DESC:FIELD OF THE INVENTION

This present invention relates to pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl wherein the composition is devoid of any basic amino acids. Further this invention also relates to process for the preparation of said composition & use of the said composition in treatment of certain diseases.

BACKGROUND OF THE INVENTION

Linagliptin is a DPP-IV inhibitor, having antidiabetic activity. Chemically, linagliptin is 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine. Its structure is as follows:

Figure 1: Linagliptin
Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water, soluble in methanol, sparingly soluble in ethanol, very slightly soluble in Isopropanol, and very slightly soluble in acetone. It has a molecular weight of 472.54.

Metformin, chemical name of which is N, N-dimethylimidodicarbonimidic diamide, is a molecule belonging to biguanide class. Its structure is as follows:

Figure 2: Metformin
Metformin was first disclosed in the application numbered US3174901. It is known that metformin is especially effective in the treatment of type-2 diabetic patients who are overweight and obese but have healthy kidney functions. On the market, metformin can be found in metformin hydrochloride (HCl) form of 500 mg, 750 mg and 1000 mg film tablet and prolonged-release tablets.

Linagliptin is commercially available as a Tradjenta® brand name in 5 mg tablet. Further it is also marketed in combination with metformin as a brand name Jentadueto® which is contains 2.5+500 mg, 2.5+850 mg and 2.5+1000 mg linagliptin & metformin HCl respectively as active ingredients and following inactive ingredients: arginine, corn starch, copovidone, colloidal silicon dioxide, magnesium stearate, titanium dioxide, propylene glycol, hypromellose, talc, yellow ferric oxide and/or red ferric oxide.

US patent no 7407955 discloses linagliptin as a product. Further this patent also discloses a pharmaceutical composition of linagliptin comprising one or more inert carriers or diluents.

US patent no 8119648 disclose method of use of linagliptin in treatment of type II diabetes mellitus or obesity.

US patent no 8178541 describe the pharmaceutical composition of linagliptin with metformin HCl. Further this patent also discloses the use of linagliptin and metformin HCl combination in treatment in type II diabetes mellitus.

US2011206766 discloses pharmaceutical composition comprising or made from DPP-4 inhibitor, a partner drug, and one or more pharmaceutical excipients, and a nucleophilic and/or basic agents for stabilizing said DPP-4 inhibitor against degradation. The DPP-4 inhibitor is linagliptin and partner drug is metformin HCl.

Furthermore, US2011206766 discloses use of a basic amino acid L-arginine, which may be suitable for stabilizing, such as e.g. a suitable buffering agent as stabilizer, to overcome the problems of incompatibility and poor stability, especially decomposition and/or "assay decrease" which may be caused e.g. by reaction of free base type DPP-4 inhibitors when combined with an incompatible partner drug, or its impurity product and/or a pharmaceutical excipient having such functional group (such as a reducing end of a sugar or an acyl group, such as e.g. an acetyl or carbamoyl group).

The prior art references emphasize on using basic amino acid to overcome the problem of chemical degradation of free base of linagliptin when combined with metformin HCl. Hence, there is still a need exists which would address the issue relating to degradation of linagliptin and provides a chemically stable pharmaceutical composition of linagliptin in the presence of its partner drug metformin HCl.

The inventors of the present invention surprisingly found a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl that overcomes the above mentioned problem even without the use of basic amino acid.

OBJECTS OF THE INVENTION

The object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients.

Another object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid.

Another object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of colloidal silicon dioxide.

Another object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.

Another object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the pharmaceutically acceptable excipients selected form one or more fillers or diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers, and the like, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.

Another object of the present invention is to provide a process for the preparation of chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.

Another object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl, which is intended for the treatment of diabetes and/or to achieve glycemic control in a type 1 or type 2 diabetes mellitus patients.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl wherein the composition is devoid of any basic amino acids. Said composition provides a stable composition to overcome the problem of chemical degradation of free base of linagliptin when combined with metformin HCl. Further the present invention also provides a method for the preparation of said composition.

DETAILED DESCRIPTION

Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

It has been observed that the several active ingredients including linagliptin with primary amino group shows incompatibilities, degradation problems with incompatible partner drugs, excipients and/or impurities of excipients used in solid dosage form and produce degradation products in the final formulation. Considering the prior efforts as disclosed in the backgrounds, basic amino acid, preferably L-arginine can overcome the above degradation problem.

Inventors of this invention surprisingly developed chemically stable pharmaceutical fixed dose combination of linagliptin free base and metformin HCl to overcome the above mentioned problem even without the use of basic amino acid.

The inventors of the present invention provides a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl wherein the composition is devoid of any basic amino acids and/or colloidal silicon dioxide. The “chemically stable pharmaceutical composition” may be defined as a pharmaceutical composition wherein the linagliptin related impurities A, B, C and D are individually not more than 0.5% w/w, 0.5% w/w, 0.5% w/w and 0.4% w/w respectively and total impurity is not more than 2% w/w, when stored at 3 month at 40°C / 75% Relative Humidity (RH).

To specify the impurities A, B, C and D of Linagliptin, impurity A of linagliptin is chemically N-acetyl impurity, impurity B of linagliptin is chemically Boc impurity, impurity C of linagliptin is chemically dimer impurity and impurity D of linagliptin is maximum unknown impurity.

Basic amino acid may be defined as amino acids having an intra-molecular amino group & have basic side chain at neutral pH, such as e.g. L-arginine, L-lysine or L-histigine. Further the said amino acids have alkaline characteristics.

Further, the present invention provides a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid.

In one embodiment, the present invention is directed to a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, particularly stable against chemical degradation.

One of the preferred embodiments of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of colloidal silicon dioxide.

In another more preferred embodiment of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.

In more detailed aspects, the present invention provides a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the pharmaceutically acceptable excipients selected form one or more fillers or diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers, and the like, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.

Pharmaceutical excipients for the present invention is selected from one or more fillers, one or more binders, one or more diluents, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers, and the like.

In more detail, fillers or diluent may include but not limited to mannitol, starch, corn starch, potato starch, pregelatinized starch, silicified microcrystalline cellulose, dicalcium phosphate and mixtures thereof. Of these, corn starch and mannitol are preferably used.

According to present invention, binders may include but not limited to copovidone, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, polyethylene oxide, povidone, starch, pregelatinized starch and mixtures thereof. Of these, copovidone is preferably used.

According to present invention, disintegrant may include but not limited to crospovidone, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch and mixtures thereof.

According to present invention, lubricant may include but not limited to calcium stearate, glyceryl behenate, magnesium stearate, starch, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and mixtures thereof. Of these, magnesium stearate is preferably used.

The dose & dosing ratio of linagliptin free base and metformin HCl can be changed depending on various factors such as symptoms, age & body weight of the patients. According to present invention, the dosage of the linagliptin free base is typically from 0.1 to 100 mg, in particular 0.5 to 10 mg. Thus, particular dosage strengths of linagliptin free base are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg. More particular unit dosage strength of linagliptin free base for inclusion into fixed dose combination pharmaceutical compositions of the present invention is 2.5 mg.

According to present invention, the unit dosage strengths of the metformin HCl for use in the present invention may be from 100 mg to 2000, preferably from 250 mg to 1000 mg. More particular unit dosage strengths of metformin HCl for incorporation into the fixed dose combination pharmaceutical compositions of the present invention are 500mg, 850mg and 1000 mg of metformin HCl.

According to present invention, the particular fixed dose combination of linagliptin and metformin HCl may be administred once or twice daily to the patient, in particular twice daily.

In more preferred aspect of the invention; the present invention provides a process for the preparation of chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide. Excipients are those described herein before.

The pharmaceutical composition described herein may be prepared by conventional technology well known to those skilled in the art such as wet granulation, dry granulation and direct compression and the like.

In a particular preferred embodiment, the dosage form of the present invention is solid dosage form such as tablets, capsules, powders, sachets, preferably oral tablets; more preferably mono layer tablet, bilayer tablet, drug layered tablet.

A typical mono-layer tablet of this invention comprises a linagliptin free base, metformin HCl, one or more fillers (such as e.g. corn starch and/or mannitol), one or more binders (such as e.g. copovidone), one or more lubricants (such as e.g. magnesium stearate) and an optional film coat.

A typical bi-layer tablet of this invention comprises a linagliptin portion comprising linagliptin free base, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone) and one or more lubricants (such as e.g. magnesium stearate), and a metformin portion comprising metformin HCl, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone) and one or more lubricants (such as e.g. magnesium stearate).

A drug layered tablet (linagliptin coating on metformin core, i.e. drug layering of linagliptin on metformin core) of this invention comprises a metformin core portion comprising metformin HCl, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone) and one or more lubricants (such as e.g. magnesium stearate), wherein said core portion is seal-coated with a film coat comprising one or more film-coating agents (such as e.g. hypromellose and/or polyvinyl alcohol), one or more plasticizers (such as e.g. propylene glycol), one or more pigments; and a linagliptin layer comprising a linagliptin free base, one or more film-coating agents (such as e.g. hypromellose) and one or more plasticizers (such as e.g. propylene glycol).

According to present invention, chemically stable pharmaceutical composition is intended for the treatment of diabetes and/or to achieve glycemic control in a type 1 or type 2 diabetes mellitus patients.

EXAMPLES

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

Example 1: (Mono layer Tablet)
Strength 2.5/500 mg 2.5/850 mg 2.5/1000 mg 2.5/500 mg 2.5/850 mg 2.5/1000 mg
Sr. No. Ingredients mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet
Dry mixing
1 Linagliptin 2.50 2.50 2.50 2.50 2.50 2.50
2 Metformin HCl 500.00 850.00 1000.00 500.00 850.00 1000.00
3 Mannitol 11.80 20.00 23.60 ---- ---- ----
4 Corn starch 40.3 67.50 83.1 52.10 87.50 106.7
Binder solution
5 Copovidone 29.50 50.00 59.00 29.50 50.00 59.00
6 Purified water q.s. q.s. q.s. q.s. q.s. q.s.
Blending
7 Magnesium stearate 5.90 10.00 11.80 5.90 10.00 11.80
Total core weight 590.00 1000.00 1180.00 590.00 1000.00 1180.00
Film coating
8 Coating material 12.00 16.00 24.00 12.00 16.00 24.00
9 Purified water q.s. q.s. q.s. q.s. q.s. q.s.
Total tablet weight 602.00 1020.00 1204.00 602.00 1020.00 1204.00

Process:
1. Co-sift Linagliptin, Metformin HCl, with excipients (Mannitol and / or Corn starch).
2. Dissolve Copovidone in purified water to prepare binding solution.
3. Dry mix the material of step 1 and granulate the dry mixed material with binder solution of step 2 using rapid mixer granulator.
4. Dry wet mass at 55 ºC to achieve loss on drying less than 1.5% w/w.
5. Sift dried granules through #20 ASTM.
6. Sift magnesium stearate through #60 ASTM.
7. Lubricate the granules of step 5 with magnesium stearate in a suitable blender.
8. Compress the blend into tablets with appropriate tooling.
9. Disperse the coating material in purified water. Coat the core tablets using coating solution in suitable coater to achieve desired weight gain.

Example 2: (Mono Layer Tablet)
Strength 2.5/500 mg 2.5/850 mg 2.5/1000 mg
Sr. No. Ingredients mg / tablet mg / tablet mg / tablet
Dry mixing
1 Linagliptin 2.50 2.50 2.50
2 Metformin HCl 500.00 850.00 1000.00
3 Mannitol 17.94 29.80 35.65
4 Corn starch 16.46 27.70 35.65
5 Copovidone 17.70 30.00 ------
Binder solution
6 Copovidone 29.50 50.00 94.40
7 Purified water q.s. q.s. q.s.
Blending
8 Magnesium stearate 5.90 10.00 11.80
Total core weight 590.00 1000.00 1180.00
Film coating
9 Coating material 12.00 20.00 24.00
10 Purified water q.s. q.s. q.s.
Total tablet weight 602.00 1020.00 1204.00

Process:
1. Co-sift Linagliptin, Metformin HCl, Mannitol, Corn starch and Copovidone.
2. Dissolve Copovidone in purified water to prepare binding solution.
3. Dry mix the material of step 1 and granulate the dry mixed material with binder solution of step 2 using rapid mixer granulator.
4. Dry wet mass at 55 ºC to achieve loss on drying less than 1.5% w/w.
5. Sift dried granules through #20 ASTM.
6. Sift magnesium stearate through #60 ASTM.
7. Lubricate the granules of step 5 with magnesium stearate in suitable blender.
8. Compress the blend into tablets with appropriate tooling.
9. Disperse the coating material in purified water. Coat the core tablets using coating solution in suitable coater to achieve desired weight gain.

Example 3: (Linagliptin drug layering on metformin drug core)
Strength 2.5/500 mg 2.5/850 mg 2.5/1000 mg
Sr. No. Ingredients mg / tablet mg / tablet mg / tablet
Metformin part-Dry mixing
1 Metformin HCl 500.00 850.00 1000.00
2 Corn starch 31.10 52.40 62.20
Binder solution
3 Copovidone 28.25 48.00 56.50
4 Purified water q.s. q.s. q.s.
Blending
5 Magnesium stearate 5.65 9.60 11.30
Total core weight 565.00 960.00 1130.00
Seal Coating
6 Hypromellose 6 cps/ Polyvinyl alcohol 10.80 18.00 21.60
7 Propylene glycol 1.20 2.00 2.40
8 Purified water q.s. q.s. q.s.
Seal coated tablets weight 577.00 980.00 1154.00
Drug layering
9 Linagliptin 2.50 2.50 2.50
10 Hypromellose 6 cps 11.00 20.90 24.50
11 Propylene glycol 1.50 2.60 3.00
12 Purified water q.s. q.s. q.s.
Drug layered tablet weight 592.00 1006.00 1184.00
Film coating
13 Coating material 12.00 20.00 24.00
14 Purified water q.s. q.s. q.s.
Total tablet weight 604.00 1026.00 1208.00

Process:
1. Co-sift Metformin HCl and Corn starch.
2. Dissolve Copovidone in purified water to prepare binding solution.
3. Dry mix the material of step 1 and granulate the dry mixed material with binder solution of step 2 using rapid mixer granulator.
4. Dry wet mass at 55 ºC to achieve loss on drying less than 1.5% w/w.
5. Sift dried granules through #20 ASTM.
6. Sift magnesium stearate through #60 ASTM.
7. Lubricate the granules of step 5 with magnesium stearate in suitable blender.
8. Compress the blend into tablets with appropriate tooling.
9. For seal coating, dissolve Hypromellose 6 cps/ polyvinyl alcohol & propylene glycol in purified water using stirrer. Coat the core tablets of step 8 using seal coating solution using suitable coating equipment.
10. For drug coating, dissolve linagliptin, Hypromellose 6 cps and Propylene glycol in purified water using overhead stirrer.
11. Coat the seal coated tablets using drug solution of step 10.
12. Disperse the coating material in purified water. Coat the drug coated tablets using coating solution in suitable coater to achieve desired weight gain.

Example 4: (Bi-layer Tablet)
Strength 2.5/500 mg 2.5/850 mg 2.5/1000 mg
Sr. No. Ingredients mg / tablet mg / tablet mg / tablet
Linagliptin layer-I (Blending or Wet granulation)
1 Linagliptin 2.50 2.50 2.50
2 Corn starch 176.10 301.12 354.70
3 Copovidone 9.50 16.15 19.00
4 Magnesium stearate 1.90 3.23 3.80
Total weight (Layer-I) 190.00 323.00 380.00
Metformin layer-II (granulation)
Dry mixing
7 Metformin HCl 500.00 850.00 1000.00
8 Corn starch 26.40 44.88 52.80
Binder solution
9 Copovidone 28.00 47.60 56.00
10 Purified water q.s. q.s. q.s.
Blending
12 Magnesium stearate 5.60 9.52 11.20
Total weight (Layer-II) 560.00 952.00 1120.00
Total tablet weight (Core tablet) 750.00 1275.00 1500.00
Film coating
13 Coating material 15.00 25.00 30.00
14 Purified water q.s. q.s. q.s.
Total tablet weight 765.00 1300.00 1530.00

Process:
Linagliptin Blending (Layer-I):
1. Co-sift Linagliptin, Corn starch and Copovidone and mix them geometrically in blender.
2. Sift magnesium stearate.
3. Mix magnesium stearate with blend of step 3 in blender.
OR
Linagliptin Granulation (Layer-I):
4. Co-sift Linagliptin and Corn starch.
5. Dissolve Copovidone in purified water to prepare binding solution.
6. Dry mix the material of step 4 and granulate the dry mixed material with binder solution of step 5 using rapid mixer granulator.
7. Dry the wet mass at 55 ºC to achieve loss on drying less than 1.5% w/w.
8. Sift dried granules.
9. Sift the magnesium stearate and mix with granules of step 8 in blender.

Metformin granulation (Layer-II):
10. Co-sift Metformin and corn starch.
11. Dissolve Copovidone in Purified water.
12. Dry mix the material of step 10 and granulate the dry mixed material with binder solution of step 11 using rapid mixer granulator.
13. Dry the wet mass at 55 ºC to achieve loss on drying less than 1.5% w/w.
14. Sift dried granules.
15. Sift magnesium stearate and mix with the granules of step 14 in blender.

Compression & Coating:
16. Compress the two blends into bilayer tablets with appropriate tooling.
17. Disperse the coating material in purified water.

Stability study:

Study of the linagliptin related impurity for the above examples were carried out at initial and upon storage at 40°C / 75% RH for 3 months.

Below data depicts the stability results of highest strengths of all the representative examples (linagliptin 2.5mg + metformin HCl 1000mg):
Example–1 Example-2 Example-3 Example–4
Tests Initial 3 M Initial 3 M Initial 3 M Initial 3 M
Related compounds (Linagliptin)
Impurity A 0.149% 0.173% 0.127% 0.127% ND 0.129% ND 0.155%
Impurity B ND ND ND ND ND ND ND ND
Impurity C 0.016 0.024 0.015% 0.024% ND ND ND ND
Impurity D 0.143%
(1.08) 0.230%
(1.21) 0.196%
(1.72) 0.194% (1.70) 0.228 (1.43) 0.223%
(1.42) 0.138 (1.07) 0.151%
(1.43)
Total Impurities 0.518 0.830% 0.617% 1.012% 0.719% 1.038% 0.473% 0.672%

*Impurity A of linagliptin is chemically N-acetyl impurity
*Impurity B of linagliptin is chemically Boc impurity
*Impurity C of linagliptin is chemically Dimer impurity
*Impurity D of linagliptin is max unknown impurity (at retention time when measured through HPLC)
*ND: Not detected

Acceptable limits of the above said impurities A, B, C and D are individually not more than 0.5% w/w, 0.5% w/w, 0.5% w/w and 0.4% w/w respectively wherein the impurity level is express by weight of linagliptin.

Further, the total impurity of linagliptin related substances is not more than 2% w/w when determined after 3 month kept on 40?C/ 75% RH.

Also, the assay of Linagliptin and metformin HCl performed at initial and at 3 month at 40°C and 75% RH are within the acceptable limits of 95% - 105%.

It can be observed that, at initial and upon storage for 3 month at 40°C and 75% RH, the compositions of present invention are meets the acceptance criteria of individual and total impurity of linagliptin as disclosed herein above.
,CLAIMS:1. A pharmaceutical composition comprising linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients can be selected form one or more fillers or diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers and combinations thereof.
3. The pharmaceutical composition according to claim 1, further optionally comprises film coating.
4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of mono-layer, bi-layer, or drug layered tablet.
5. The pharmaceutical composition according to claim 1, wherein the linagliptin related impurities A, B, C, D and total impurity are individually not more than 0.5% w/w, 0.5% w/w, 0.5% w/w 0.4% w/w and 2% w/w respectively, when determined after 3 month on 40?C/ 75% RH.
6. A process for the preparation of pharmaceutical composition comprising linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid.
7. The process for the preparation of pharmaceutical composition according to claim 6, comprising the steps of:
(a) preparing a dry mix of linagliptin and metformin HCl and one or more pharmaceutically acceptable excipients;
(b) preparing granulation solution by using binder and one or more solvents;
(c) granulating the mixture obtain in step (a) by using a solution of step (b);
(d) drying above prepared granules;
(e) lubricating the above dried granules with lubricant and compressed into tablets;
(f) optionally coating the tablets obtained in step (e).
8. The process for the preparation of pharmaceutical composition according to claim 6, comprising the steps of:
(a) preparing granules of linagliptin comprising linagliptin and one or more pharmaceutically acceptable excipients by using granulation liquid comprising a binder and one or more solvent;
(b) preparing granules of metformin HCl comprising metformin HCl and one or more pharmaceutically acceptable excipients by using granulation liquid comprising a binder and one or more solvent;
(c) compressing the above granules obtained in step (a) and step (b) optionally with one or more pharmaceutically acceptable excipients into bilayer tablets;
(d) optionally coating the bilayer tablets obtained in step (c).
9. The process for the preparation of pharmaceutical composition according to claim 6, comprising the steps of:
(a) preparing blend of linagliptin by dry mixing of linagliptin and one or more pharmaceutically acceptable excipients;
(b) preparing granules of metformin HCl comprising metformin HCl and one or more pharmaceutically acceptable excipients by using granulation liquid comprising a binder and one or more solvent;
(c) compressing the blend obtained in step (a) and granules obtained in step (b) optionally with one or more pharmaceutically acceptable excipients into bilayer tablets;
(d) optionally coating the bilayer tablets obtained in step (c).
10. The process for the preparation of pharmaceutical composition according to claim 6, comprising the step of:
(a) preparing a dry mix of metformin HCl and one or more pharmaceutically acceptable excipients;
(b) preparing granulation solution by using binder and one or more solvents;
(c) granulating the metformin HCl dry mixture obtain in step (a) by using a solution of step (b);
(d) lubricating the above granules with magnesium stearate and compressed into tablets;
(e) preparing the solution by dissolving the hypromellose and /or polyvinyl alcohol, propylene glycol in one or more solvents and coating the tablets obtained in step (d);
(f) preparing linagliptin drug solution by dissolving linagliptin, hypromellose, polyvinyl alcohol in one or more solvents;
(g) coating the tablets obtained in step (e) by using the linagliptin drug solution obtained in step (f);
(h) optionally coating the tablets obtained in step (g).