PHARMACEUTICAL COMPOSITION CONTAINING QUINOLINE DERIVATIVE

Abstract

The present invention provides a pharmaceutical composition comprising quinoline derivative. Specifically, the present invention provides a process for preparing 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. The process for preparing is suitable for large-scale industrial production, and the obtained sample has the characteristics such as rapid and uniform dissolution.

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, which is obtained by mixing the active ingredient, a wetting agent with at least one pharmaceutical excipient optionally selected from a disintegrant, a filler, an adhesive or a lubricant, granulating, dynamic drying, and optionally compressing into tablets or filling into capsules after mixing with a lubricant.

2. The pharmaceutical composition according to claim 1, wherein, the wetting agent is at least one selected from ethanol, methanol, acetone, isopropanol and water, preferably at least one selected from ethanol, methanol and water.

3. The pharmaceutical composition according to claim 1 or 2, wherein, the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and cross-linked polyvinyl pyrrolidone, the content of the disintegrant is preferably 2-20% based on the total weight of the composition.

4. The pharmaceutical composition according to claim 1 or 2, wherein, the filler is selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch and lactose, the content of the filler is preferably 5-80% based on the total weight of the composition.

5. The pharmaceutical composition according to claim 1 or 2, wherein, the adhesive is preferably selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone and methyl cellulose, the content of the adhesive is preferably 0.5-15% based on the total weight of the composition.

6. The pharmaceutical composition according to claim 1 or 2, 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, the content of the lubricant is preferably 0.5-5% based on the total weight of the composition.

7. The pharmaceutical composition according to any one of claims 1-6, wherein, the dynamic drying is selected from stirring drying and fluidized drying, and preferably fluidized drying.

8. The pharmaceutical composition according to any one of claims 1-7, wherein, the granulating method adopts a high-speed shear granulating method or a fluidized bed spray granulating method.

9. The pharmaceutical composition according to any one of claims 1-8, wherein, the pharmacologically acceptable salt is maleate, preferably dimaleate.

10. The pharmaceutical composition according to any one of claims 1-9, wherein, the content of the active ingredient is 5%-70%, preferably 10%-50%, based on the total weight of the composition.

11. The pharmaceutical composition according to any one of claims 1-10, 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; 4) 0.5-5 wt % of a lubricant, the lubricant is selected from at least one of magnesium stearate and talc.

12. The pharmaceutical composition according to any one of claims 1-11, wherein, under the condition of a 0.1 mol/L hydrochloric acid solution medium, the dissolution rate (%) of the active ingredient in the pharmaceutical composition reaches 85% or higher at 30 minutes, preferably 90% or higher.

13. A process for preparing the pharmaceutical composition according to any one of claims 1-11, 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 a pharmacologically acceptable salt thereof with at least one pharmaceutical excipient optionally selected from a disintegrant, a filler, an adhesive or a lubricant; b) adding a wetting agent for wet granulating; c) dynamic drying, which is preferably fluidized drying; d) adding a lubricant, and compressing into tablets or filling into capsules after mixing.

14. Use of the pharmaceutical composition according to any one of claims 1-12 or the pharmaceutical composition prepared by the process according to claim 13 for preparing a medicine for treating cancer; the cancer is preferably gastric cancer, lung cancer or breast cancer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG. 1 shows the dissolution curves of tablets of Example 1 and Comparative Example 1 in 0.1 mol/L of hydrochloric acid solution

[0037] FIG. 2 shows the dissolution curves of tablets of Example 2 and Comparative Example 2 in 0.1 mol/L of hydrochloric acid solution.

[0038] FIG. 3 shows the dissolution curves of tablets of Example 3 and Comparative Example 3 in 0.1 mol/L of hydrochloric acid solution.

[0039] FIG. 4 shows the dissolution curve of tablets of Example 4 and Comparative Example 4 in 0.1 mol/L of hydrochloric acid solution.

[0040] 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 ILLUSTRATED EMBODIMENTS

[0041] 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

[0042] (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.

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 A 27.1 38.1 31.1 15.5 43.6 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-linked 8 8 8 8 8 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 20wt % anhydrous 93.75wt % 93.75wt % 93.75wt % agent aqueous ethanol aqueous aqueous aqueous ethanol ethanol ethanol ethanol Unit: mass %.

Experimental Example 1: Dissolution Experiment

[0043] 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.

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

[0044] (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.

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 20wt % anhydrous 93.75wt % 93.75wt % 93.75wt % aqueous ethanol aqueous aqueous aqueous ethanol ethanol ethanol ethanol Unit: mass %.

Experimental Example 2: Dissolution Experiment

[0045] 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.

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