Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
A pharmaceutical composition comprising: an active ingredient consisting of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, salt thereof, or solvate of the foregoing; and (i) a compound, a 5% (w/w) aqueous solution or suspension of which has a pH of 8 or more, and/or (ii) silicic acid, salt thereof, or solvate of the foregoing is a highly stable pharmaceutical composition, wherein under humidified and heated storage conditions, the decomposition of said compound is sufficiently reduced, or the gelation on the surface of the pharmaceutical composition is sufficiently inhibited.
1. A pharmaceutical composition comprising:
an active ingredient consisting of 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a salt thereof, or a solvate of either of the foregoing; and
1-10 w/w % of one or more stabilizer compounds selected from the group consisting of magnesium oxide, calcium oxide, sodium carbonate, disodium hydrogenphosphate, sodium citrate, dipotassium hydrogenphosphate, sodium acetate, sodium hydrogencarbonate, and sodium hydroxide, wherein the 1-10 w/w % represents a percentage of the total weight of the pharmaceutical composition.
2. The pharmaceutical composition according to claim 1 , wherein the active ingredient is a hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate, or ethanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a solvate of any one of the foregoing salts.
3. The pharmaceutical composition according to claim 1 , wherein the active ingredient is a methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a solvate of the salt.
4. The pharmaceutical composition according to claim 1 , wherein the active ingredient is a methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
5. The pharmaceutical composition according to claim 1 , wherein the active ingredient is a hydrate of a methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
6. The pharmaceutical composition according to claim 1 , wherein the active ingredient is a dimethyl sulfoxide solvate of a methanesulfonate salt of 4-(3-chloro-4(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
7. The pharmaceutical composition according to claim 1 , wherein the active ingredient is an acetic acid solvate of a methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
8. The pharmaceutical composition according to claim 4 , wherein the methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is crystalline and has a powder X-ray diffraction pattern comprising diffraction peaks at diffraction angles (2θ±0.2°) 9.65° and 18.37° that are characteristic of form (A).
9. The pharmaceutical composition according to claim 4 , wherein the methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is crystalline and has a powder X-ray diffraction pattern comprising diffraction peaks at diffraction angles (2θ±0.2°) 5.72° and 13.84° that are characteristic of form (B).
10. The pharmaceutical composition according to claim 5 , wherein the hydrate of a methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is crystalline and has a powder X-ray diffraction pattern comprising diffraction peaks at diffraction angles (2θ±0.2°) 8.02° and 18.14° that are characteristic of form (F).
11. The pharmaceutical composition according to claim 7 , wherein the acetic acid solvate of a methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is crystalline and has a powder X-ray diffraction pattern comprising diffraction peaks at diffraction angles (2θ±0.2°) 9.36° and 12.40° that are characteristic of form (I).
12. The pharmaceutical composition according to claim 8 , wherein the crystalline salt is prepared by a process comprising mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a solvent, and methanesulfonic acid to dissolve the carboxamide.
13. The pharmaceutical composition according to claim 8 , wherein the crystalline salt is prepared by a process comprising mixing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid, and methanesulfonic acid to dissolve the carboxamide.
14. The pharmaceutical composition according to claim 9 , wherein the crystalline salt is prepared by a process comprising removing acetic acid from a crystalline acetic acid solvate of a methanesulfonate salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide having form (I).
15. The pharmaceutical composition according to claim 10 , wherein the crystalline salt is prepared by a process comprising mixing together 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid, and methanesulfonic acid to dissolve the carboxamide.
16. The pharmaceutical composition according to claim 11 , wherein the crystalline salt is prepared by a process comprising mixing together 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, acetic acid, and methanesulfonic acid to dissolve the carboxamide.
17. The pharmaceutical composition of claim 1 wherein the stabilizer compound is magnesium oxide.
18. The pharmaceutical composition of claim 4 wherein the stabilizer compound is magnesium oxide.
19. A process for improving stability of a pharmaceutical composition comprising an active ingredient consisting of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a salt thereof, or a solvate of either of the foregoing, comprising adding 1-10 w/w % of one or more stabilizer compounds selected from the group consisting of magnesium oxide, calcium oxide, sodium carbonate, disodium hydrogenphosphate, sodium citrate, dipotassium hydrogenphosphate, sodium acetate, sodium hydrogencarbonate, and sodium hydroxide, wherein the 1-10 w/w % represents a percentage of the total weight of the pharmaceutical composition.