DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation

1 . A stable pharmaceutical composition comprising a dipeptidyl peptidase-4 (DPP-4) inhibitor which is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base, a partner drug which is metformin hydrochloride, one or more pharmaceutical excipients, and a stabilizing agent for stabilizing said DPP-4 inhibitor against degradation to form an impurity and/or degradation product caused by reaction of the primary amino group of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base when combined with metformin hydrochloride in the composition;

wherein the stabilizing agent is a nucleophilic and/or basic agent or a buffering agent that is a basic amino acid having an intramolecular amino group and alkaline characteristics;

wherein the pharmaceutical composition is bioequivalent to the free combination of the DPP-4 inhibitor and metformin hydrochloride;

wherein the DPP-4 inhibitor is present in a dosage range from 0.5 mg to 10 mg, and the stabilizing agent is present in an amount minimized to not alter the bioequivalence of the pharmaceutical composition to the free combination but sufficient to stabilize said DPP-4 inhibitor against degradation, and

wherein the impurity and/or degradation product is an N-acetyl or N-carbamoyl derivative of the free base DPP-4 inhibitor.

2 . The pharmaceutical composition according to claim 1 , wherein the stabilizing agent is the buffering agent.

3 . The pharmaceutical composition according to claim 1 , wherein said DPP-4 inhibitor is stabilized against chemical degradation.

4 . The pharmaceutical composition according to claim 1 , wherein the basic amino acid having an intramolecular amino group and alkaline characteristics is selected from the group consisting of L-arginine, L-lysine and L-histidine.

5 . The pharmaceutical composition according to claim 1 , wherein the DPP-4 inhibitor is present in a dosage strength of 0.5, 1, 2.5, 5 or 10 mg; or wherein the DPP-4 inhibitor is present in a dosage strength of 2.5 mg.

6 . The pharmaceutical composition according to claim 1 , wherein the metformin hydrochloride is present in a dosage range from about 100 mg to about 1500 mg; or wherein the metformin hydrochloride is present in a dosage strength of 250, 500, 625, 750, 850 or 1000 mg; or wherein the metformin hydrochloride is present in a dosage strength of 500 mg, 850 mg or 1000 mg.

7 . The pharmaceutical composition according to claim 1 , wherein the nucleophilic and/or basic agent or the buffering agent is L-arginine.

8 . The pharmaceutical composition according to claim 7 , wherein L-arginine is present from about 1 mg to about 50 mg, or from about 1 mg to about 25 mg.

9 . The pharmaceutical composition according to claim 7 , wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio from about 1:20 to about 10:1, or from about 1:15 to about 10:1, or from about 1:10 to about 10:1.

10 . The pharmaceutical composition according to claim 1 , wherein the excipients are selected from the group consisting of:

one or more fillers selected from the group consisting of D-mannitol, corn starch and pregelatinized starch;

a binder which is copovidone;

a lubricant which is magnesium stearate; and

a glidant which is colloidal anhydrous silica.

11 . The pharmaceutical composition according to claim 1 , further comprising copovidone as binder; and optionally one or more of the following: a filler which is corn starch, a lubricant which is magnesium stearate, and a glidant which is colloidal anhydrous silica.

12 . The pharmaceutical composition according to claim 1 , wherein the composition is in the dosage form of a tablet; wherein the tablet is selected from the group consisting of a mono-layer tablet, a bi-layer tablet, a press-coated tablet, and a tablet which is film-coated for drug-loading.

13 . The pharmaceutical composition according to claim 12 , wherein the tablet comprises a film-coat.

14 . The pharmaceutical composition according to claim 13 , wherein the film-coat comprises:

a film-coating agent;

a plasticizer;

optionally a glidant, and

optionally one or more pigments.

15 . The pharmaceutical composition according to claim 12 , wherein the composition is an immediate release dosage form, characterized in that in a dissolution test after 45 minutes at least 75% by weight of each of the DPP-4 inhibitor and partner drug is dissolved.

16 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is in the dosage form of a coated tablet, which comprises one or more of the following amounts:

0.1-0.5%

DPP-4 inhibitor,

47-85%

metformin HCl,

0.07-2.2%

L-arginine,

3.9-8.1%

binder,

2.3-5.9%

first filler,

0-4.4%

second filler,

0-33%

third filler,

0.7-1.5%

lubricant, and

0.1-0.5%

glidant;

each % by weight of total coated tablet mass.

17 . The pharmaceutical composition according to claim 1 , wherein the 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base has a particle size distribution of X90<200 μm.

18 . The pharmaceutical composition according to claim 17 , wherein the 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base has a particle size distribution of X90≤50 μm.

19 . The pharmaceutical composition according to claim 17 , wherein the 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base has a particle size distribution of 10 μm≤X90≤50 μm.

20 . The pharmaceutical composition according to claim 1 , wherein the composition contains about <5%, or about <4%, or about <3%, or less than about 2%, of the individual or total impurity or degradation product(s) by total weight.

21 . The pharmaceutical composition according to claim 1 , which includes less than 1% of the individual or total impurity or degradation product(s) by total weight.

22 . The pharmaceutical composition according to claim 1 , which includes less than 0.5% of the individual or total impurity or degradation product(s) by total weight.

23 . The pharmaceutical composition according to claim 1 , which includes less than 0.2% of the individual or total impurity or degradation product(s) by total weight.