IMMEDIATE-RELEASE TABLET FORMULATIONS OF A THROMBIN RECEPTOR ANTAGONIST
Immediate-release formulations for oral administration of a thrombin receptor antagonist are provided. Certain formulations of higher API loading demonstrate sufficient moisture uptake after storage at stressed conditions to retard dissolution. The formulations of the present invention incorporate either lower API loading or elevated disintegrant-to-API ratios, found necessary to achieve disintegration rates required for immediate-release performance.
1 . A solid pharmaceutical formulation for oral administration comprising COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof and at least one disintegrant, wherein the amount of COMPOUND 1 is less than about 10% of the weight of the formulation.
2 . The pharmaceutical formulation according to claim 1 , wherein said formulation is a tablet.
3 . The pharmaceutical formulation according to claim 1 , wherein the amount of COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof is less than about 7% of the weight of the formulation.
4 . The pharmaceutical formulation according to claim 1 , wherein the ratio of disintegrant to COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof is between about 0.6 and about 12 on a weight/weight basis.
5 . The pharmaceutical formulation according to claim 1 , wherein said ratio is between about 0.75 and about 1.0.
6 . The pharmaceutical formulation according to claim 5 , wherein said ratio is about 0.9.
7 . The pharmaceutical formulation according to claim 4 , wherein said ratio is about 2.4.
8 . The pharmaceutical formulation according to claim 1 , wherein the weight of COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof is between about 10 and about 50 mg and the total weight of the formulation is between about 200 and about 1500 mg.
9 . The pharmaceutical formulation according to claim 1 , wherein the weight of COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof is about 40 mg and the total weight of the formulation is between about 400 and about 800 mg.
10 . The pharmaceutical formulation according to claim 1 , wherein the weight of COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof is about 40 mg and the total weight of the formulation is about 600 mg.
11 . The pharmaceutical formulation according to claim 1 wherein the weight of COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof is between about 0.5 mg and about 10 mg and the total weight of the formulation is between about 100 mg and 400 mg.
12 . The pharmaceutical formulation according to claim 1 , wherein the weight of COMPOUND 1 or a pharmaceutically acceptable salt or solvate thereof is about 2.5 mg and the total weight of the formulation is about 100 mg.
13 . The pharmaceutical formulation according to claim 1 , wherein the COMPOUND 1 is a bisulfate salt.
14 . The pharmaceutical formulation according to claim 1 resulting in a 30-minute dissolution of COMPOUND 1 of at least about 80%.
15 . The pharmaceutical formulation according to claim 1 resulting in a 30-minute dissolution of COMPOUND 1 of at least about 85%.
16 . The pharmaceutical formulation according to claim 1 wherein said disintegrant is selected from the group consisting of croscarmellose sodium, starch, sodium starch glycolate, crospovidone and microcrystalline cellulose.
17 . The pharmaceutical formulation according to claim 1 wherein said disintegrant is croscarmellose sodium.
18 . The pharmaceutical formulation according to claim 1 further comprising at least one diluent, at least one binder and at least one lubricant.
19 . The pharmaceutical formulation according to claim 18 wherein said diluent is selected from one or more of the group consisting of lactose monohydrate, microcrystalline cellulose, mannitol, sorbitol, tribasic calcium phosphate, diabasic calcium phosphate, compressible sugar, starch, and calcium sulfate.
20 . The pharmaceutical formulation according to claim 18 wherein said diluent is selected from one or more of the group consisting of lactose monohydrate and microcrystalline cellulose.
21 . The pharmaceutical formulation according to claim 18 wherein said binder is selected from the group consisting of povidone, acacia, tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sucrose, sorbitol, and ethylcellulose.
22 . The pharmaceutical formulation according to claim 18 wherein said binder is povidone.
23 . The pharmaceutical formulation according to claim 18 wherein said lubricant is selected from the group consisting of magnesium stearate, stearic acid and talc.
24 . The pharmaceutical formulation according to claim 18 wherein said lubricant is magnesium stearate.
25 . A solid pharmaceutical formulation for oral administration comprising about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof and at least about 5 wt percent of a disintegrant.
26 . The formulation according to claim 25 , wherein the total weight of said formulation is between about 100 mg and about 1000 mg.
27 . The formulation according to claim 25 , wherein the total weight of said formulation is about 600 mg.
28 . The formulation according to claim 25 , wherein said formulation is a tablet.
29 . A solid pharmaceutical formulation for oral administration comprising:
Ingredient
Amount (mg)
COMPOUND 1 Bisulfate
40
Lactose Monohydrate
383
Microcrystalline Cellulose
120
Croscarmellose Sodium
36
Povidone
18
Magnesium Stearate
3.
30 . A solid pharmaceutical formulation for oral administration comprising about 2.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof and at least about 5 weight percent of a disintegrant.
31 . The formulation according to claim 30 , wherein the total weight of said formulation is between about 50 mg and about 400 mg.
32 . The formulation according to claim 30 , wherein the total weight of said formulation is about 100 mg.
33 . The formulation according to claim 30 , wherein said formulation is a tablet.
34 . A solid pharmaceutical formulation for oral administration comprising:
Ingredient
Amount (mg)
COMPOUND 1 Bisulfate
2.5
Lactose Monohydrate
68
Microcrystalline Cellulose
20
Croscarmellose Sodium
6
Povidone
3
Magnesium Stearate
0.5.
35 . An immediate-release tablet formulation of a thrombin receptor antagonist that results in a 30-minute dissolution of said thrombin receptor antagonist of at least about 80%, wherein said thrombin receptor antagonist is selected from the group consisting of:
or a pharmaceutically acceptable isomer, salt or solvate thereof.
36 . A method of treating acute coronary syndrome by orally administering to a patient in need of such treating the pharmaceutical formulation according to any of claims 1 , 3 , 5 , 9 , 12 , 25 , 30 and 35 .
37 . A method of treating a patient in need of secondary prevention by orally administering to said patient the pharmaceutical formulation according to any of claims 1 , 3 , 5 , 9 , 12 , 25 , 30 and 35 .
38 . A method of treating peripheral arterial disease by orally administering to a patient in need of such treating the pharmaceutical formulation according to any of claims 1 , 3 , 5 , 9 , 12 , 25 , 30 and 35 .