Pharmaceutical composition comprising quinoline derivative or salt thereof

Abstract

The present invention provides a pharmaceutical composition containing a quinoline derivative or a salt thereof. Specifically, the invention provides a pharmaceutical composition containing (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propeneamide or a pharmaceutically acceptable salt thereof, a cross-linked polyvinylpyrrolidone, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition has a property of rapid dissolution.

Claims

1. A pharmaceutical composition, comprising: 1) an active drug that is (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propeneamide or a pharmacologically acceptable salt thereof; and 2) cross-linked polyvinylpyrrolidone.

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

3. The pharmaceutical composition according to claim 2, wherein the pharmacologically acceptable salt is a dimaleate salt.

4. The pharmaceutical composition according to claim 1, wherein the cross-linked polyvinylpyrrolidone is present in an amount of 2%-20% by weight, relative to the total weight of the composition.

5. The pharmaceutical composition according to claim 1, wherein the active drug is present in an amount of 5%-70% by weight, relative to the total weight of the composition.

6. The pharmaceutical composition according to claim 1, further comprising a binder, wherein the binder is one or more selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose, and wherein the binder is present in an amount of 0.5%-15% by weight, relative to the total weight of the composition.

7. The pharmaceutical composition according to claim 1, further comprising a filler, wherein the filler is one or more selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose, and wherein the filler is present in an amount of 5%-80% by weight, relative to the total weight of the composition.

8. The pharmaceutical composition according to claim 1, further comprising a lubricant, wherein the lubricant is one or more selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and colloidal silicon dioxide, and wherein the lubricant is present in an amount of 0.5%-5% by weight, relative to the total weight of the composition.

9. The pharmaceutical composition according to claim 1, wherein a wetting agent is used in preparation of the pharmaceutical composition, and wherein the wetting agent comprises at least one organic solvent.

10. The pharmaceutical composition according to claim 9, wherein the wetting agent further comprises water.

11. The pharmaceutical composition according to claim 9, wherein the organic solvent is ethanol or acetone.

12. The pharmaceutical composition according to claim 9, wherein the organic solvent is present in an amount of 20-100 wt %, relative to the total weight of the wetting agent.

13. The pharmaceutical composition according to claim 11, wherein the organic solvent is ethanol.

14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral solid formulation.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a tablet or a capsule.

16. A method of treating cancer, comprising administering to a subject in need thereof the pharmaceutical composition according to claim 1.

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

18. A pharmaceutical composition, comprising: 1) 5-70 wt % of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propeneamide or a pharmacologically acceptable salt thereof; 2) 2-20 wt % of cross-linked polyvinylpyrrolidone; 3) 5-80 wt % of a filler, wherein the filler is one or more selected from the group consisting of lactose and microcrystalline cellulose; 4) 0.5-15 wt % of a binder, wherein the binder is one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose and hydroxypropyl cellulose; and 5) 0.5-5 wt % of a lubricant, wherein the lubricant is one or more selected from the group consisting of magnesium stearate and talc.

19. A method for preparing the pharmaceutical composition according to claim 1, comprising mixing (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propeneamide or the pharmacologically acceptable salt thereof and cross-linked polyvinylpyrrolidone.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the dissolution profiles of the tablets of Example 1 and Comparative Examples 1-4 in a 0.1 mol/L hydrochloric acid solution.

(2) FIG. 2 shows the dissolution profiles of the tablets of Examples 2-7 in a 0.1 mol/L hydrochloric acid solution.

(3) FIG. 3 shows the particle size distribution of Examples 8-12 and Comparative Example 5.

(4) FIG. 4 shows the dissolution profiles of multiple tablet samples of Comparative Example 5 in a 0.1 mol/L hydrochloric acid solution.

(5) FIG. 5 shows the dissolution profiles of multiple tablet samples of Example 8 in a 0.1 mol/L hydrochloric acid solution.

(6) FIG. 6 shows the dissolution profiles of multiple tablet samples of Example 9 in a 0.1 mol/L hydrochloric acid solution.

(7) FIG. 7 shows the dissolution profiles of multiple tablet samples of Example 10 in a 0.1 mol/L hydrochloric acid solution.

(8) FIG. 8 shows the dissolution profiles of multiple tablet samples of Example 11 in a 0.1 mol/L hydrochloric acid solution.

(9) FIG. 9 shows the dissolution profiles of multiple tablet samples of Example 12 in a 0.1 mol/L hydrochloric acid solution.

DETAILED DESCRIPTION OF THE INVENTION

(10) The present invention will be further described in detail 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.

Example 1, Comparative Examples 1-4

(11) The maleate salt of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propeneamide (hereinafter referred to as compound A), lactose, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone were mixed in a ratio of Example 1 shown in Table 1. Wet granulation was carried out using an appropriate amount of 93.75 wt % ethanol solution in water as a wetting agent. The granules were dried until the moisture content was lower than 2%, and then dry milling was carried out. A prescription amount of magnesium stearate was added, and the mixture was mixed by a rotating mixer. The resulting total mixed granules were tableted and coated to prepare tablets. The tablets of Comparative Examples 1-4 that comprise low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, or starch were prepared according to the same method.

(12) TABLE-US-00001 TABLE 1 Comparative Comparative Comparative Comparative Components Example 1 Example 2 Example 3 Example 4 Example 1 Compound A 31.1 31.1 31.1 31.1 31.1 Lactose 39.6 39.6 39.6 39.6 39.6 Microcrystalline 20.0 20.0 20.0 20.0 20.0 cellulose Cross-linked 0 0 0 0 5 polyvinylpyrrolidone Low-substituted 5 0 0 0 0 hydroxypropyl cellulose Sodium carboxymethyl 0 5 0 0 0 starch Croscarmellose 0 0 5 0 0 sodium Starch 0 0 0 5 0 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 Unit: weight %

(13) Experimental Example 1: Dissolution Test

(14) The dissolution tests of the tablets of Example 1 and Comparative Examples 1-4 were carried out according to the second method (paddle method) of the dissolution rate test described in the appendix of volume II of Chinese Pharmacopeia (2010 edition), using 900 ml of 0.1 mol/L hydrochloric acid solution as a dissolution medium at 37±0.5° C. and at the paddle speed of 50 rpm. The results showed that in the tablets of Example 1 that comprise cross-linked polyvinylpyrrolidone, the dissolution of compound A was rapid and complete, however in the tablets of Comparative Examples 1-4 that comprise low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium or starch, the dissolution of compound A was slow and incomplete.

(15) The dissolution profiles are shown in FIG. 1.

Examples 2-7

(16) Compound A, lactose, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone were mixed in a ratio shown in Table 2. Wet granulation was carried out using an appropriate amount of 93.75 wt % ethanol solution in water as a wetting agent. The granules were dried until the moisture content was lower than 2%, and then dry milling was carried out. A prescription amount of magnesium stearate was added, and the mixture was mixed by a rotating mixer. The resulting total mixed granules were tableted and coated to prepare tablets.

(17) TABLE-US-00002 TABLE 2 Components Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Compound A 31.1 31.1 31.1 31.1 15.5 46.6 Lactose 42.6 36.6 29.6 24.6 52.2 21.1 Microcrystalline 20.0 20.0 20.0 20.0 20.0 20.0 cellulose Cross-linked 2 8 15 20 8 8 polyvinylpyrrolidone Polyvinylpyrrolidone 3.3 3.3 3.3 3.3 3.3 3.3 Magnesium stearate 1.0 1.0 1.0 1.0 1.0 1.0 Total 100 100 100 100 100 100 Unit: weight %

(18) Experimental Example 2: Dissolution Test

(19) The dissolution tests of the tablets of Examples 2-7 were carried out according to the second method (paddle method) of the dissolution rate test described in the appendix of volume II of Chinese Pharmacopeia (2010 edition), using 900 ml of 0.1 mol/L hydrochloric acid solution as a dissolution medium at 37±0.5° C. and at the paddle speed of 50 rpm. The results showed that in the tablets of Examples 2-5 that comprise cross-linked polyvinylpyrrolidone in different ratios and the tablets of Examples 6-7 that comprise compound A in different ratios, the dissolution of compound A was rapid and complete.

(20) The dissolution profiles are shown in FIG. 2.

Examples 8-12, Comparative Example 5

(21) Compound A, lactose, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone were mixed in a ratio shown in Table 3. Wet granulation was carried out using an appropriate amount of purified water, 20 wt % ethanol solution in water, 50 wt % ethanol solution in water, 80 wt % ethanol solution in water, 93.75 wt % ethanol solution in water and anhydrous ethanol respectively as a wetting agent. The granules were dried until the moisture content was lower than 2%, and then dry milling was carried out. A prescription amount of magnesium stearate was added, and the mixture was mixed by a rotating mixer. 100 g of the resulting total mixed granules were separated for sieving, and the rest of the granules were tableted and coated to prepare tablets.

(22) TABLE-US-00003 TABLE 3 Comparative Ingredients Example 5 Example 8 Example 9 Example 10 Example 11 Example 12 Compound A 31.1 31.1 31.1 31.1 31.1 31.1 Lactose 40.6 40.6 36.6 32.6 32.6 29.6 Microcrystalline 20.0 20.0 20.0 20.0 20.0 20.0 cellulose Cross-linked 8 8 8 8 8 8 polyvinylpyrrolidone Polyvinylpyrrolidone 3.3 3.3 3.3 3.3 3.3 3.3 Magnesium stearate 1.0 1.0 1.0 1.0 1.0 1.0 Total 100 100 100 100 100 100 Wetting agent Purified 20 wt % 50 wt % 80 wt % 93.75 wt % Anhydrous water Ethanol Ethanol Ethanol Ethanol ethanol Unit: weight %

(23) Experimental Example 3: Sieving Test

(24) 100 g of separated granules obtained in Examples 8-12 and Comparative Example 5 were shaken and sieved by using 50 mesh and 100 mesh screens. When purified water was used as a wetting agent in Comparative Example 5, there were a lot of large particle and fine powder in the resulting granule, and the particle size distribution was undesirable. When wetting agents comprising ethanol were used in Examples 8-12, there were less large particle and fine powder in the resulting granule, and the particle size distribution was more uniform.

(25) The sieving results are shown in FIG. 3.

(26) Experimental Example 4: Dissolution Test

(27) The dissolution tests of the tablets of Examples 8-12 and Comparative Example 5 were carried out according to the second method (paddle method) of the dissolution rate test described in the appendix of volume II of Chinese Pharmacopeia (2010 edition), using 900 ml of 0.1 mol/L hydrochloric acid solution as a dissolution medium at 37±0.5° C. and at the paddle speed of 50 rpm. The results showed that when 20 wt % ethanol solution in water, 50 wt % ethanol solution in water, 80 wt % ethanol solution in water, 93.75 wt % ethanol solution in water and anhydrous ethanol were used respectively as a wetting agent in Examples 8-12, the resulting granules had a desirable particle size distribution, and the dissolution of compound A was rapid and complete; when purified water was used as a wetting agent in Comparative Example 5, in the resulting tablets, the dissolution uniformity of compound A was poor. When wetting agents comprising ethanol were used as wetting agents in Examples 8-12, in the resulting tablets, the dissolution uniformity of compound A was good.

(28) The dissolution profiles are shown in FIGS. 4-9, and the R1-R6 shown in the figures represent tested samples Tablet 1-Tablet 6.