40) q.s. -- q.s. q.s.
Extra granular Part
7 Microcrystalline Cellulose (Hicel 90 M) 36.70 18.35 36.70 18.35
8 Croscarmellose sodium
(Crospovidone XL 10) 3.00 1.50 3.00 1.50
9 Colloidal silicon Di oxide (Aerosil 200) 6.00 3.00 6.00 3.00
10 Calcium stearate 6.00 3.00 6.00 3.00
Total weight of Dapagliflozin Layer 200.00 100.00 200.00 100.00
Bilayer Compression
11 Compression of Linagliptin + Metformin Layer and Dapagliflozin Layer Blends 775.00 --- 1350.00 ---
Film coating (12%w/w solid content and 3%w/w weight gain)
12 Opadry Yellow* 23.25 3.00 -- --
13 Opadry Orange^ -- -- 40.50 3.00
14 Purified water q.s. -- q.s. --
Total weight of tablets 798.25 -- 1390.50
Manufacturing Process:
Sifting
i. Co-sift Microcrystalline cellulose 50M, Anhydrous lactose, Croscarmellose sodium and Hydroxypropylmethylcellulose E5 through sieve # 30 ASTM (600 µm).
Dry mixing and Granulation
ii. Load the sifted materials of step i in rapid mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Drug Solution Preparation
iii. Weigh the required quantities of Purified water and Isopropyl alcohol at 30:70 ratios and add in SS container with proper closure under continuous stirring.
iv. Separate 10% quantity from step iii in to SS container for rinsing purpose.
v. Dissolve Dapagliflozin Propanediol Monohydrate in remaining 90% quantity of step iii under stirring and stir until a clear solution is formed.
Granulate step ii dry mix with prepared drug solution of step no. v & rinsing solution of step iv by the following granulation parameters.
Wet milling:
vi. Unload the wet mass from RMG and mill through co-mill fitted with 8.0 mm screen at slow speed.
Drying
vii. Load the contents of step vi in FBD and dry the granules initially for 15 minutes at inlet temperature of 25°C ± 5°C and then at inlet temperature of 45°C ± 10°C until the LOD of the granules reaches 1.0 – 3.0 % w/w at 60°C.
Sizing and Milling
viii. Sift the dried granules of step vii through sieve #40 ASTM (425 µm) and collect in doubled lined polybag.
ix. Mill the retentions of step viii by using co-mill fitted with 1.0 mm screen at slow speed and sift through #40 ASTM (425 µm) and collect in doubled lined polybag.
x. Ensure that all materials of step ix passed through #40 ASTM (425 µm), if any retains present continue the step ix until all granules pass through #40 ASTM (425 µm).
Sifting of extra-granular material
xi. Co-Sift microcrystalline cellulose pH 102, Croscarmellose sodium and Colloidal silicon dioxide through sieve # 40 ASTM (425 µm).
xii. Sift Calcium stearate through sieve #60 ASTM (250 µm).
Blending and Lubrication
xiii. Load the sifted materials of step viii, ix, x and step xi in to blender and mix for 20 minutes.
xiv. Add step xii of sifted magnesium stearate to step xiii and mix for 5 minutes and collect in doubled lined polybag.
Bilayer Compression
xv. Compress the lubricated blend of step-xiii of Linagliptin and Metformin Part and step xiv of Dapagliflozin Part with the suitable punch and parameters.
Film Coating:
xv. Weigh required quantity of purified water in a stainless steel vessel.

xvi. Disperse Opadry 03H520022 Yellow (for 5 mg/ 2.5 mg/ 500 mg) and Opadry 03H530006 Orange (for 5 mg/ 2.5 mg/ 1000 mg) (12% w/w solids) under stirring and continue stirring for 45 minutes to form uniform dispersion.
xvii. Load the core tablets of step-xiv in coating pan and pre-warm for 5 minutes at inlet temperature 45°C ± 10°C and check the pre warmed tablet weights.
xviii. Coat the tablets for 3.0 ± 1.0 % w/w by using coating dispersion of step xvi, under continuous stirring with following coating parameters. After achieving the desired weight gain dry the coated tablets for 10 minutes with inlet temperature of 35°C - 55°C.
Example 2:
S.No. Ingredients mg/Tablet Approx.
% w/w
5 mg /
2.5 mg 5 mg /
5 mg 10 mg /
2.5 mg 10 mg /
5 mg
Intra Granular Agents:
1. Linagliptin 2.50 5.00 2.50 5.00 1.25 – 5.00
2. Mannitol 25.00 25.00 50.00 50.00 25.00
3. Microcrystalline Cellulose 101 56.35 52.35 112.20 112.70 52.35 – 56.35
4. Copovidone 2.00 2.00 4.00 4.00 2.00
5. Crospovidone 2.50 2.50 5.00 5.00 2.50
Drug Solution:
6. Dapagliflozin Propanediol Monohydrate 6.15 6.15 12.30 12.30 6.15
7. Purified Water (70) q.s. q.s. q.s. q.s. q.s.
8. Iso Propyl Alcohol (30) q.s. q.s. q.s. q.s. q.s.
Extra-Granular Agents:
9. Crospovidone 3.00 3.00 6.00 6.00 3.00
10. Colloidal Silicon Dioxide 1.00 1.00 2.00 2.00 1.00
11. Calcium Stearate 3.00 3.00 6.00 6.00 3.00
Total weight of uncoated tablets 100.00 100.00 200.00 200.00 100.00
Film Coating:
12. Opadry (contains Poly Vinyl Alcohol, Titanium Dioxide, Talc, Poly Ethylene Glycol, Iron Oxides) 3.00 3.00 6.00 6.00 3.00
13. Purified Water q.s. q.s. q.s. q.s. q.s.
Total weight of coated tablets 103.00 103.00 206.00 206.00 --

Sifting
i. Co-sift Copovidone & Crospovidone through sieve # 30 ASTM (600 µm).
ii. Co-sift Half quantity of Mannitol with Linagliptin through sieve # 30 ASTM (600 µm) and add to step no. i.
iii. Co-sift remaining half quantity of Mannitol and the contents of step no. ii through sieve # 30 ASTM (600 µm).
iv. Co-sift Half quantity of Microcrystalline Cellulose 101 and the contents of step no. iii through sieve # 30 ASTM (600 µm).
v. Co-sift remaining half quantity of Microcrystalline Cellulose 101 and the contents of step no. iv through sieve # 30 ASTM (600 µm).
Dry Mixing
vi. Load the sifted materials of step no. v in rapid mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Drug Solution
vii. Weigh the required quantities of purified water + isopropyl alcohol at 70:30 ratio and add in SS container with proper closure under continuous stirring.
viii. Separate 10% quantity from step no. vii in to SS container for rinsing purpose.
ix. Dissolve Dapagliflozin Propanediol Monohydrate in remaining 90% quantity of step no. vii under continuous stirring, till formation of clear solution.
x. Granulate step no. vi dry mix with prepared drug solution of step no. ix & rinsing solution of step-viii with following granulation parameters.
Wet milling
xi. Mill the wet mass of step no. x through co-mill fitted with 6.0 mm screen at high speed and collect in double lined polybag.
Drying
xii. Load the contents of step no. xi in Fluid Bed Drier and dry the granules initially for 15 minutes at inlet temperature of 25°C ± 5°C and then at inlet temperature of 45°C ± 10°C until the LOD of the granules reaches 1.0 – 3.0% w/w at 60°C in automode.
Sifting, Milling
xiii. Sift the dried granules of step no. xii through sieve #30 ASTM (600 µm) and collect the fines and retentions separately in double lined polybag.
xiv. Mill the retentions of step no. xiii by using co-mill fitted with 1.00 mm screen at medium speed and sift through #30 ASTM (600 µm) and collect in double lined polybag.
xv. Ensure that all materials of step no. xiv passed through #30 ASTM (600 µm), if any retains present continue the step no. xiv untill all granules pass through #30 ASTM (600 µm).
Sifting of extra-granular material
xvi. Sift Crospovidone & Colloidal Silicon Dioxide through sieve # 30 ASTM (600 µm).
xvii. Sift Calcium Stearate through sieve #60 ASTM (250 µm).
Blending and Lubrication
xviii. Load the sifted materials of step-xiii, step-xiv, step-xv and step-xvi in to blender and blend for 20 minutes at slow speed.
xix. Add step no. xvii of sifted calcium stearate to step no. xviii and mix for 5 minutes at slow speed and collect in double lined polybag.
Compression
xx. Compress the lubricated blend of step-xix with the suitable parameters.
Coating
xxi. Coat the tablets of step-xx with the suitable coating material.

Strategy 3:
S.
No. Ingredients Qty. per Unit (mg) & % w/w
10 mg /
2.5 mg /
500 mg % w/w 10 mg /
2.5 mg /
1000 mg % w/w 10 mg /
5 mg /
500 mg % w/w 10 mg /
5 mg /
1000 mg % w/w
Metformin Hydrochloride Extended Release Layer
Intra granular agents
1 Metformin HCl 500.00 47.94 1000.00 65.66 500.00 44.64 1000.00 62.50
2 Hydroxypropylmethyl cellulose K100M CR 240.00 23.01 195.00 12.80 240.00 21.43 195.00 12.19
3 Polyvinyl pyrrolidone K-90 20.00 1.92 25.00 1.64 20.00 1.79 25.00 1.56
4 Micro Crystalline Cellulose 8.00 0.77 14.00 0.92 8.00 0.71 14.00 0.88
Binder solution
5 Polyvinyl pyrrolidone K-90 20.00 1.92 20.00 1.31 20.00 1.79 20.00 1.25
6 Iso Propyl Alcohol q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Extra granular agents
7 Colloidal Silicon Dioxide 7.50 0.72 7.00 0.46 7.50 0.67 7.00 0.44
8 Sodium Stearyl Fumarate 24.50 2.35 39.00 2.56 24.50 2.19 39.00 2.44
Metformin HCl ER Layer weight (mg) 820.00 78.62 1300.00 85.36 820.00 73.21 1300.00 81.25
Dapagliflozin Blend
Intra granular agents
9 Maize Starch 10.00 0.96 10.00 0.66 10.00 0.89 10.00 0.63
10 Copovidone 4.20 0.40 4.20 0.28 4.20 0.38 4.20 0.26
11 Mannitol 114.40 10.97 114.40 7.51 114.40 10.21 114.40 7.15
Drug solution
12 Dapagliflozin Propanediol Monohydrate 12.30 1.18 12.30 0.81 12.30 1.10 12.30 0.77
13 Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
14 Isopropyl Alcohol q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Linagliptin Blend
15 Maize Starch 5.00 0.48 5.00 0.33 10.00 0.89 10.00 0.63
16 Copovidone 2.10 0.20 2.10 0.14 4.20 0.38 4.20 0.26
17 Mannitol 55.40 5.31 55.40 3.64 110.80 9.89 110.80 6.93
Drug solution
18 Linagliptin 2.50 0.24 2.50 0.16 5.00 0.45 5.00 0.31
19 Meglumine 10 0.96 10 0.66 20.00 1.79 20.00 1.25
20 Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Extra granular agents
21 Sunset Yellow 0.10 0.01 0.10 0.01 0.00 0.00 0.00 0.00
22 Erythrosine Lake 0.00 0.00 0.00 0.00 0.10 0.01 0.10 0.01
23 Sodium Stearyl Fumarate 7.00 0.67 7.00 0.46 9.00 0.80 9.00 0.56
Dapagliflozin + Linagliptin IR Layer Weight (mg) 223.00 21.38 223.00 14.64 300.00 26.79 300.00 18.75
Core Tablet Weight (mg) 1043.00 100.00 1523.00 100.00 1120.00 100.00 1600.00 100.00
Film Coating (3% weight build up)
24 Opadry Polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and iron oxides) 31.29 3.00 45.69 3.00 33.60 3.00 48.00 3.00
25 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Coated Tablet Weight (mg) 1074.29 -- 1568.69 -- 1153.60 -- 1648.00 --
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, PVP 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.

Wet 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 Colloidal Silicon Dioxide through sieve #40 ASTM.
xiii. Sift Sodium Stearyl Fumarate through sieve #60 ASTM.
Blending and Lubrication
xiv. Load the granules of step ix, x, xi and xii in blender and blend for 10 minutes at slow speed.
xv. Load Sodium Stearyl Fumarate of step-xiii to the step xiv and blend for 5 minutes at slow speed and collect in doubled lined polybag.
Dapagliflozin Blend:
Milling & Sifting:
xvi. Co-sift Maize starch, Mannitol and Copovidone 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. Weigh the required quantities of Purified water and Isopropyl alcohol at 50:50 ratio and add in SS container with proper closure under continuous stirring.
xix. Separate 10% quantity from step xviii in to SS container for rinsing purpose.
xx. Dissolve Dapagliflozin Propanediol Monohydrate in remaining 90% quantity of step xviii under stirring and stir until a clear solution is formed.
xxi. Granulate step xvii dry mix with prepared drug solution of step no. xx & rinsing solution of step xix by the following granulation parameters.
Wet milling:
xxii. Unload the wet mass of step-xxi from RMG and mill through co-mill fitted with 8.0 mm screen at high speed.
Drying
xxiii. Load the contents of step xxii in FBD and dry the granules initially for 15 minutes at inlet temperature of 25°C ± 5°C and then at inlet temperature of 45°C ± 10°C until the LOD of the granules reaches 1.0 – 2.0 % w/w at 60°C (Auto mode) using IR moisture balance.
Sizing and Milling
xxiv. Sift the dried granules of step xxiii through sieve #30 ASTM and collect in double lined polybag.
xxv. Mill the retentions of step xxiv by using co-mill fitted with 1.0 mm screen at slow speed and sift through #30 ASTM and collect in double lined polybag.
xxvi. Mill the retentions of step-xxv 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.
Linagliptin Blend:
Milling & Sifting:
xxvii. Co-sift Maize starch, Mannitol and Copovidone through sieve # 30 ASTM.
Dry mixing
xxviii. Load the sifted materials of step xxvii in rapid mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Binder Preparation and Granulation:
xxix. Disperse required quantities of Meglumine followed by Linagliptin in required quantity of purified water under stirring and stir until a uniform dispersion is formed.
xxx. Granulate step xxviii dry mix with prepared drug solution of step no. xxix by the following granulation parameters.
Wet milling:
xxxi. Unload the wet mass of step-xxx from RMG and mill through co-mill fitted with 8.0 mm screen at high speed.
Drying
xxxii. Load the contents of step xxxi 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
xxxiii. Sift the dried granules of step xxxii through sieve #30 ASTM and collect in double lined polybag.
xxxiv. Mill the retentions of step xxxiii by using co-mill fitted with 1.0 mm screen at slow speed and sift through #30 ASTM and collect in double lined polybag.
xxxv. Mill the retentions of step-xxxiv 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.
Dapagliflozin + Linagliptin Layer:
Sifting of extra-granular material
xxxvi. Sift required colorant (Sunset Yellow or Erythrosine Lake) through sieve # 80 ASTM.
xxxvii. Sift Sodium Stearyl Fumarate through sieve #60 ASTM.
Blending and Lubrication
xxxviii. Load the sifted materials of step xxiv, step xxv, step xxvi and xxxiii, xxxiv, xxxv and step xxxvi in to blender and mix for 20 minutes at slow speed.
xxxix. Add step xxxvii of sifted Sodium Stearyl Fumarate to step xxxviiii and mix for 5 minutes at slow speed and collect in doubled lined polybag.
Compression
xl. Compress the lubricated blend of step xv (Metformin Layer) and step xxxix (Dapagliflozin + Linagliptin layer) with the suitable parameters.
Film Coating:
xli. Weigh required quantity of purified water in a stainless steel vessel.
xlii. Disperse Opadry in purified water (10% w/w solids) of step xli under stirring and continue stirring for 45 minutes to form uniform dispersion.
xliii. Load the core tablets of step xl (Compressed tablets) in coating pan and pre-warm for 10 minutes at product temperature 30° - 50° C and check the pre warmed tablet weights.
xliv. Coat the tablets for 3 ± 1% w/w by using coating dispersion of step xlii, 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.
Strategy-4:
Manufacturing Formula:
S.
No. Ingredients Qty. per Unit (mg) Approx.
% w/w
2.5 mg / 1000 mg 5 mg / 500 mg 5 mg / 1000 mg 10 mg / 500 mg 10 mg / 1000 mg
Metformin Hydrochloride Extended Release Layer
Intra granular agents
1. Metformin HCl 1000.00 500.00 1000.00 500.00 1000.00 49.41 to 66.7
2. Hydroxypropyl methyl cellulose K100M CR 197.00 260.00 197.00 260.00 197.00 13.13 to 25.00
3. Polyvinyl pyrrolidone K-90 25.00 22.00 25.00 22.00 25.00 1.67 to 2.12
4. Micro Crystalline Cellulose 15.00 8.00 15.00 8.00 15.00 0.77 to 1.00
Binder solution
5. Polyvinyl pyrrolidone K-90 25.00 25.00 25.00 25.00 25.00 1.67 to 1.98
6. Iso Propyl Alcohol q.s. q.s. q.s. q.s. q.s.
Extra granular agents
7. Sodium Stearyl Fumarate 38.00 25.00 38.00 25.00 38.00 2.40 to 2.53
Metformin Hydrochloride ER Tablet weight (mg) 1300.00 840.00 1300.00 840.00 1300.00
Dapagliflozin Immediate Release layer
Intra granular agents
8. Micro Crystalline Cellulose 144.825 141.75 141.75 135.60 135.60 9.04 to 13.63
9. Croscarmellose sodium 4.00 4.00 4.00 4.00 4.00 0.27 to 0.38
10. Hydroxy Propyl Methyl Cellulose E5 6.00 6.00 6.00 6.00 6.00 0.40 to 0.58
Drug solution
11. Dapagliflozin Propanediol Monohydrate 3.075 6.15 6.15 12.30 12.30 0.2 to 0.82
12. Purified Water (70) q.s. q.s. q.s. q.s. q.s.
13. Iso Propyl Alcohol (30) q.s. q.s. q.s. q.s. q.s.
Extra granular agents
14. Microcrystalline cellulose 30.00 30.00 30.00 30.00 30.00 2.0 to 2.88
15. Croscarmellose sodium 2.00 2.00 2.00 2.00 2.00 0.13 to 0.19
16. Colloidal Silicon Dioxide 4.00 4.00 4.00 4.00 4.00 0.27 to 0.38
17. Sunset Yellow 0.10 0.10 0.10 -- -- 0.01
18. Erythrosine Lake -- -- -- 0.10 0.10 0.01
19. Sodium Stearyl Fumarate 6.00 6.00 6.00 6.00 6.00 0.4 to 0.58
Dapagliflozin IR Tablet Weight (mg) 200.00 200.00 200.00 200.00 200.00 ---
Total tablet weight (mg) 1500.00 1040.00 1500.00 1040.00 1500.00 100.00
Film Coating $ (3.0% weight build up)
20. Opadry II Yellow 45.00 31.20 45.00 -- --
21. Opadry II Pink -- -- -- 31.20 45.00
22. Purified water q.s. q.s. q.s. q.s. q.s.
Coated Tablet Weight (mg) 1545.00 1071.20 1545.00 1071.20 1545.00
Metformin HCl Layer:
Milling & Sifting:
xlv. 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.
xlvi. Co-sift Metformin Hydrochloride, Hydroxypropylmethyl cellulose K100M CR, PVP K-90 and Microcrystalline cellulose through sieve # 20 ASTM and collect in double lined polybag.
xlvii. Again Co-sift materials of step ii through sieve # 20 ASTM and collect in double lined polybag.
Dry Mixing:
xlviii. 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:
xlix. Dissolve Polyvinyl pyrrolidone K-90 in Iso Propyl Alcohol under stirring and continue stirring until it forms clear solution.
l. Granulate step iv dry mix by using step-v binder solution with the following granulation parameters
li. Unload the wet mass through co-mill fitted with 8.0 mm screen at fast speed.
Drying
lii. Load the contents of step vii in FBD and air dry the granules at least for 15 minutes at inlet temperature of 25°C ± 5°C and sift the air dried granules through sieve #10 and collect the retains and undersize granules separately.
liii. Mill the retentions (oversized granules) of step viii using co-mill fitted with 3.0 mm screen at high speed and sift through sieve #10 ASTM. Continue this to mill the granules with 3.0 mm screen until all the material passes through sieve #10 ASTM and collect in double lined polybag
liv. Load the contents of step viii and step ix in FBD and dry the granules at inlet temperature of 50°C ± 15°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
lv. Sift the step viii dried granules through sieve #20 and collect the retains and undersize granules separately.
lvi. Mill the retentions (oversized granules) of step xi using co-mill fitted with 2.0 mm screen at medium speed and sift through sieve #20 ASTM.
lvii. Mill the retentions of step xii 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
lviii. Sift Sodium Stearyl Fumarate through sieve #60 ASTM.
Blending and Lubrication
lix. Load the granules of step xi, xii and xiii in blender and blend for 10 minutes at slow speed.
lx. Load magnesium stearate of step-xiv to the step xv and blend for 5 minutes at slow speed and collect in doubled lined polybag.
Dapagliflozin Layer:
Milling & Sifting:
lxi. Co-sift Micro Crystalline Cellulose 101, Croscarmellose sodium and Hydroxy Propyl Methyl Cellulose E5 through sieve # 30 ASTM.
Dry mixing
lxii. Load the sifted materials of step xvii in rapid mixer granulator and mix for 15 minutes using impeller at slow speed and chopper off.
Drug Solution Preparation and Granulation:
lxiii. Weigh the required quantities of Purified water and Isopropyl alcohol at 70:30 ratio and add in SS container with proper closure under continuous stirring.
lxiv. Separate 10% quantity from step xix in to SS container for rinsing purpose.
lxv. Dissolve Dapagliflozin Propanediol Monohydrate in remaining 90% quantity of step xix under stirring and stir until a clear solution is formed. If required, take extra quantity of Water + IPA which should not be more than 10% w/w of total dry mix to dissolve Dapagliflozin Propanediol Monohydrate.
lxvi. Granulate step xviii dry mix with prepared drug solution of step no. xxi & rinsing solution of step xx by the following granulation parameters.
Note: Granulation parameters may change accordingly with the batch size to equipment.
Wet milling:
lxvii. Unload the wet mass from RMG and mill through co-mill fitted with 8.0 mm screen at slow speed.
Drying
lxviii. Load the contents of step xxiii 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 2.0 – 4.0 % w/w at 60°C (Auto mode) using IR moisture balance.
Sizing and Milling
lxix. Sift the dried granules of step xxiv through sieve #30 ASTM and collect in double lined polybag.
lxx. Mill the retentions of step-xxv 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.
Blending and Lubrication
lxxi. Load the sifted materials of step xxv, step xxvi and step xxvii in to blender and mix for 20 minutes at slow speed.
lxxii. Add step xxviii of sifted calcium stearate to step xxix and mix for 5 minutes at slow speed and collect in doubled lined polybag.
Compression
lxxiii. Compress the lubricated blend of step xvi (Metformin Layer) and step xxx (Dapagliflozin layer) with the suitable parameters.
,CLAIMS:1) A bilayer composition comprising a combination of Dapagliflozin or its salts thereof and Linagliptin or its salts thereof optionally in combination with Metformin or its pharmaceutically acceptable salts with one or more pharmaceutical acceptable excipients.

2) The bilayer composition as claimed in claim 1, wherein the Linagliptin is incorporated into the binder solution with binder and stabilizer, and one are more pharmaceutically acceptable salts.

3) The bilayer composition as claimed in claim 1, wherein the Metformin is in the form of immediate release or extended-release dosage form.

4) The bilayer composition as claimed in claim 1, wherein the Dapagliflozin is used in the percentage from 0.1-90%, specifically 0.1-70% and more specifically 0.1-25% from total weight of the composition.

5) The bilayer composition as claimed in claim 1, wherein the Linagliptin is used in the percentage from 0.1-90%, specifically 0.1-70% and more specifically 0.1-25% from total weight of composition.

6) The bilayer composition as claimed in claim 1, wherein the Metformin is used in the percentage from 20-95%, specifically 40-95% and more specifically 60-95% from total weight of the composition.

7) The bilayer composition as claimed in claim 1, wherein the stabilizer used in the composition is Meglumine.

8) The bilayer composition as claimed in claim 1, wherein the formulation is prepared by wet granulation fluid bed process.

9) The process for the preparation of bilayer composition as claimed in claim 1, contain
a) Sifting and milling the Metformin, dry mixing and granulation.
b) Preparing Linagliptin layer by adding binder with Linagliptin, stabling agent and other ingredient, sifting of extra-granular material, blend and lubricate the material.
c) Preparing Dapagliflozin layer by adding binder with Dapagliflozin and other ingredients sifting of extra-granular material, blending and Lubricating the material.
d) Compress the lubricated blend of Linagliptin and Metformin part and Dapagliflozin part with suitable punch and parameters, perform the film coating.