DPP-IV INHIBITOR COMBINED WITH A FURTHER ANTIDIABETIC AGENT, TABLETS COMPRISING SUCH FORMULATIONS, THEIR USE AND PROCESS FOR THEIR PREPARATION
The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.
1 . A pharmaceutical composition comprising or made from a DPP-4 inhibitor, a partner drug, and one or more pharmaceutical excipients, and a nucleophilic and/or basic agent for stabilizing said DPP-4 inhibitor against degradation.
2 . The pharmaceutical composition according to claim 1 further comprising a buffering agent for stabilizing said DPP-4 inhibitor against degradation.
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 partner drug is selected from the group consisting of biguanides, thiazolidinones, statins, and Angiotensin II receptor blockers (ARBs).
5 . The pharmaceutical composition according to claim 1 , wherein the nucleophilic and/or basic agent or the buffering agent is a basic amino acid having an intramolecular amino group and alkaline characteristics.
6 . The pharmaceutical composition according to claim 5 , 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.
7 . The pharmaceutical composition according to claim 1 , wherein the DPP-4 inhibitor has an intramolecular free primary or secondary amino group.
8 . The pharmaceutical composition according to claim 1 , wherein the DPP-4 inhibitor is selected from the group consisting of vildagliptin, saxagliptin alogliptin, and 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base.
9 . The pharmaceutical composition according to claim 1 , wherein the DPP-4 inhibitor is present in a dosage range from about 0.5 mg to about 20 mg, or from about 0.5 mg to about 10 mg; or 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.
10 . The pharmaceutical composition according to claim 1 , wherein the partner drug is metformin hydrochloride.
11 . The pharmaceutical composition according to claim 10 , 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.
12 . The pharmaceutical composition according to claim 1 , wherein the nucleophilic and/or basic agent or the buffering agent is L-arginine.
13 . The pharmaceutical composition according to claim 12 , wherein L-arginine is present from about 1 mg to about 50 mg, or from about 1 mg to about 25 mg.
14 . The pharmaceutical composition according to claim 12 , 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.
15 . 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.
16 . The pharmaceutical composition according to claim 1 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.
17 . The pharmaceutical composition according to claim 1 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.
18 . The pharmaceutical composition according to claim 17 , wherein the tablet comprises a film-coat.
19 . The pharmaceutical composition according to claim 18 , wherein the film-coat comprises:
a film-coating agent;
a plasticizer;
optionally a glidant, and
optionally one or more pigments.
20 . The pharmaceutical composition according to claim 1 , in which the pharmaceutical composition is a mono-layer tablet, wherein:
the percentage of metformin hydrochloride is about 85% by weight of total tablet core,
the percentage of DPP-4 inhibitor is about 0.2% -0.4% by weight of total tablet core,
the percentage of L-arginine is about 2% by weight of total tablet core,
the tablet crushing strength is higher than or equal to 100 N,
the tablet friability is lower than or equal to 0.5%,
the tablet thickness is from about 5.7 to about 8.4 mm,
the tablet core weight is from about 590 to about 1180 mg, and/or
the tablet disintegration time is lower than or equal 15 min.
21 . The pharmaceutical composition according to claim 17 , which 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.
22 . A solid pharmaceutical composition comprising or made from
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,
metformin hydrochloride,
L-arginine,
and one or more fillers, one or more binders, one or more glidants and/or one or more lubricants;
optionally wherein 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine has a particle size distribution of X90<200 μm.
23 . 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 (% by weight of total coated tablet mass):
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.
24 . Granules comprising a DPP-4 inhibitor which has a free or primary amino group, metformin hydrochloride, L-arginine, a binder and a filler; optionally said granules prepared by fluid bed granulation.