WO2017028660A1 - Pharmaceutical composition containing quinoline derivative or salt thereof - Google Patents

Abstract

A pharmaceutical composition, comprising 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof; and at least one compound of a basic amino acid or meglumine, and/or at least one selected from potassium carbonate or potassium bicarbonate. The composition does not contain microcrystalline cellulose.

Description

Pharmaceutical composition containing quinoline derivative or salt thereof Technical field

The invention belongs to the field of pharmaceutical preparations, in particular to a quinoline derivative containing 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide. Or a pharmaceutical composition of the salt, which has the characteristics of rapid dissolution and good stability.

Background technique

WO2002032872 discloses a quinoline derivative 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, which is known to have inhibitory participation. RTK, which is involved in other proangiogenic and oncogenic signaling pathways of tumor proliferation, can also selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptor, and is clinically useful for the treatment of various tumors such as thyroid cancer, lung cancer, and melanoma.

However, 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof is prepared into a pharmaceutical combination When the substance is present, the drug is decomposed under the conditions of wetness and heat, and the drug composition absorbs moisture, resulting in a decrease in drug dissolution.

Patent CN101001629A discloses a composition comprising 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof The use of alkaline inorganic compounds such as magnesium oxide to solve the problem of degradation of the drug, while using silicic acid compounds to solve the problem of drug dissolution. However, the amount of the silicic acid compound is large, the density of the silicic acid compound is extremely small, and it is easy to fly in production, causing damage to the operator's respiratory system. At the same time, in the mixing process, due to the difference between the density and other auxiliary materials, the risk of uneven material mixing may be caused, which makes the industrialization of the preparation difficult.

Summary of the invention

It is an object of the present invention to provide a pharmaceutical composition which has good stability and rapid dissolution, and which is simple in preparation process and more suitable for large-scale production.

The pharmaceutical composition provided by the present invention includes an active pharmaceutical ingredient and a basic substance. The active pharmaceutical ingredient is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable salt thereof, and The pharmaceutical compositions described are free of microcrystalline cellulose.

Alkaline substances include one or more of the following:

(1) basic amino acids,

(2) meglumine,

(3) at least one compound of potassium carbonate or potassium hydrogencarbonate;

Among them, the basic amino acid is preferably selected from one or more of lysine, arginine and histidine.

In a preferred embodiment of the invention, the basic substance is a mixture of at least one compound of arginine or meglumine and at least one compound of potassium carbonate or potassium hydrogencarbonate.

In a particularly preferred embodiment of the invention, the basic substance is a mixture of at least one compound of arginine or meglumine and potassium hydrogencarbonate.

In another preferred embodiment of the invention, the basic substance is a mixture of arginine and meglumine.

When the basic substance of the present invention is a mixture of two substances, the ratio of the two kinds of the mixture is not particularly limited, and in a preferred embodiment, their weight ratio may be between 1:0.1 and 1:10, preferably. Between 1:0.5 and 1:2, most preferably 1:1.

The content of the basic substance is not limited, and as long as a small amount of the above-mentioned basic substance is contained, the effect of improving elution and increasing stability can be achieved. For convenience of formulation, in a preferred embodiment of the invention, the content of the basic substance may range from 0.5% to 90%, preferably from 1% to 50%; more preferably from 1 to 35%, based on the total weight of the composition; Most preferably 5-20%.

In the pharmaceutical composition of the present invention, the pharmacologically acceptable salt of the active ingredient may be selected from the group consisting of a hydrochloride, a hydrobromide, a p-toluenesulfonate, a methanesulfonate, a sulfate or an ethanesulfonate. . The active ingredient may be included in an amount ranging from 0.5% to 30%, preferably from 1% to 25%, most preferably from 1% to 15%, based on the total weight of the composition.

The pharmaceutical composition provided by the present invention may contain a filler such as one or more of calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose. The filler content is from about 5% to 80%, based on the total weight of the composition.

The pharmaceutical composition provided by the present invention may contain a disintegrating agent, wherein the disintegrant is one of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. Or a variety. The disintegrant content is from about 1% to about 30%, based on the total weight of the composition.

The present invention provides that the pharmaceutical composition may contain a binder, which may be selected from the group consisting of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, and the like. Alternatively, the binder may be present in an amount of from about 0.5% to about 15%, based on the total weight of the composition.

The pharmaceutical compositions provided herein may also comprise one or more lubricants to aid in filling the capsule or tableting. The lubricant may be selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal silica, and the like. The lubricant is present in an amount of from about 0.5% to about 5%, based on the total weight of the composition.

In a preferred embodiment of the invention, the composition consists of the following ingredients:

(1) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable salt thereof;

(2) alkaline substances;

(3) a filler;

(4) a disintegrating agent;

(5) Adhesive

(6) Lubricant.

In a most preferred embodiment, the composition consists of the following ingredients:

(1) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable salt thereof;

(2) arginine, 5-20%;

(3) potassium hydrogencarbonate, 10 to 40%;

(4) mannitol, 30% to 60%;

(5) low-substituted hydroxypropyl cellulose, 1% to 10%;

(6) hydroxypropyl cellulose, 1% to 5%;

(7) Talc powder, 1% to 5%.

The pharmaceutical composition of the present invention can be prepared by a method common in the art, for example, high shear wet granulation, dry granulation, one-step granulation, etc., to prepare granules of a pharmaceutical composition, and then filled into capsules to prepare a hard capsule.

The microcrystalline cellulose-free pharmaceutical composition provided by the invention has higher stability, reduces the generation of new impurities, and has good dissolution properties.

DRAWINGS

Figure 1 shows the dissolution profiles of the capsules of Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.

Figure 2 shows the dissolution profiles of the capsules of Examples 4 to 6 in a 0.1 mol/L hydrochloric acid solution.

Figure 3 shows the dissolution profiles of the capsules of Comparative Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.

4 shows the dissolution profile of the capsule of Example 3 and the 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

Figure 5 shows the dissolution profile of the capsule of Example 6 in a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

Fig. 6 shows a dissolution profile of the capsule of Comparative Example 1 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

Fig. 7 shows a dissolution profile of the capsule of Comparative Example 2 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

Fig. 8 shows a dissolution profile of the capsule of Comparative Example 3 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

detailed description

The invention is further illustrated in detail by the following examples and experimental examples. The examples and the examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Examples 1-3

4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), refined ammonia Acid, potassium bicarbonate, D-mannitol, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, wet granulation by high-speed shear granulator according to the ratio in Table 1, to purify Water is a wetting agent, wet and granules are dried and dried, then dry granules (less than 2% moisture) are dry granulated, and a prescribed amount of talc powder is added and mixed by a rotary total mixer. The obtained total mixed particles are filled into capsules to prepare capsules.

Table 1

ingredient	Example 1	Example 2	Example 3
Compound A	2.5	4.9	12.3
Arginine	10.0	10.0	10.0
Potassium bicarbonate	20.0	20.0	20.0
D-mannitol	56.5	54.1	46.7
Hydroxypropyl cellulose	3.0	3.0	3.0
Low substituted hydroxypropyl cellulose	5.0	5.0	5.0
talcum powder	3.0	3.0	3.0
total	100	100	100

Unit: mass%

Examples 4 to 6

4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), refined ammonia Acid, potassium carbonate, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, wet granulation using a high-speed shear granulator according to the ratio in Table 2, using purified water as a wetting agent Wet granules and drying the wet materials, then dry granules (less than 2% moisture), add the prescribed amount of talc, and mix with a rotary total mixer. The obtained total mixed particles are filled into capsules to prepare capsules.

Table 2

ingredient	Example 4	Example 5	Example 6
Compound A	2.5	4.9	12.3
Arginine	10.0	10.0	10.0
Potassium carbonate	20.0	20.0	20.0
D-mannitol	56.5	54.1	46.7
Hydroxypropyl cellulose	3.0	3.0	3.0
Low substituted hydroxypropyl cellulose	5.0	5.0	5.0
talcum powder	3.0	3.0	3.0
total	100	100	100

Unit: mass%

Comparative Examples 1-3

4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter abbreviated as compound A) arginine , potassium bicarbonate or potassium carbonate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, wet granulation using a high-speed shear granulator according to the ratio in Table 3. Using purified water as a wetting agent, wet granules and drying the wet materials, then dry granules (less than 2% moisture), adding the prescribed amount of talcum powder, mixing with a rotary total mixer . The obtained total mixed particles were filled and capsules, and capsules of Comparative Examples 1 to 3 were prepared.

table 3

ingredient	Comparative example 1	Comparative example 2	Comparative example 3
Compound A	12.3	12.3	12.3
Arginine	0	10	10
Potassium carbonate	0	20	0
Potassium bicarbonate	0	0	20
D-mannitol	43.7	13.7	13.7
Microcrystalline cellulose	33	33	33
Hydroxypropyl cellulose	3	3	3
Low substituted hydroxypropyl cellulose	5	5	5
talcum powder	3	3	3
total	100	100	100

Unit: mass%

Experimental Example 1: Dissolution experiment

The dissolution rates of the capsules of Examples 1 to 6 were measured according to the second method (paddle method) of the dissolution test of the Appendix 2 of the Chinese Pharmacopoeia. 900 ml of a 0.1 mol/L hydrochloric acid solution was used as a dissolution medium, and a dissolution test was performed at 37 ± 0.5 ° C at a paddle speed of 50 rpm. As a result, in the capsules of Examples 1 to 6 containing arginine and potassium carbonate or potassium hydrogencarbonate in the formulation, the dissolution of Compound A was quickly completed.

The dissolution profile is shown in Figure 1 and Figure 2.

Experimental Example 2: Dissolution experiment

The dissolution rate of the capsules of Comparative Examples 1 to 3 was measured according to the second method (paddle method) for the dissolution measurement of the second edition of the Chinese Pharmacopoeia 2010 edition. 900 ml of a 0.1 mol/L hydrochloric acid solution was used as a dissolution medium, and a dissolution test was performed at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in the comparative example 1 which did not contain the alkaline adjuvant in the prescription, the dissolution of the compound A was slow; in the capsule of Comparative Example 2 and Comparative Example 3 containing arginine, potassium carbonate or potassium hydrogencarbonate, the dissolution of the compound A was rapid. Completely, indicating that the addition of microcrystalline cellulose does not affect the drug Dissolution of matter.

The dissolution profile is shown in Figure 3.

Experimental Example 3: Stability study

The capsules of Examples 3 and 6 and the capsules of Comparative Examples 1 to 3 were packaged in high-density polyethylene, and placed in an environment of a temperature of 40 ° C and a relative humidity of 75% for one month, two months, and three. After month and 6 months, the formation of the degradant was determined by HPLC. The second method (paddle method) of the dissolution test of the second edition of the Chinese Pharmacopoeia 2010 was used to determine the dissolution of the sample after the placement.

The degradation product measurement results showed that the degradation product was not increased in the capsules of Example 3 (containing arginine and potassium hydrogencarbonate) and Example 6 (containing arginine and potassium carbonate), and Comparative Example 1 did not contain alkaline adjuvants. The degradant increased significantly with the extension of the standing time. Comparative Example 2 and Comparative Example 3 contained alkaline excipients and microcrystalline cellulose, and the new impurities were produced after being left for 1 month in a temperature of 40 ° C and a relative humidity of 75%. The impurity increases significantly with the extension of the standing time, and the other degradants do not increase. (See Tables 4 to 8)

The dissolution results showed that in the capsules of Example 3 (containing arginine and potassium hydrogencarbonate) and Example 6 (containing arginine and potassium carbonate), the dissolution rate of Compound A was 40 ° C and the relative humidity was 75%. After being placed in the environment, there was no significant decrease compared with the initial stage, and the dissolution was complete. In the capsule of Comparative Example 1 (without alkaline adjuvant), the dissolution of the compound A at the initial stage and the environment at a temperature of 40 ° C and a relative humidity of 75% was incomplete, and in the capsules of Comparative Example 2 and Comparative Example 3, The dissolution rate of the compound A was not significantly decreased compared with the initial stage after being placed in an environment of a temperature of 40 ° C and a relative humidity of 75%, and the dissolution was complete (see FIGS. 4 to 8 ), indicating that the addition of the microcrystalline cellulose did not affect the dissolution, but Produces impurity 1.

Table 4

table 5

Table 6

Table 7

Table 8

Claims (19)

1. A pharmaceutical composition comprising 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable salt thereof And an alkaline substance selected from one or more of the following:

   1) Basic amino acids,

   2) meglumine,

   3) at least one compound selected from the group consisting of potassium carbonate and potassium hydrogencarbonate;

   Wherein the composition is free of microcrystalline cellulose.
2. The pharmaceutical composition according to claim 1, wherein the basic amino acid is one or more selected from the group consisting of lysine, arginine or histidine.
3. The pharmaceutical composition according to claim 1, wherein the basic substance is meglumine.
4. The pharmaceutical composition according to claim 1, wherein the basic amino acid is arginine.
5. The pharmaceutical composition according to claim 1, wherein the basic substance is a mixture of meglumine and at least one compound of lysine, arginine or histidine.
6. The pharmaceutical composition according to claim 1, wherein the basic substance is a mixture of arginine and at least one of potassium carbonate or potassium hydrogencarbonate.
7. The pharmaceutical composition according to claim 1, wherein the basic substance is a mixture of meglumine and at least one of potassium carbonate or potassium hydrogencarbonate.
8. The pharmaceutical composition according to claim 1, wherein the alkaline substance is contained in an amount of from 0.5% to 90% by weight based on the total weight of the composition; preferably from 1% to 50%; more preferably from 1 to 35%; most preferably from 5% 20%.
9. The pharmaceutical composition according to any one of claims 1 to 8, which contains a disintegrant.
10. The pharmaceutical composition according to claim 9, wherein the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. Kind.
11. The pharmaceutical composition according to any one of claims 1 to 8, which consists of the following components:

    1) 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or its pharmacology a salt that is acceptable for learning;

    2) alkaline substances;

    3) a filler;

    4) disintegrant;

    5) Adhesive

    6) Lubricant.
12. The pharmaceutical composition according to claim 11, wherein the filler is selected from one or more of calcium hydrogen phosphate, mannitol, pregelatinized starch, lactose, etc., preferably the filler content is based on the total weight of the composition. It is 5% to 80%, more preferably 30% to 60%.
13. The pharmaceutical composition according to claim 11, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone One or more, preferably in an amount of from 1% to 30%, more preferably from 1% to 10%, based on the total weight of the composition.
14. The pharmaceutical composition according to claim 11, wherein the binder is selected from the group consisting of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, or the like A plurality, preferably in an amount of from 0.5 to 15%, more preferably from 1% to 5%, based on the total weight of the composition.
15. The pharmaceutical composition according to claim 11, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal silica, and the like. Preferably, the content is from 0.5% to 5%, more preferably from 1% to 5%, based on the total weight of the composition, based on the total weight of the composition.
16. The pharmaceutical composition according to claim 11, which is composed of the following components:

    1) 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable salt thereof;

    2) arginine, 5-20%;

    3) Potassium hydrogencarbonate, 10-40%;

    4) mannitol, 30% to 60%;

    5) low-substituted hydroxypropyl cellulose, 1% to 10%;

    6) hydroxypropyl cellulose, 1% to 5%;

    7) Talc powder, 1% to 5%.
17. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmacologically acceptable salt is selected from the group consisting of a hydrochloride, a hydrobromide, a p-toluenesulfonate, a methanesulfonate, a sulfate or Ethane sulfonate.
18. The pharmaceutical composition according to claim 17, wherein the pharmacologically acceptable salt is a mesylate salt.
19. Use of the pharmaceutical composition according to any one of claims 1 to 18 for the preparation of a medicament for treating cancer; the cancer is preferably thyroid cancer, lung cancer or melanoma.

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