PHARMACEUTICAL COMPOSITIONS OF COMBINATIONS OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS WITH PIOGLITAZONE
This invention relates to pharmaceutical compositions comprising fixed-dose combinations of a dipeptidyl peptidase-4 inhibitor and pioglitazone, methods of preparing such pharmaceutical compositions, and methods of treating Type 2 diabetes with such pharmaceutical compositions.
1 . A pharmaceutical composition comprising:
(a) an intragranular portion comprising
(i) about 15 to 60% by weight of a dipeptidyl peptidase-4 inhibitor, or a pharmaceutically acceptable salt thereof;
(ii) about 2 to 24% by weight of pioglitazone hydrochloride; and
(iii) about 1 to 8% by weight of a binding agent; and
(b) an extragranular portion.
2 . The pharmaceutical composition of claim 1 wherein the intragranular portion further comprises about 1 to 8% of a disintegrant.
3 . The pharmaceutical composition of claim 1 wherein the extragranular portion comprises one or more excipients selected from the group consisting of: (a) a diluent; (b) a lubricant; and (c) a disintegrant.
4 . The pharmaceutical composition of claim 1 comprising:
(a) an intragranular portion comprising:
(i) about 15 to 60% by weight of a dipeptidyl peptidase-4 inhibitor, or a pharmaceutically acceptable salt thereof;
(ii) about 2 to 24% by weight of pioglitazone hydrochloride; and
(iii) about 1 to 8% by weight of a binding agent; and
(b) an extragranular portion comprising:
(i) about 2 to 9% by weight of a disintegrant;
(ii) about 0 to 80% by weight of a diluent; and
(iii) about 0.1 to 10% by weight of a lubricant.
5 . The pharmaceutical composition of claim 4 wherein the intragranular portion further comprises about 1 to 8% of a disintegrant.
6 . The pharmaceutical composition of claim 4 wherein the binding agent is hydroxypropylcellulose; the disintegrant is crospovidone; the diluent is microcrystalline cellulose, mannitol or anhydrous dibasic calcium phosphate, or a mixture thereof; and the lubricant is magnesium stearate or sodium stearyl fumarate, or a mixture thereof.
7 . The pharmaceutical composition of claim 4 wherein the binding agent is hydroxypropylcellulose; the disintegrant is crospovidone; the diluent is a mixture of microcrystalline cellulose and mannitol; and the lubricant is sodium stearyl fumarate.
8 . The pharmaceutical composition of claim 4 wherein the binding agent is hydroxypropylcellulose; the disintegrant is crospovidone; the diluent is microcrystalline cellulose; and the lubricant is sodium stearyl fumarate.
9 . The pharmaceutical composition of claim 4 wherein the binding agent is hydroxypropylcellulose; the disintegrant is crospovidone; the diluent is a mixture of microcrystalline cellulose and anhydrous dibasic calcium phosphate; and the lubricant is sodium stearyl fumarate.
10 . The pharmaceutical composition of claim 4 wherein the dipeptidyl peptidase-4 inhibitor is selected from the group consisting of alogliptin, carmegliptin, denagliptin, dutogliptin, linagliptin, melogliptin, saxagliptin, sitagliptin, and vildagliptin, or a pharmaceutically acceptable salt of each thereof.
11 . The pharmaceutical composition of claim 10 wherein the dipeptidyl peptidase-4 inhibitor is sitagliptin, or the dihydrogenphosphate salt thereof.
12 . The pharmaceutical composition of claim 1 comprising:
(a) an intragranular portion comprising:
(i) about 21 to 33% by weight of a dipeptidyl peptidase-4 inhibitor, or a pharmaceutically acceptable salt thereof;
(ii) about 3 to 13% by weight of pioglitazone hydrochloride;
(iii) about 2 to 6% by weight of a binding agent; and
(iv) about 2 to 6% of a disintegrant; and
(b) an extragranular portion comprising:
(i) about 2 to 6% by weight of a disintegrant;
(ii) about 40 to 55% by weight of a diluent; and
(iii) about 0.5 to 4% by weight of a lubricant.
13 . The pharmaceutical composition of claim 1 comprising:
(a) an intragranular portion comprising:
(i) about 21 to 33% by weight of a dipeptidyl peptidase-4 inhibitor, or a pharmaceutically acceptable salt thereof;
(ii) about 4 to 13% by weight of pioglitazone hydrochloride;
(iii) about 2 to 6% by weight of a binding agent; and
(iv) about 2 to 4% of a disintegrant; and
(b) an extragranular portion comprising:
(i) about 2 to 5% by weight of a disintegrant;
(ii) about 44 to 54% by weight of a diluent; and
(iii) about 0.5 to 4% by weight of a lubricant.
14 . The pharmaceutical composition of claim 1 comprising:
(a) an intragranular portion comprising:
(i) about 21 to 33% by weight of a dipeptidyl peptidase-4 inhibitor, or a pharmaceutically acceptable salt thereof;
(ii) about 4 to 13.5% by weight of pioglitazone hydrochloride;
(iii) about 2 to 6% by weight of a binding agent; and
(iv) about 2 to 4% of a disintegrant; and
(b) an extragranular portion comprising:
(i) about 2 to 5% by weight of a disintegrant;
(ii) about 44 to 55% by weight of a diluent; and
(iii) about 0.5 to 4% by weight of a lubricant.
15 . The pharmaceutical composition of claim 12 wherein the dipeptidyl peptidase-4 inhibitor is sitagliptin, or a pharmaceutically acceptable salt thereof; the lubricant is sodium stearyl fumarate; the binding agent is hydroxypropylcellulose; the diluent is a mixture of microcrystalline cellulose and mannitol; and the disintegrant is crospovidone.
16 . The pharmaceutical composition of claim 12 wherein the dipeptidyl peptidase-4 inhibitor is sitagliptin, or a pharmaceutically acceptable salt thereof; the lubricant is sodium stearyl fumarate; the binding agent is hydroxypropylcellulose; the diluent is a mixture of microcrystalline cellulose and anhydrous dibasic calcium phosphate; and the disintegrant is crospovidone.
17 . The pharmaceutical composition of claim 12 wherein the dipeptidyl peptidase-4 inhibitor is present in a unit dosage strength of 25, 50, 75, 100, 150, or 200 milligrams, and the pioglitazone is present in a unit dosage strength of 15, 30, or 45 milligrams.
18 . The pharmaceutical composition of claim 17 wherein the dipeptidyl peptidase-4 inhibitor is present in a unit dosage strength of 50 or 100 milligrams, and the pioglitazone is present in a unit dosage strength of 15, 30, or 45 milligrams.
19 . The pharmaceutical composition of claim 18 wherein the dipeptidyl peptidase-4 inhibitor is sitagliptin.
20 . The pharmaceutical composition of claim 19 wherein the sitagliptin is present in a unit dosage strength of 50 or 100 milligrams, and the pioglitazone is present in a unit dosage strength of 15, 30 or 45 milligrams.
21 . The pharmaceutical composition of claim 1 wherein the composition is in the dosage form of a tablet.
22 . A method of treating Type 2 diabetes in a human in need thereof comprising orally administering to the human a pharmaceutical composition of claim 1 .
23 . The pharmaceutical composition of claim 1 further comprising one or more agents selected from the group consisting of flavoring agents, colorants, and sweeteners.
24 . The pharmaceutical composition of claim 1 prepared by wet granulation methods,
25 . The pharmaceutical composition of claim 1 wherein the dipeptidyl peptidase-4 inhibitor is vildagliptin, or a pharmaceutically acceptable salt of each thereof.
26 . The pharmaceutical composition of claim 1 wherein the dipeptidyl peptidase-4 inhibitor is saxagliptin, or a pharmaceutically acceptable salt of each thereof.
27 . The pharmaceutical composition of claim 1 wherein the dipeptidyl peptidase-4 inhibitor is alogliptin, or a pharmaceutically acceptable salt of each thereof.