Pharmaceutical composition containing quinoline derivative

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.

Claims

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.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

(1) FIG. 1 shows the dissolution curves of tablets of Example 1 and Comparative Example 1 in 0.1 mol/L of hydrochloric acid solution

(2) FIG. 2 shows the dissolution curves of tablets of Example 2 and Comparative Example 2 in 0.1 mol/L of hydrochloric acid solution.

(3) FIG. 3 shows the dissolution curves of tablets of Example 3 and Comparative Example 3 in 0.1 mol/L of hydrochloric acid solution.

(4) FIG. 4 shows the dissolution curve of tablets of Example 4 and Comparative Example 4 in 0.1 mol/L of hydrochloric acid solution.

(5) FIG. 5 shows the dissolution curve of tablets of Example 5 and Comparative Example 5 in 0.1 mol/L of hydrochloric acid solution.

DETAILED DESCRIPTION OF THE INVENTION

(6) The present invention is further illustrated by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Examples 1-5

(7) (R, E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy) phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidinyl-2-yl)-acrylamide maleate (hereinafter referred as Compound A), lactose, microcrystalline cellulose, polyvinylpyrrolidone and cross-linked polyvinylpyrrolidone were mixed according to the prescription ratio prescription in Table 1, wet granulation was carried out by using an appropriate amount of 20 wt % aqueous ethanol, anhydrous ethanol, and 93.75 wt % aqueous ethanol as wetting agents. The wet particles were placed in a fluidized bed, and the fan flow was set at 5-15 m.sup.3/min, inlet air temperature was set at 50-70° C., material temperature was set at 20-55° C., and drying time was set at 10-30 min. Dynamic drying was performed until the moisture became less than 2%, and dry granulating was carried out, the prescription amount of magnesium stearate was added, and mixed in a rotary mixer. The obtained total mixed particles were compressed and coated to prepare tablets.

(8) TABLE-US-00001 TABLE 1 Ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Preparation 10.3 7.3 9.0 18.0 6.4 quantity (kg) Compound 27.1 38.1 31.1 15.5 43.6 A Lactose 40.6 29.6 36.6 52.2 24.1 Micro- 20.0 20.0 20.0 20.0 20.0 crystaline cellulose Cross- 8 8 8 8 8 linked polyvinyl- pyrrolidone Polyvinyl- 3.3 3.3 3.3 3.3 3.3 pyrrolidone Magnesium 1.0 1.0 1.0 1.0 1.0 stearate Total 100 100 100 100 100 Wetting 20 wt anhydrous 93.75 wt 93.75 wt 93.75 wt agent % ethanol % % % aqueous aqueous aqueous aqueous ethanol ethanol ethanol ethanol Unit: mass %.

Experimental Example 1: Dissolution Experiment

(9) The dissolution rates of tablets of Examples 1-5 were measured according to the second method of General Regulation 0931 of the Chinese Pharmacopoeia 2015 (Volume IV). 900 mL of a 0.1 mol/L hydrochloric acid solution was used as the dissolution medium, and a dissolution test was performed at a paddle speed of 50 rpm at 37±0.5° C. The results show that Compound Ain the particles prepared by the dynamic drying process in Examples 1-5 was dissolved rapidly and completely. The results of the dissolution experiment are shown in Table 2 and the comparison diagrams of the dissolution curves are shown in FIGS. 1-5.

(10) TABLE-US-00002 TABLE 2 Time Dissolution rates (%) (min) Example 1 Example 2 Example 3 Example 4 Example 5 15 61.2 82.5 78.6 89.5 52.2 30 93.9 97.7 98.4 98.8 90.5

Comparative Examples 1-5

(11) (R, E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy) phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidinyl-2-yl)-acrylamide maleate (hereinafter referred as Compound A), lactose, microcrystalline cellulose, polyvinylpyrrolidone and cross-linked polyvinylpyrrolidone were mixed according to the prescription ratio in Table 3, wet granulation was carried out by using an appropriate amount of 20 wt % a aqueous ethanol, anhydrous ethanol, and 93.75 wt % aqueous ethanol as wetting agents. The wet particles were placed in a blast air drying oven, and dried at the drying temperature set at 50-60° C. for 60-180 min, the particles were turned over every 30 min. Static drying was performed until the moisture became less than 2%, and dry granulating was carried out, the prescription amount of magnesium stearate was added, and mixed in a rotary mixer. The obtained total mixed particles were compressed and coated to prepare tablets.

(12) TABLE-US-00003 TABLE 3 Comparative Comparative Comparative Comparative Comparative Ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Preparation quantity 10.3 7.3 9.0 18.0 6.4 (kg) Compound A 27.1 38.1 31.1 15.5 43.6 Lactose 40.6 29.6 36.6 52.2 24.1 Microcrystaline 20.0 20.0 20.0 20.0 20.0 cellulose Cross-linked 8 8 8 8 8 polyvinylpyrrolidone Polyvinylpyrrolidone 3.3 3.3 3.3 3.3 3.3 Magnesium stearate 1.0 1.0 1.0 1.0 1.0 Total 100 100 100 100 100 Wetting agent 20 wt % anhydrous 93.75 wt % 93.75 wt % 93.75 wt % aqueous ethanol aqueous aqueous aqueous ethanol ethanol ethanol ethanol Unit: mass %.

Experimental Example 2: Dissolution Experiment

(13) The dissolution rates of tablets of Comparative Examples 1-5 were measured according to the second method of General Regulation 0931 of the Chinese Pharmacopoeia 2015 (Volume IV). 900 mL of a 0.1 mol/L hydrochloric acid solution was used as the dissolution medium, and a dissolution test was performed at a paddle speed of 50 rpm at 37±0.5° C. The results show that the dissolution rate of the Compound A in the tablets of Comparative Examples 1-5 prepared by the static drying process was significantly lower than that of the tablets with the same prescription of Examples prepared by the dynamic drying process. The results of the dissolution experiments are shown in Table 4, and the comparison diagrams of the dissolution curves are shown in FIGS. 1-5.

(14) TABLE-US-00004 TABLE 4 Dissolution rates (%) Com- Com- Com- Com- Com- parative parative parative parative parative Time Example Example Example Example Example (min) 1 2 3 4 5 15 36.6 44.8 47.2 51.4 32.5 30 68.4 82.3 83.1 86.3 61.7