Method for preparing pharmaceutical composition comprising quinoline derivative or salt thereof

Abstract

The present invention provides a method for preparing a pharmaceutical composition containing a quinoline derivative or a salt thereof. Specifically, the invention provides a method for preparing 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. The method uses a wetting agent containing at least one organic solvent for a wet granulation in a preparation process of the pharmaceutical composition. The pharmaceutical composition prepared using the method has a uniform distribution of grain sizes during the preparation process and a property of rapid and uniform dissolution.

Claims

1. A method for preparing a pharmaceutical composition, comprising: (1) mixing the active ingredient (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 with a wetting agent and one or more additional ingredients to obtain a mixture, (2) granulating the mixture to obtain granules, (3) drying the granules to obtain dried granules, and (4) tableting the dried granules into tablets or filling dried granules into capsules to obtain the pharmaceutical composition, wherein: the wetting agent is a mixed solvent of ethanol and water, the ethanol is present in an amount of 50-80% by weight relative to the total weight of the wetting agent, and the pharmaceutical composition further comprises: 1) 2-20 wt % of a disintegrant, wherein the disintegrant is cross-linked polyvinylpyrrolidone; 2) 5-80 wt % of a filler, wherein the filler is one or more selected from the group consisting of lactose and microcrystalline cellulose; 3) 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 4) 0.5-5 wt % of a lubricant, wherein the lubricant is one or more selected from the group consisting of magnesium stearate and talc, wherein the pharmaceutical composition provides a dissolution rate such that at least 80% of the active ingredient is released from the pharmaceutical composition within 30 minutes when measured in a dissolution medium containing 0.1 mol/L hydrochloric acid solution at 370.5 C. and at a paddle speed of 50 rpm.

2. A pharmaceutical composition prepared by the method according to claim 1.

3. A method of preparing a tablet, comprising: (1) mixing the following ingredients to obtain a first mixture: (i) 10%-50 wt % of the active ingredient (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; (i) 2-20 wt % of a cross-linked polyvinylpyrrolidone; (ii) 5-80 wt % of a filler comprising one or more agents selected from the group consisting of lactose and microcrystalline cellulose; and (iii) 0.5-15 wt % of a binder comprising one or more agents selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose and hydroxypropyl cellulose; (2) granulating the first mixture using a wetting agent to obtain wet granules, wherein the wetting agent contains a mixed solvent of ethanol and water, and ethanol is present in an amount of 50-95% by weight relative to the total weight of the wetting agent; (3) drying the granules to obtain dried granules, (4) mixing the dried granules with 0.5-5 wt % of a lubricant comprising one or more agent selected from the group consisting of magnesium stearate and talc to obtain a second mixture; and (4) tableting the second mixture into the tablets.

4. A pharmaceutical composition prepared by the method according to claim 3.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the particle size distribution of the tablets of Examples 1-5 and Comparative Example 1.

(2) FIG. 2 shows the dissolution profiles of multiple tablet samples of Comparative Example 1 in a 0.1 mol/L hydrochloric acid solution.

(3) FIG. 3 shows the dissolution profiles of multiple tablet samples of Example 1 in a 0.1 mol/L hydrochloric acid solution.

(4) FIG. 4 shows the dissolution profiles of multiple tablet samples of Example 2 in a 0.1 mol/L hydrochloric acid solution.

(5) FIG. 5 shows the dissolution profiles of multiple tablet samples of Example 3 in a 0.1 mol/L hydrochloric acid solution.

(6) FIG. 6 shows the dissolution profiles of multiple tablet samples of Example 4 in a 0.1 mol/L hydrochloric acid solution.

(7) FIG. 7 shows the dissolution profiles of multiple tablet samples of Example 5 in a 0.1 mol/L hydrochloric acid solution.

(8) FIG. 8 shows the dissolution profiles of the tablets of Examples 6-11 in a 0.1 mol/L hydrochloric acid solution.

DETAILED DESCRIPTION OF THE INVENTION

(9) 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.

Examples 1-5, Comparative Example 1

(10) 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 shown in Table 1. 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 with 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.

(11) TABLE-US-00001 TABLE 1 Comparative Example Example Example Example Example Components Example 1 1 2 3 4 5 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 %

Experimental Example 1: Sieving Test

(12) 100 g of separated granules obtained in Examples 1-5 and Comparative Example 1 were shaken and sieved by using 50 mesh and 100 mesh screens. When purified water was used as a wetting agent in Comparative Example 1, there were a lot of large particles and fine powder in the resulting granules, and the particle size distribution was undesirable. When wetting agents comprising ethanol were used in Examples 1-5, there were less large particle and fine powder in the resulting granules, and the particle size distribution was more uniform.

(13) The sieving results are shown in FIG. 1.

Experimental Example 2: Dissolution Test

(14) The dissolution rates of the tablets of Examples 1-5 and Comparative Example 1 were determined according to the second method (paddle method) of the dissolution rate test disclosed in the appendix of volume II of Chinese Pharmacopeia (2010 edition). The dissolution test was carried out using 900 ml of 0.1 mol/L hydrochloric acid solution as a dissolution medium at 370.5 C. and at the paddle speed of 50 rpm. The results show that when 20 wt % ethanol aqueous solution, 50 wt % ethanol aqueous solution, 80 wt % ethanol aqueous solution, 93.75 wt % ethanol aqueous solution and anhydrous ethanol were used respectively as a wetting agent in Examples 1-5, 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 1, in the resulting tablets, the dissolution uniformity of compound A was poor. When wetting agents comprising ethanol were used as wetting agents in Examples 1-5, in the resulting tablets, the dissolution uniformity of compound A was good.

(15) The dissolution profiles are shown in FIGS. 2-7, and the R1-R6 shown in the figures represent tested samples Tablet 1-Tablet 6.

Examples 6-11

(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 aqueous solution 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 with a rotating mixer. The resulting total mixed granules were tableted and coated to prepare tablets.

(17) TABLE-US-00002 TABLE 2 Example Example Example Example Example Example Components 6 7 8 9 10 11 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 Micro- 20.0 20.0 20.0 20.0 20.0 20.0 crystalline cellulose Cross-linked 2 8 15 20 8 8 poly- vinyl- pyrrolidone Polyvinyl- 3.3 3.3 3.3 3.3 3.3 3.3 pyrrolidone Magnesium 1.0 1.0 1.0 1.0 1.0 1.0 stearate Total 100 100 100 100 100 100 Unit: % weight %

Experimental Example 3: Dissolution Test

(18) The dissolution rates of the tablets of Examples 6-11 were determined according to the second method (paddle method) of the dissolution rate test disclosed in the appendix of volume II of Chinese Pharmacopeia (2010 edition). The dissolution test was carried out using 900 ml of 0.1 mol/L hydrochloric acid solution as a dissolution medium at 370.5 C. and at the paddle speed of 50 rpm. The results show that in the tablets of Examples 6-9 that comprise the disintegrant in different ratios and the tablets of Examples 10 and 11 that comprise compound A in different ratios, the dissolution of compound A was rapid and complete.

(19) The dissolution profiles are shown in FIG. 8.