Pharmaceutical composition containing quinoline derivative

Patent metadata

Field	Value
Publication number	US-11701349-B2
Application number	US-201816757363-A
Country	US
Kind code	B2
Filing date	Oct 23, 2018
Priority date	Oct 24, 2017
Publication date	Jul 18, 2023
Grant date	Jul 18, 2023

Abstract

The present invention provides a pharmaceutical composition comprising (R, E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy) phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidinyl-2-yl)-acrylamide or a pharmacologically acceptable salt thereof, which is obtained by mixing the quinoline derivative or a pharmacologically acceptable salt thereof, a wetting agent, a disintegrant, and at least one pharmaceutical excipient; granulating; dynamic drying; and optionally compressing into tablets or filling into capsules after mixing with a lubricant.

First claim

What is claimed is:

1. A pharmaceutical composition comprising an active ingredient (R, E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy) phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidinyl-2-yl)-acrylamide or a pharmacologically acceptable salt thereof, a disintegrant, a filler, an adhesive and a lubricant;
the pharmaceutical composition is obtained by a) mixing the active ingredient (R, E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy) phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidinyl-2-yl)-acrylamide or the pharmacologically acceptable salt thereof with the disintegrant, the filler, and the adhesive;
b) wet granulating by adding a wetting agent;
c) fluidized drying;
d) adding the lubricant and mixing; and
e) compressing into tablets or filling into capsules;
wherein the wetting agent is ethanol or ethanol and water, wherein the disintegrant is cross-linked polyvinyl pyrrolidone, and wherein the wet granulating is fluidized bed spray granulating.

2. The pharmaceutical composition according to claim 1 , wherein the filler is selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose.

3. The pharmaceutical composition according to claim 1 , wherein the adhesive is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose.

4. The pharmaceutical composition according to claim 1 , wherein the lubricant is selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and colloidal silica.

5. The pharmaceutical composition according to claim 1 , wherein the filler is selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose;
the adhesive is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose; and
the lubricant is selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and colloidal silica.

6. The pharmaceutical composition according to claim 1 , wherein the pharmacologically acceptable salt is maleate.

7. The pharmaceutical composition according to claim 1 , wherein the content of the active ingredient is 5%-70%, based on the total weight of the composition.

8. The pharmaceutical composition according to claim 1 , wherein the content of the disintegrant is 2-20% based on the total weight of the composition.

9. The pharmaceutical composition according to claim 2 , wherein the content of the filler is 5-80% based on the total weight of the composition.

10. The pharmaceutical composition according to claim 3 , wherein the content of the adhesive is 0.5-15% based on the total weight of the composition.

11. The pharmaceutical composition according to claim 4 , wherein the content of the lubricant is 0.5-5% based on the total weight of the composition.

12. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition comprises:
1) 2-20 wt % of disintegrant, the disintegrant is cross-linked polyvinyl pyrrolidone;
2) 5-80 wt % of filler, the filler is selected from at least one of lactose and microcrystalline cellulose;
3) 0.5-15 wt % of adhesive, the adhesive is selected from at least one of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose; and
4) 0.5-5 wt % of a lubricant, the lubricant is selected from at least one of magnesium stearate and talc.

13. The pharmaceutical composition according to claim 1 , wherein the dissolution rate (%) of the active ingredient in the pharmaceutical composition reaches 85% or higher at 30 minutes in a 0.1 mol/L hydrochloric acid solution.

14. A process for preparing the pharmaceutical composition according to claim 1 , comprising:
a) mixing the active ingredient (R, E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy) phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidinyl-2-yl)-acrylamide or the pharmacologically acceptable salt thereof with the disintegrant, the filler, and the adhesive;
b) wet granulating by adding the wetting agent;
c) fluidized drying; and
d) adding the lubricant and mixing; and
e) compressing into tablets or filling into capsules.

15. The process for preparing the pharmaceutical composition according to claim 14 , wherein the filler is selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose;
the adhesive is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose; and
the lubricant is selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and colloidal silica.

16. A method for treating cancer comprising administering to a subject thereof a therapeutically effective amount of the pharmaceutical composition according to claim 1 .

17. The method of claim 16 , wherein the cancer is gastric cancer, lung cancer or breast cancer.

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Zhang Xinhua
• Wang Chenyang
• Zhang Daimei
• Bai Jianfeng

Classifications

• A61K31/4709 Primary

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K9/2013 Primary

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title

• A61K9/2027 Primary

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title