Substituted crotonamide pharmaceutical composition and preparation method therefor

Abstract

A composition of substituted crotonamide pharmaceutical and a preparation method therefor. The pharmaceutical composition comprises 5-50 parts of (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide maleate, 40-120 parts of a filler, 2-20 parts of a disintegrant, 0-6 parts of an adhesive, and 0.5-5 parts of a lubricant. The filler is selected from carbohydrates.

Claims

1. A pharmaceutical composition of (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide or its salt, characterized in that it contains the following components in parts by weight: (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide or its salt 5-50 parts, filler 40-120 parts, disintegrant 2-20 parts, adhesive 0-6 parts, lubricant 0.5-5 parts.

2. The pharmaceutical composition according to claim 1, characterized in that it contains the following components in parts by weight: (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide or its salt 8-12 parts, filler 50-100 parts, disintegrant 4-15 parts, adhesive 0.3-5 parts, lubricant 0.3-6 parts.

3. The pharmaceutical composition according to claim 1, characterized in that it contains the following components in parts by weight: (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide or its salt 9-11 parts, filler 65-90 parts, disintegrant 5-12 parts, adhesive 0.5 to 3 parts, 0.5 to 4 parts of lubricant.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the filler is selected from carbohydrates, preferably sugar compounds, more preferably sugar alcohols.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the sugar alcohol is mannitol, xylitol, sorbitol, lactose, more preferably one or more of mannitol and lactose.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disintegrant is one or two of sodium carboxymethyl starch and croscarmellose sodium, preferably carboxymethyl Sodium starch base.

7. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the binder is one or two of hydroxypropyl cellulose or hypromellose, preferably hydroxypropyl cellulose Further, the lubricant is one or more of glyceryl behenate, sodium stearyl fumarate, and talc, preferably glyceryl behenate.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the salt is hydrochloride, benzenesulfonate, methanesulfonate or maleate, and further is hydrochloride, benzenesulfonate hemihydrate or monohydrate of acid salt, methanesulfonate or maleate, preferably maleate monohydrate; preferably, the water content of the pharmaceutical composition is within 5 wt % or 3 wt % or 1.5 wt % %.

9. The method for preparing a pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises the following steps: (1) premix: Add (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide maleate, filler and disintegrant; mixing uniformly; (2) wet granulation: adding a binder solution to make a softened material, sieving and granulating to obtain wet granules; (3) drying, granulation and total mixing: the wet granules are dried and then sieved and granulated, and a lubricant is added for total mixing to prepare the pharmaceutical composition.

10. The method of according to claim 9, characterized in that the binder in step (2) is prepared with purified water, the concentration of which is 2-10% by weight; the moisture content of the particles after drying in step (3) is controlled at within 1.5 wt %, preferably within 1 wt %.

Description

DETAILED EXAMPLES

[0040] The following examples present some details disclosure of (E)-N-(3-cyano-7-ethoxy-4-(3-ethynylphenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide maleate monohydrate (hereinafter referred to as “active pharmaceutical ingredient” or “API”) and the preparation method for the pharmaceutical compositions of the API. But these examples do not limit the present invention in any possible ways. The API is prepared according to the method described in CN104513200A, the content of which is incorporated in its entirety.

Example 1

[0041] The single-dose prescription composition is shown in Table 2.

TABLE-US-00002 TABLE 2 Ingredient Single dose (mg) API 20 Mannitol 120 Microcrystalline cellulose 35 Crospovidone 7 Povidone K30 5 Magnesium stearate 1 Colloidal silica 5 Total 193

[0042] Add the previously determined amount of API, mannitol, microcrystalline cellulose, and cross-linked povidone into a wet granulator, mix well and prepare a softened material with 15 wt % povidone K30 as a binder, and pass through a 20-mesh sieve to form granules. Dry and control the particle moisture within 1.5 wt %. After granulated by 10 mesh, the granules are added with the previously determined amount of magnesium stearate and colloidal silicon dioxide, and the intermediate granules are mixed for capsule filling.

Example 2

[0043] The single-dose prescription composition is shown in Table 3.

TABLE-US-00003 TABLE 3 Ingredient Single dose (mg) API 20 Microcrystalline cellulose 170 Povidone K30 10 Glyceryl behenate 4 Colloidal silica 2 Total 206

[0044] Add the pre-determined amount of API and microcrystalline cellulose into the wet granulator, mix well, and prepare a softened material with 15 wt % povidone K30 as the binder, pass through a 20-mesh sieve, granulate and dry, and control the particle moisture to within 1.5 wt %. After passing 0-30 mesh size, the granules are added with the pre-determined amount of glyceryl behenate and colloidal silicon dioxide, and the intermediate granules are mixed for capsule filling.

Example 3

[0045] The single-dose prescription composition is shown in Table 4.

TABLE-US-00004 TABLE 4 Ingredient Single dose (mg) API 20 Microcrystalline cellulose 170 Povidone K30 10 Glyceryl behenate 4 Colloidal silica 2 Total 206

[0046] Add the pre-determined amount of API and mannitol into a wet granulator, mix well, and prepare a softened material with 15 wt % povidone K30 as a binder, pass through a 20-mesh sieve to granulate, and dry. Control the water content of the granules to within 1.5 wt %. After sizing, the granules are added with the pre-determined amount of glyceryl behenate and colloidal silicon dioxide, and the intermediate granules are filled in capsules after total mixing.

Example 4

[0047] Single-dose prescription composition, see Table 5.

TABLE-US-00005 TABLE 5 Ingredient Single dose (mg) API 20 Mannitol 160 Sodium Carboxymethyl Starch 10 Hydroxypropyl cellulose 1 Glyceryl behenate 4 Total 195

[0048] Add the pre-determined amount of API, mannitol, and sodium carboxymethyl starch into a wet granulator, mix well, and prepare a softened material with 4 wt % hydroxypropyl cellulose as a binder, pass through a 20-mesh sieve to granulate, dry, and control the granulation. The moisture content is controlled to be within 1.5 wt %. After granulated with 10 mesh, the granules are added with the pre-determined amount of glyceryl behenate, and the intermediate granules are mixed for capsule filling.

[0049] The capsule granules of Examples 1, 2, 3, and 4 were placed in an open weighing bottle and placed at a high temperature of 40° C. for 1 month. After being taken out, the content (%) of related substances was measured. The results are shown in Table 6.

TABLE-US-00006 TABLE 6 time Example 1 Example 2 Example 3 Example 4  0 days 0.08 0.07 0.05 0.04 14 days 0.15 0.32 0.12 0.08 January 0.24 0.46 0.26 0.14

[0050] The above results indicate that the impurity A of the composition of Example 4 increases slowly after being placed for 1 month under high temperature conditions. It shows that the pharmaceutical composition prepared according to the technical aspects of the present invention is significantly more stable than previously prepared/reported compositions.

Example 5

[0051] The single-dose prescription composition is shown in Table 7.

TABLE-US-00007 TABLE 7 Ingredient Single dose (mg) API 20 Mannitol 200 Sodium Carboxymethyl Starch 10 Hydroxypropyl cellulose 3 Glyceryl behenate 5 Total 238

[0052] Add the prescription amount of active ingredients, mannitol and sodium starch glycolate into the wet granulator, mix well and prepare a softened material with 4% hydroxypropyl cellulose as the binder, pass through a 20-mesh sieve, granulate, dry, and prepare Moisture 0.8 wt %, 1.0 wt %, 1.4 wt % particles. After sizing, each granule is added with a prescription amount of glyceryl behenate, and the intermediate granules are encapsulated after total mixing.

[0053] The capsule particles containing different moisture of Example 5 were placed for 14 days under the conditions of high temperature 40° C., high humidity 92.5% RH, light 4500 lux, and accelerated (high temperature 40° C., high humidity 75%), and then the related substances were measured after being taken out. The content (%) of impurity A is shown in Table 8.

TABLE-US-00008 TABLE 8 Relative substance 0.8% moisture 1.0% moisture 1.4% moisture (%) particles particles particles 0 days 0.03 0.03 0.04 High temperature 0.09 0.10 0.10 14 days High humidity for 0.08 0.07 0.08 14 days 14 days of light 0.07 0.08 0.08 14 days accelerated 0.09 0.08 0.09

[0054] The above results indicate that the formulation composition with the particle moisture within 1.5 wt % is relatively stable.

Example 6

[0055] Single-dose prescription composition, see Table 9.

TABLE-US-00009 TABLE 9 Ingredient Single dose (mg) API 20 Mannitol 160 Crospovidone 10 Hydroxypropyl cellulose 1 Glyceryl behenate 4 Total 195

[0056] Add the prescription amount of active ingredients, mannitol, and cross-linked povidone into a wet granulator, mix well and prepare a softened material with 4 wt % hydroxypropyl cellulose as a binder, pass through a 20-mesh sieve to granulate, and dry. Control the moisture of the granules to be within 1.5 wt %. After sizing, the granules are added with the prescription amount of glyceryl behenate, and the intermediate granules are filled in the capsule after the total mixing.

Example 7

[0057] Single-dose prescription composition, see Table 10.

TABLE-US-00010 TABLE 10 Ingredient Single dose (mg) API 20 Mannitol 130 Sodium starch glycolate 20 Hydroxypropyl cellulose 1 Glyceryl behenate 1 Total 172

[0058] Add the active ingredients, mannitol, and sodium starch glycolate into the wet granulator and mix well, prepare the softened material with 4 wt % hydroxypropyl cellulose as the binder, pass through a 20-mesh sieve to granulate and dry, and control the water content of the granules to be within 1.5 wt %. The pre-determined amount of glyceryl behenate is added, and the intermediate is mixed for capsule filling.

Example 8

[0059] Single-dose prescription composition, see Table 11.

TABLE-US-00011 TABLE 11 ingredient Single dose (mg) API 20 Lactose monohydrate 160 Sodium starch glycolate 10 Hydroxypropyl cellulose 1.5 Glyceryl behenate 8 Total 199.5

[0060] Add the pre-determined amount of active ingredients, lactose monohydrate and sodium starch glycolate into the wet granulator, mix well and prepare the softened material with 4% hydroxypropyl cellulose as the binder, pass through a 20-mesh sieve to granulate and dry to control the moisture of the granules to be within 1.5%. After sizing, the granules are added with the pre-determined amount of glyceryl behenate, and the intermediate granules are filled in the capsule after the total mixing.

[0061] The capsules of Examples 1, 2, 3, 4, 6, 7, and 8 were packaged in high-density polyethylene bottles, 20 capsules/bottle, and 2 bags/bottle of desiccant were added to an accelerated conditions (high temperature 40° C., high humidity 75%) and placed under the accelerated conditions for 3 months. The content (%) change results of impurity A in each batch are shown in Table 12.

TABLE-US-00012 TABLE 12 Impurity A (%) Example 1 Example 4 Example 6 Example 7 Example 8 0 days 0.08 0.04 0.09 0.05 0.06 After 1 month 0.28 0.14 0.15 0.15 0.12 After 2 month 0.48 0.20 0.25 0.21 0.18 After 3 month 0.62 0.20 0.47 0.22 0.20

[0062] The above results show that the stability of the formulations of Examples 4, 7, and 8 is significantly higher than the other formulations after being placed for 3 months under accelerated conditions, indicating that the stability of the capsule prepared according to the technical designs of the present invention is significantly improved.