Pharmaceutical composition including a quinoline derivative or its salt, its use and method of preparation

Abstract

the present invention provides a pharmaceutical composition comprising a quinoline derivative or a salt thereof. specifically, the invention provides a pharmaceutical composition comprising a (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 cross-linked polyvinylpyrrolidone, and at least one pharmaceutically acceptable excipient. the pharmaceutical composition has a fast dissolving property.

Description

1 / 11 Pharmaceutical composition comprising a quinoline derivative or salt thereof, its use and method of preparation. Field of Invention

[001] The present invention pertains to the field of pharmaceutical formulations, and relates specifically to a pharmaceutical composition comprising (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propenamide or a pharmaceutically acceptable salt thereof. The pharmaceutical composition has a rapid dissolution property. Background of the Invention

[002] Document CN102471312B discloses a small molecule compound (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propenamide which has the structure shown in Formula I,

[003] It is known as a small molecule receptor tyrosine kinase inhibitor that inhibits the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (ERBB2). It can covalently bind to the ATP binding site of the EGFR and ERBB2 kinase domain in cells, prevent the formation of homogeneous and heterogeneous dimers of EGFR and ERBB2 in tumor cells, inhibit their own phosphorylation, and block the activation of the downstream signaling pathway, thereby inhibiting the growth of tumor cells. It can be clinically used for the treatment Petition 870260059370, dated 06 / 18 / 2026, page 5 / 45 2 / 11 of various tumors such as gastric cancer, lung cancer, and breast cancer, etc.

[004] Document CN102933574B discloses a maleate salt form of the compound of Formula I which has more advantages in terms of solubility, bioavailability and pharmacokinetics compared with other salts and with the compound of Formula I itself.

[005] Document CN103974949B discloses the crystalline form of the dimaleate salt of the compound of Formula I. This crystalline form exhibits good crystal stability and chemical stability, and can be used in the preparation of a medicament to treat diseases associated with EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase.

[006] However, when (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenamide or a pharmaceutically acceptable salt thereof is prepared as a solid pharmaceutical composition, a high viscosity will form on site when the active ingredient is dissolved in water. This is not conducive to the preparation of the pharmaceutical formulation and causes a decline in the drug dissolution rate. Summary of the Invention

[007] The object of the present invention is to provide a fast-dissolving pharmaceutical composition. The process for preparing the pharmaceutical composition is simple and is best suited for large-scale production.

[008] The pharmaceutical composition offered by the present invention comprises an active pharmaceutical ingredient and cross-linked polyvinylpyrrolidone. The active pharmaceutical ingredient is (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propenamide or a pharmaceutically acceptable salt thereof, for example, hydrochloride salt, maleate salt, salt of Petition 870260059370, dated 06 / 18 / 2026, page 6 / 45 3 / 11 hydrobromide, p-toluenesulfonate salt, methanesulfonate salt, sulfate salt or ethanesulfonate salt, preferably maleate salt, and more preferably dimaleate salt. The active ingredient may be present in an amount of 5-70%, preferably 10-50%, and more preferably 20-40% by weight, relative to the total weight of the composition. Crosslinked polyvinylpyrrolidone may be present in an amount of about 2-20%, preferably 4-15% and more preferably 6-10% by weight, relative to the total weight of the composition.

[009] The pharmaceutical composition offered by the present invention may also comprise a filler, for example, one or more of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose, etc. The filler is present in an amount of about 5-80% by weight, relative to the total weight of the composition.

[0010] The pharmaceutical composition offered by the present invention may also comprise a binder, for example, one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose, etc. The binder is present in an amount of about 0.5-15% by weight, relative to the total weight of the composition.

[0011] The pharmaceutical composition offered by the present invention may also comprise other disintegrants, for example, one or more of croscarmellose sodium, sodium carboxymethyl starch, starch, and slightly substituted hydroxypropyl cellulose, etc. The disintegrant is present in an amount of about 0-20% by weight, relative to the total weight of the composition.

[0012] The pharmaceutical composition offered by the present invention may also comprise one or more lubricants that facilitate capsule filling or tableting. The lubricant includes talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, silicon dioxide, Petition 870260059370, dated 06 / 18 / 2026, page 7 / 45 4 / 11 loidal, among others. The lubricant is present in an amount of approximately 0.5-5% by weight, relative to the total weight of the composition.

[0013] The present invention also provides a pharmaceutical composition comprising:

[0014] 5-70% by weight of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2yl)-propenamide or a pharmaceutically acceptable salt thereof;

[0015] 2-20% by weight of cross-linked polyvinylpyrrolidone;

[0016] 5-80% by weight of a feedstock, wherein the feedstock is one or more selected from the group consisting of lactose and microcrystalline cellulose;

[0017] 0.5-15% by weight of a binder, wherein the binder is one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose; and

[0018] 0.5-5% by weight of a lubricant, wherein the lubricant is one or more selected from the group consisting of magnesium stearate and talc.

[0019] It can be observed from the dissolution test that, due to the addition of cross-linked polyvinylpyrrolidone to the pharmaceutical composition of the present invention, the dissolution rate of the active ingredient is significantly improved. Dissolution is rapid and complete, which is advantageous for the drug to enter the body to act quickly and exert its effectiveness rapidly.

[0020] The present invention also provides a pharmaceutical composition, in which a humectant can be added during the preparation of the pharmaceutical composition. The humectant may comprise at least one organic solvent, and may also comprise water, wherein the organic solvent may be a low-toxicity organic solvent, preferably ethanol and acetone, among others, and more preferably ethanol. The organic solvent may be present in Petition 870260059370, dated 06 / 18 / 2026, page 8 / 45 5 / 11 an amount of 20-100%, preferably 50-95%, and more preferably 50-80% by weight, relative to the total weight of the wetting agent.

[0021] As the wetting agent added during the preparation of the pharmaceutical composition comprises an organic solvent with low toxicity such as ethanol, among others, the resulting granules have a desired particle size distribution, and the dissolution of the active ingredient is rapid and complete, which facilitates the drug exerting its effectiveness.

[0022] The pharmaceutical composition of the present invention dissolves rapidly and has a significant effect, and can be used for the treatment of cancers such as gastric cancer, lung cancer or breast cancer, etc.

[0023] The present invention also offers a method for preparing the pharmaceutical composition, comprising a step of mixing (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propenamide or a pharmaceutically acceptable salt thereof and cross-linked polyvinylpyrrolidone. The pharmaceutical composition can be prepared in the form of granules by means of conventional methods in the literature, such as wet granulation, and finally prepared in the form of an oral formulation such as a tablet or a capsule. Description of the Drawings

[0024] Figure 1 shows the dissolution profiles of the tablets from Example 1 and Comparative Examples 1-4 in a 0.1 mol / L hydrochloric acid solution.

[0025] Figure 2 shows the dissolution profiles of the tablets from Examples 2-7 in a 0.1 mol / L hydrochloric acid solution.

[0026] Figure 3 shows the particle size distribution of Examples 8-12 and Comparative Example 5.

[0027] Figure 4 shows the dissolution profiles of multiple Petition 870260059370, dated 06 / 18 / 2026, page 9 / 45 6 / 11 tablet samples from Comparative Example 5 in a 0.1 mol / L hydrochloric acid solution.

[0028] Figure 5 shows the dissolution profiles of multiple tablet samples from Example 8 in a 0.1 mol / L hydrochloric acid solution.

[0029] Figure 6 shows the dissolution profiles of multiple tablet samples from Example 9 in a 0.1 mol / L hydrochloric acid solution.

[0030] Figure 7 shows the dissolution profiles of multiple tablet samples from Example 10 in a 0.1 mol / L hydrochloric acid solution.

[0031] Figure 8 shows the dissolution profiles of multiple tablet samples from Example 11 in a 0.1 mol / L hydrochloric acid solution.

[0032] Figure 9 shows the dissolution profiles of multiple tablet samples from Example 12 in a 0.1 mol / L hydrochloric acid solution. Detailed Description of the Invention

[0033] The present invention will be further described in detail by means of 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

[0034] (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenamide maleate salt (hereinafter referred to as compound A), lactose, microcrystalline cellulose, polyvinylpyrrolidone, and crosslinked polyvinylpyrrolidone were mixed in the proportion of Example 1 shown in Table 1. Wet granulation was carried out using an appropriate amount of a 93.75% by weight ethanol solution in water. Petition 870260059370, dated 06 / 18 / 2026, page 10 / 45 7 / 11 as a wetting agent. The granules were dried until the moisture content was less than 2%, and then dry grinding was performed. A predetermined amount of magnesium stearate was added, and the mixture was mixed by a rotary mixer. The resulting mixed granules were tableted and coated to prepare tablets. The tablets of Comparative Examples 1-4 comprising slightly substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, or starch were prepared by the same method. Table 1 Components Example Comparative 1 Example Comparative 2 Example Comparative 3 Example Comparative 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 cellulose 20.0 20.0 20.0 20.0 20.0 Cross-linked polyvinylpyrrolidone 0 0 0 0 5 Slightly substituted hydroxypropyl cellulose 5 0 0 0 0 Sodium carboxymethyl starch 0 5 0 0 0 Croscarmellose sodium 0 0 5 0 0 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: % by weight Experimental Example 1: Dissolution Test Petition 870260059370, dated 06 / 18 / 2026, page 11 / 45 8 / 11

[0035] Dissolution tests of the tablets of Example 1 and Comparative Examples 1-4 were performed according to the second method (paddle method) of the dissolution rate test described in the appendix of volume II of the Chinese Pharmacopeia (2010 edition), using 900 mL of a 0.1 mol / L hydrochloric acid solution as the dissolution medium at 37±0.5°C and a paddle speed of 50 rpm. The results showed that in the tablets of Example 1 comprising cross-linked polyvinylpyrrolidone, the dissolution of compound A is rapid and complete; however, in the tablets of Comparative Examples 1-4 comprising slightly substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, or starch, the dissolution of compound A is slow and incomplete.

[0036] The dissolution profiles are shown in Figure 1. Examples 2-7

[0037] Compound A, lactose, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone were mixed in the proportion shown in Table 2. Wet granulation was performed using an appropriate amount of a 93.75% by weight ethanol solution in water as a wetting agent. The granules were dried until the moisture content was less than 2%, and then dry grinding was performed. A predetermined amount of magnesium stearate was added, and the mixture was mixed using a rotary mixer. The resulting mixed granules were tableted and coated to prepare tablets. 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 cellulose 20.0 20.0 20.0 20.0 20.0 20.0 Petition 870260059370, dated 06 / 18 / 2026, page 12 / 45 9 / 11 Components Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Crosslinked polyvinylpyrrolidone 2 8 15 20 8 8 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: % by weight Experimental Example 2: Dissolution Test

[0038] 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 the Chinese Pharmacopeia (2010 edition), using 900 mL of a 0.1 mol / L hydrochloric acid solution as the dissolution medium at 37±0.5°C and a paddle speed of 50 rpm. The results showed that in the tablets of Examples 2-5 comprising cross-linked polyvinylpyrrolidone in different proportions and the tablets of Examples 6-7 comprising compound A in different proportions, the dissolution of compound A is rapid and complete.

[0039] The dissolution profiles are shown in Figure 2. Examples 8-12, Comparative Example 5

[0040] Compound A, lactose, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone were mixed in the proportion shown in Table 3. Wet granulation was performed using an appropriate amount of purified water, a 20% by weight ethanol solution in water, a 50% by weight ethanol solution in water, an 80% by weight ethanol solution in water, a 93.75% by weight ethanol solution in water, and anhydrous ethanol, respectively, as a wetting agent. The granules were dried until the moisture content was less than 2%, and then dry grinding was performed. Petition 870260059370, dated 06 / 18 / 2026, page 13 / 45 A predetermined quantity of magnesium stearate (10 / 11) was added, and the mixture was mixed using a rotary mixer. 100 g of the resulting total mixed granules were separated for sieving, and the remainder of the granules were tableted and coated to prepare tablets. Table 3 Ingredients Example Comparison 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 cellulose 20.0 20.0 20.0 20.0 20.0 20.0 Cross-linked polyvinylpyrrolidone 8 8 8 8 8 8 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 Humectant Purified water 20 % by weight of ethanol 50% by weight of ethanol 80% by weight of ethanol 93.75% by weight of ethanol Anhydrous ethanol Unit: % by weight Experimental Example 3: Sieving Test

[0041] 100 g of the separated granules obtained in Examples 8-12 and Comparative Example 5 were shaken and sieved using 50 mesh and 100 mesh sieves. Purified water was used as a wetting agent in Comparative Example 5, resulting in a large number of large particles and fine powder in the resulting granule, and an undesirable particle size distribution. Wetting agents comprising ethanol were used in Examples 8-12, resulting in fewer large particles and fine powder in the resulting granule, and a better particle size distribution. Petition 870260059370, dated 06 / 18 / 2026, page 14 / 45 11 / 11 particle size being more uniform.

[0042] The results of the sieving are shown in Figure 3. Experimental Example 4: Dissolution Test

[0043] The dissolution tests of the tablets in 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 the Chinese Pharmacopeia (2010 edition), using 900 mL of a 0.1 mol / L hydrochloric acid solution as the dissolution medium at 37±0.5°C and a paddle speed of 50 rpm. The results showed that when a 20% by weight ethanol solution in water, a 50% by weight ethanol solution in water, an 80% by weight ethanol solution in water, a 93.75% by weight ethanol solution in water, and anhydrous ethanol as a wetting agent were used in Examples 8-12, respectively, 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, the dissolution uniformity of compound A was poor in the resulting tablets.Humectants comprising ethanol were used as humectants in Examples 8-12; in the resulting tablets, the uniformity of dissolution of compound A was satisfactory.

[0044] Dissolution profiles are shown in Figures 4-9, and R1-R6 shown in the figures represent the samples tested Tablet 1- Tablet 6. Petition 870260059370, dated 06 / 18 / 2026, page 15 / 45

Claims

1 / 5 CLAIMS 1. Pharmaceutical composition, characterized in that it comprises: (1) an active drug, which is (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-propenamide, or a pharmaceutically acceptable salt thereof; and (2) cross-linked polyvinylpyrrolidone; wherein the cross-linked polyvinylpyrrolidone is present in an amount of 2%-20% relative to the total weight of the composition.

2. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable salt is a maleate salt.

3. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable salt is dimaleate salt.

4. Pharmaceutical composition according to claim 3, characterized in that cross-linked polyvinylpyrrolidone is present in an amount of 4%-15% relative to the total weight of the composition. 5.Pharmaceutical composition according to claim 3, characterized in that cross-linked polyvinylpyrrolidone is present in an amount of 6-10% by weight relative to the total weight of the composition.

6. Pharmaceutical composition according to claim 1, characterized in that the active drug is present in an amount of 5%-70% relative to the total weight of the composition.

7. Pharmaceutical composition according to claim 6, characterized in that the active drug is present in an amount of 10%-50% relative to the total weight of the composition.

8. Pharmaceutical composition according to claim 6, characterized in that the active drug is present in an amount of 20-40% by weight relative to the total weight of the composition.

9. Pharmaceutical composition according to claim 1, characterized in that it further comprises a binder. 10.Pharmaceutical composition according to claim 9, characterized in that the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and methyl cellulose.

11. Pharmaceutical composition according to claim 9, characterized in that the binder is present in an amount of 0.5%–15% by weight relative to the total weight of the composition.

12. Pharmaceutical composition according to claim 1, characterized in that it further comprises a filler.

13. Pharmaceutical composition according to claim 12, characterized in that the filler is one or more of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose.

14. Pharmaceutical composition according to claim 12, characterized in that the filler is present in an amount of 5%–80% by weight relative to the total weight of the composition. 15.Pharmaceutical composition according to claim 1, characterized in that it further comprises a lubricant.

16. Pharmaceutical composition according to claim 15, characterized in that the lubricant is one or more of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and colloidal silicon dioxide. Petition 870260059370, dated 06 / 18 / 2026, page 17 / 45 3 / 5 17. Pharmaceutical composition according to claim 15, characterized in that the lubricant is present in an amount of 0.5%-5% by weight, relative to the total weight of the composition.

18. Pharmaceutical composition, characterized in that it comprises: (1) 5-70% by weight of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2yl)-propenamide, or a pharmaceutically acceptable salt thereof; (2) 2-20% by weight of crosslinked polyvinylpyrrolidone; (3) 5-80% by weight of a feedstock, wherein the feedstock is one or more selected from the group consisting of lactose and microcrystalline cellulose; (4) 0.5-15% by weight of a binder, wherein the binder is one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose; and (5) 0.5-5% by weight of a lubricant, wherein the lubricant is one or more selected from the group consisting of magnesium stearate and talc.

19. Pharmaceutical composition according to claim 1, characterized in that a wetting agent is added during the preparation of the pharmaceutical composition, and the wetting agent comprises at least one organic solvent.

20. Pharmaceutical composition according to claim 19, characterized in that the wetting agent further comprises water.

21. Pharmaceutical composition according to claim 19, characterized in that the organic solvent is ethanol or acetone.

22. Pharmaceutical composition, according to claim Petition 870260059370, dated 06 / 18 / 2026, page.18 / 45 4 / 5 19, characterized in that the organic solvent is ethanol.

23. Pharmaceutical composition according to claim 19, characterized in that the organic solvent is present in an amount of 20-100% by weight, relative to the total weight of the humectant.

24. Pharmaceutical composition according to claim 19, characterized in that the organic solvent is present in an amount of 50-95% by weight, relative to the total weight of the humectant.

25. Pharmaceutical composition according to claim 19, characterized in that the organic solvent is present in an amount of 50-80% by weight, relative to the total weight of the humectant.

26. Pharmaceutical composition according to any one of claims 1 to 17, characterized in that it is an oral solid formulation.

27. Pharmaceutical composition according to claim 26, characterized in that it is a tablet and a capsule. 28.Pharmaceutical composition, according to claim 26, characterized in that it is a tablet.

29. Use of the pharmaceutical composition, as defined in any one of claims 1 to 28, characterized in that it is in the preparation of a medicament for the treatment of cancer.

30. Use, according to claim 29, characterized in that it is in the preparation of a medicament for the treatment of gastric cancer, lung cancer or breast cancer.

31. Method for preparing the pharmaceutical composition, as defined in any one of claims 1 to 28, characterized in that it comprises a step of mixing (R,E)-N(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-(1-methylpyrrolidin-2-yl)-propenamide, or a pharmaceutically acceptable salt thereof, and crosslinked polyvinylpyrrolidone. 20 / 45.

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