Pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition and application thereof. The pharmaceutical composition comprises 1wt%-70wt% of the compound represented by the formula (I) or pharmaceutically acceptable salts, crystal forms and isomers thereof, and at least one pharmaceutic adjuvant. Through research, the invention develops a pharmaceutical composition, and the pharmaceutical composition can be prepared into final dosage forms such as tablets, capsules, particles and the like. When the medicine composition is prepared into tablets, compared with other medicine combination modes, the medicine composition has good compressibility, good dissolution rate and good particle fluidity; # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a pharmaceutical composition and use thereof. Background Art

[0002] WO2018108079A1 discloses a compound as shown in formula (I), which is a kinase spectrum selectively focused multi-target small molecule kinase inhibitor with a new mechanism, which can act on multiple targets including FGFR1-3, KDR, Aurora A / B and JAK, and shows good anti-tumor effects.

[0003] At present, there is no literature reporting on the research of the preparation of this compound. Therefore, in order to meet clinical needs, the inventors also need to study the physical and chemical characteristics of the raw materials in order to obtain a stable and pharmaceutically usable drug preparation. Summary of the invention

[0004] The present invention studies the following pharmaceutical composition, comprising 1wt%-70wt% of an active ingredient, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, isomer thereof, and at least one pharmaceutical excipient;

[0005]

[0006] In some embodiments, the pharmaceutical excipients in the pharmaceutical composition of the present invention include fillers, binders, disintegrants or lubricants.

[0007] In some embodiments, in the pharmaceutical composition of the present invention, the pharmaceutical excipient further includes a glidant.

[0008] In some embodiments, the pharmaceutical composition of the present invention contains 1wt%-30wt% of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer; 10wt%-90wt% of filler; 0.1wt%-10wt% of binder; 1wt%-10wt% of disintegrant; 0.1wt%-2wt% of lubricant.

[0009] In some embodiments, the pharmaceutical composition of the present invention further contains 0.1wt%-2wt% of a glidant;

[0010] Preferably, the pharmaceutical composition of the present invention contains 1wt%-20wt% of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer; 80wt%-90wt% of filler; 2wt%-5wt% of binder; 2wt%-8wt% of disintegrant; and 0.6wt%-1wt% of lubricant.

[0011] Preferably, the pharmaceutical composition of the present invention contains 1wt%-10wt% of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer; 80wt%-90wt% of filler; 2wt%-5wt% of binder; 2wt%-8wt% of disintegrant; and 0.6wt%-1wt% of lubricant.

[0012] Preferably, the pharmaceutical composition of the present invention further contains 0.5wt%-1wt% of a glidant.

[0013] In some embodiments, the pharmaceutical composition of the present invention contains 1 wt%-10 wt% of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, or isomer thereof.

[0014] Preferably, the pharmaceutical composition of the present invention contains 1wt%-5wt%, 2wt%-5wt% or 2.5wt%-5wt% of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form or isomer.

[0015] In some embodiments, in the pharmaceutical composition of the present invention, the filler is selected from: one or more of lactose monohydrate, microcrystalline cellulose, corn starch, glucose, mannitol, sorbitol, calcium carbonate, and calcium hydrogen phosphate.

[0016] Preferably, the filler is selected from lactose monohydrate and microcrystalline cellulose.

[0017] Preferably, the model of the lactose monohydrate is lactose monohydrate 200M.

[0018] Preferably, the model of the microcrystalline cellulose is microcrystalline cellulose 101.

[0019] In some embodiments, the mass ratio of lactose monohydrate to microcrystalline cellulose is 1:(0.1-5).

[0020] Preferably, the mass ratio of the lactose monohydrate to the microcrystalline cellulose is 1:(0.2-2).

[0021] More preferably, the mass ratio of lactose monohydrate to microcrystalline cellulose is 1:0.2.

[0022] In some embodiments, in the pharmaceutical composition of the present invention, the binder is selected from: one or more of povidone, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose.

[0023] Preferably, the binder is selected from povidone.

[0024] Preferably, the model of the povidone is povidone K30 or povidone K90.

[0025] Preferably, the type of hydroxypropyl cellulose is hydroxypropyl cellulose EXF.

[0026] In some embodiments, in the pharmaceutical composition of the present invention, the disintegrant is selected from: one or more of sodium starch glycolate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; preferably, the disintegrant is selected from sodium starch glycolate.

[0027] Preferably, the model of the cross-linked polyvinylpyrrolidone is cross-linked polyvinylpyrrolidone XL-10.

[0028] In some embodiments, in the pharmaceutical composition of the present invention, the lubricant is selected from: magnesium stearate, sodium stearyl fumarate.

[0029] In some embodiments, in the pharmaceutical composition of the present invention, the glidant is selected from: colloidal silicon dioxide and talc.

[0030] In some embodiments, a wetting agent: water can be added to the pharmaceutical composition of the present invention according to actual conditions.

[0031] In some embodiments, in the pharmaceutical composition of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer has a particle size distribution range D90<60 μm.

[0032] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer has a particle size distribution range of D90<59.7 μm.

[0033] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer has a particle size distribution range of D90≤50.4 μm.

[0034] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer has a particle size distribution range of D90≤50 μm.

[0035] In some embodiments, in the pharmaceutical composition of the present invention, the particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is D90≤59μm, for example, D90≤58μm, D90≤57μm, D90≤56μm, D90≤55μm, D90≤54μm, D90≤53μm, D90≤52μm, D90≤51μm; including but not limited to: 0μm <D90≤59μm;18μm≤D90≤55μm;18.1μm≤D90≤55μm;18μm≤D90≤51μm;18.1μm≤D90≤51μm。

[0036] In some embodiments, in the pharmaceutical composition of the present invention, the particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 10 μm <D90<60μm。

[0037] In some embodiments, the particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 18.1 μm≤D90<59.7 μm.

[0038] In some embodiments, the particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 18 μm ≤ D90 < 60 μm.

[0039] In some embodiments, the particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 18.1 μm≤D90≤50.4 μm.

[0040] In some embodiments, the particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 18 μm≤D90≤50 μm.

[0041] In some embodiments, the particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 20 μm≤D90≤50 μm.

[0042] In some embodiments, in the pharmaceutical composition of the present invention, the content of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 1-20 mg. 1-20 mg includes any value between 1-20, such as 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg.

[0043] In some embodiments, the present invention also provides a pharmaceutical preparation, which is prepared from any one of the above-mentioned pharmaceutical compositions.

[0044] In some embodiments, the pharmaceutical preparation provided by the present invention is a tablet.

[0045] In some embodiments, the present invention also provides a medicine kit, comprising the pharmaceutical preparation and instructions for use.

[0046] In some embodiments, the present invention also provides use of any one of the pharmaceutical compositions or pharmaceutical preparations described in preparing a drug for treating cancer.

[0047] In some embodiments, the cancer comprises bile duct cancer, head and neck cancer, liver cancer, colorectal cancer, osteosarcoma, bladder cancer, prostate cancer, gastric cancer, urothelial carcinoma, lung cancer, endometrial cancer, breast cancer, thyroid cancer, ovarian cancer, peritoneal cancer, kidney cancer, B cell malignancies, oral cancer, nasopharyngeal cancer.

[0048] The pharmaceutical composition or preparation of the present invention is prepared by a wet granulation method.

[0049] In some embodiments, the step of wet granulation comprises:

[0050] The filler is premixed with the disintegrant and the active ingredient, and then wet granulated with the binder and dried to obtain dry granules.

[0051] In some embodiments, a final mixing step is further included after the wet granulation step, that is, mixing the obtained dry granules with a lubricant and a glidant.

[0052] The "D90" mentioned in the present invention refers to the particle size value corresponding to when the cumulative particle size distribution number of a sample reaches 90%.

[0053] The "wt%" mentioned in the present invention refers to the mass (weight) percentage. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 This is an example of a tablet with a smooth and complete surface and good compressibility in the compressibility evaluation;

[0055] Figure 2 This is an example of a tablet that sticks during the compressibility evaluation.

[0056] Beneficial Effects of the Invention

[0057] Through research, the present invention has developed a pharmaceutical composition that can be prepared into final dosage forms, such as tablets, capsules, granules, etc. When the pharmaceutical composition is prepared into tablets, compared with other drug combinations, it has good compressibility and good solubility, as well as good granule flowability.

[0058] Furthermore, by selecting each component and controlling the content of each component, a stable pharmaceutical preparation with better dissolution, better particle flowability and better friability can be obtained.

[0059] At the same time, the present invention controls the particle size of the active ingredient to maintain it within a suitable range, thereby preventing the inappropriate particle size from affecting the drug dissolution rate, thereby preventing the drug bioavailability from being affected. Furthermore, the present invention can also avoid the problem of inconsistent dissolution of different batches of drugs produced by the same prescription process by controlling the particle size of the active ingredient, ensuring that the drug can be dissolved stably during the preparation process and that the batch-to-batch reproducibility is good. 90 ≤50μm, the difference between drug batches is small, the drug dissolution is stable, the batch reproducibility is good, and the product quality is excellent. DETAILED DESCRIPTION

[0060] In order to make the purpose, technical scheme, and advantages of the present invention more clearly understood, the present invention is further described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0061] Examples and Comparative Examples

[0062] According to the prescription ratio in Table 1, the active ingredient compound of formula (I) was air flow-pulverized to a particle size of D90≤50 μm, and the fillers lactose monohydrate 200M, microcrystalline cellulose 101, corn starch, and mannitol 160C were sieved. During the initial mixing, the active ingredient was first fully mixed with part of the lactose monohydrate 200M, and then the remaining lactose monohydrate 200M, other fillers, and low-substituted hydroxypropyl cellulose were added and mixed evenly. Povidone K30 and water were prepared into a solution and sprayed and added for granulation. After oven drying, the particles were granulated. During the final mixing, colloidal silicon dioxide, magnesium stearate and the particles were sieved, mixed evenly, and pressed into tablets using a tablet press.

[0063] Table 1

[0064]

[0065] According to the prescription ratio in Table 2, the active ingredient compound of formula (I) was air flow-pulverized to a particle size of D90≤50 μm, the filler lactose monohydrate 200M, microcrystalline cellulose 101, and completely pregelatinized starch were sieved, the active ingredient was fully mixed with the filler lactose monohydrate (or completely pregelatinized starch), microcrystalline cellulose 101, and sodium starch glycolate during initial mixing, povidone K30 was mixed with water to form a solution and added for granulation, the granules were oven-dried and granulated, and colloidal silicon dioxide, magnesium stearate and the granules were sieved during final mixing, mixed evenly, and then pressed into tablets using a tablet press.

[0066] Table 2

[0067]

[0068]

[0069] According to the prescription ratio in Table 3, the active ingredient formula (I) compound was air flow-pulverized to a particle size D90≤50 μm, the fillers lactose monohydrate 200M and microcrystalline cellulose 101 were sieved, the active ingredient was first fully mixed with part of the lactose monohydrate 200M during initial mixing, and then the remaining lactose monohydrate, microcrystalline cellulose 101 and sodium carboxymethyl starch were added and mixed evenly, povidone K30 and water were prepared into a solution and sprayed and added for granulation, and the particles were granulated after oven drying, and colloidal silicon dioxide, magnesium stearate and particles were sieved during final mixing, mixed evenly, and then compressed into tablets using a tablet press.

[0070] Table 3

[0071]

[0072] According to the prescription ratio in Table 4, the active ingredient compound of formula (I) was air flow-pulverized to a particle size of D90≤50 μm, lactose monohydrate 200M, microcrystalline cellulose 101, and hydroxypropyl cellulose EXF were sieved, and the active ingredient was first fully mixed with part of the lactose monohydrate 200M during initial mixing, and then the remaining lactose monohydrate 200M, microcrystalline cellulose 101, and cross-linked polyvinylpyrrolidone XL-10 were added and mixed evenly, when hydroxypropyl cellulose EXF was used as a binder, the dry powder was added and mixed, and when polyvinylpyrrolidone K30 was used as a binder, it was prepared with water to form a solution and added for wet granulation, and the particles were granulated after oven drying. During final mixing, colloidal silicon dioxide, magnesium stearate and the particles were sieved, mixed evenly, and compressed into tablets using a tablet press.

[0073] Table 4

[0074]

[0075] According to the prescription ratio in Table 5, the active ingredient compound of formula (I) was air flow-pulverized to a particle size of D90≤50 μm, lactose monohydrate 200M and microcrystalline cellulose 101 were sieved, and the active ingredient was first fully mixed with part of the lactose monohydrate 200M during initial mixing, and then the remaining lactose monohydrate 200M and microcrystalline cellulose 101 were added and mixed evenly, disintegrants sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpolypyrrolidone XL-10 were added and mixed evenly, and polyvinylpolypyrrolidone K30 was prepared into a solution with water and added for wet granulation, and the particles were granulated after oven drying. During final mixing, colloidal silicon dioxide, magnesium stearate and the particles were sieved, mixed evenly, and then compressed into tablets using a tablet press.

[0076] Table 5

[0077]

[0078] According to the prescription ratio in Table 6, the active ingredient was air flow-pulverized to a particle size of D90 ≤ 50 μm, the fillers lactose monohydrate 200M and microcrystalline cellulose 101 were sieved, the active ingredient was first fully mixed with part of the lactose monohydrate 200M during the initial mixing, and then the remaining lactose monohydrate, microcrystalline cellulose 101 and sodium carboxymethyl cellulose were added and mixed evenly, povidone K30 was prepared into a solution with water and added for wet granulation, and the particles were granulated after oven drying, and colloidal silicon dioxide and / or magnesium stearate were added and sieved with the particles during the final mixing, and after mixing evenly, they were compressed into tablets using a tablet press.

[0079] Table 6

[0080]

[0081] Experimental Example 1: Compressibility Comparison

[0082] In the preparation process of the tablets of Examples 1-14 and Comparative Examples 1-4, the tableting process was observed and the compressibility was evaluated. If the tablets were easy to form, could be pressed into a suitable hardness under moderate pressure, and had a smooth and intact surface, the compressibility was good. Figure 1 If loose tablets, cracked tablets, sticky tablets, or astringent tablets occur during tableting, the compressibility is poor. The results are shown in Table 7:

[0083] Table 7

[0084] Inspection Project Examples 1-14 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Compressibility good Astringent Unable to form Sticky Sticky

[0085] Sticking: refers to the phenomenon that the fine powder on the tablet surface is adhered to the punch and die during tableting, resulting in the tablet surface being rough, uneven and with dents, such as Figure 2 shown.

[0086] Astringent punch: When the tablet press is running, the upper and lower punches cannot move normally.

[0087] Experimental Example 2: Dissolution Comparison

[0088] Dissolution test: According to the dissolution and release test method (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0931 Method 2, USP <711> ), the dissolution test was performed on the tablets of Examples 1-13, using 900 ml of dissolution medium (7.8 g of sodium dihydrogen phosphate dihydrate was dissolved in water and diluted to 1000 ml, the pH was adjusted to 4.50±0.05 with 1 mol / L sodium hydroxide solution or 10% dilute phosphoric acid, 0.5 g of sodium dodecyl sulfate was added, and the solution was dissolved by stirring), and the dissolution experiment was performed at 37.0±0.5°C with a paddle speed of 50 revolutions per minute.

[0089] The dissolution comparison under the sample setting conditions (0 days) is shown in Table 8:

[0090] Table 8

[0091]

[0092] The dissolution comparison under the sample setting conditions (60°C for 10 days) is shown in Table 9:

[0093] Table 9

[0094]

[0095] The dissolution results show that the tablets of Examples 1-13 of the present invention are rapidly dissolved after 0 days of storage, and can reach more than 80% dissolution in 45 minutes; at the same time, the tablets of the present invention can also maintain good dissolution at 60°C for 10 days.

[0096] Experimental Example 3: Repose Angle and Carr Coefficient Test

[0097] The Carle coefficient and the angle of repose are measured by a powder comprehensive property tester.

[0098] Angle of repose: The maximum angle formed by the free slope of the powder accumulation layer and the horizontal plane in a static equilibrium state.

[0099] Carr coefficient: 1. Bulk density: The density measured when the powder is filled in a measuring container without any external force is the bulk density ρ0; 2. Tap density: When a certain external force is applied, the powder is vibrated so that the freely accumulated materials are continuously compacted. The density changes with the continuous change of the number of oscillations. When the oscillation volume no longer changes, it indicates that the material is filled to the densest state, which is the tap density ρf; 3. Carr coefficient: C = (ρf-ρ0) / ρf.

[0100] The test results are shown in Table 10:

[0101] Table 10

[0102]

[0103] It can be seen from the results in Table 10 that the tablets of the present invention have good particle flowability.

[0104] Examples 15-1 to 15-8

[0105] According to the prescription ratio of Example 15 in Table 11, the active ingredient compound of formula (I) was prepared into the particle size shown in Table 12, and then according to the following steps, 200M lactose monohydrate and 101 microcrystalline cellulose were sieved, and during the initial mixing, the compound of formula (I) was first fully mixed with part of the 200M lactose monohydrate, and then the remaining 200M lactose monohydrate, 101 microcrystalline cellulose and sodium starch glycolate were added and mixed evenly, and povidone K30 was prepared into a solution with water and added for wet granulation, and the particles were granulated after oven drying. During the final mixing, colloidal silicon dioxide, magnesium stearate and the particles were sieved, mixed evenly, and then compressed into tablets using a tablet press.

[0106] Table 11

[0107]

[0108] Table 12

[0109]

[0110] Dissolution test

[0111] According to the dissolution and release test method (Chinese Pharmacopoeia 2015 Edition Part IV General Principles 0931 Method 2, USP <711> ), dissolution test was performed on Examples 15-1 to 15-8, using 900 ml of dissolution medium (7.8 g of sodium dihydrogen phosphate dihydrate was dissolved in water and diluted to 1000 ml, pH was adjusted to 4.50±0.05 with 1 mol / L sodium hydroxide solution or 10% dilute phosphoric acid, 1.0 g of sodium dodecyl sulfate was added, and the solution was dissolved by stirring), and the dissolution experiment was performed at 37.0±0.5°C with a paddle speed of 75 revolutions per minute.

[0112] Table 12

[0113]

[0114] The results show that the dissolution rate of the compound of formula (I) in the tablets of Examples 15-2 to 15-7 is relatively fast, reaching more than 90% in 45 minutes, and the dissolution similarity factor f2 is greater than 50, indicating that the dissolution between batches is basically consistent. However, the dissolution rate of the tablet of Example 15-8 is relatively slow, with only 82.8% dissolved in 45 minutes, and the similarity factor f2 is less than 50, indicating that the dissolution between batches is inconsistent.

[0115] Friability: Refer to the Tablet Friability Test Method in Part 0923 of the Chinese Pharmacopoeia 2015 Edition.

[0116] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises 1wt%-70wt% of an active ingredient, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, isomer thereof, and at least one pharmaceutical excipient; 2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical excipients include fillers, binders, disintegrants or lubricants.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical excipients also include glidants.

4. The pharmaceutical composition according to claim 3, characterized in that Containing 1wt%-30wt% of a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, or isomer thereof; 10wt%-90wt% filler; 0.1wt%-10wt% binder; 1wt%-10wt% disintegrant; 0.1wt%-2wt% lubricant; 0.1wt%-2wt% of a flow aid; Preferably, it contains 1wt%-10wt% of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, isomer thereof; 80wt%-90wt% of a filler; 2wt%-5wt% of a binder; 2wt%-8wt% of a disintegrant; 0.6wt%-1wt% of a lubricant; 0.5wt%-1wt% of a flow aid.

5. The pharmaceutical composition according to claim 3, characterized in that The filler is selected from: one or more of lactose monohydrate, microcrystalline cellulose, corn starch, glucose, mannitol, sorbitol, calcium carbonate, and calcium hydrogen phosphate; preferably, the filler is selected from lactose monohydrate and microcrystalline cellulose.

6. The pharmaceutical composition according to claim 3, characterized in that The binder is selected from: one or more of povidone, hydroxypropyl cellulose, methyl cellulose, hypromellose, and sodium carboxymethyl cellulose; preferably, the binder is selected from povidone.

7. The pharmaceutical composition according to claim 3, characterized in that The disintegrant is selected from: one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; preferably, the disintegrant is selected from sodium carboxymethyl starch.

8. The pharmaceutical composition according to claim 3, characterized in that The lubricant is selected from: magnesium stearate, sodium stearyl fumarate; the glidant is selected from: colloidal silicon dioxide, talc.

9. The pharmaceutical composition according to claim 1, characterized in that The particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is D90<60 μm; preferably, D90≤58 μm.

10. The pharmaceutical composition according to claim 1, characterized in that The particle size distribution range of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is D90≤50 μm.

11. The pharmaceutical composition according to any one of claims 1 to 10, characterized in that The content of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, isomer is 1-20 mg.

12. A pharmaceutical preparation, characterized in that The pharmaceutical preparation is prepared from the pharmaceutical composition according to any one of claims 1 to 11.

13. The pharmaceutical preparation according to claim 12, characterized in that The pharmaceutical preparation is a tablet.

14. A medicine box, characterized in that: Contains the pharmaceutical preparation according to claim 12, and instructions for use.

15. Use of the pharmaceutical composition according to any one of claims 1 to 11 or the pharmaceutical preparation according to claim 12 in the preparation of a drug for treating cancer.

16. The use according to claim 15, characterized in that The cancers include bile duct cancer, head and neck cancer, liver cancer, colorectal cancer, osteosarcoma, bladder cancer, prostate cancer, gastric cancer, urothelial carcinoma, lung cancer, endometrial cancer, breast cancer, thyroid cancer, ovarian cancer, peritoneal cancer, kidney cancer, B-cell malignancies, oral cancer, and nasopharyngeal cancer.

17. A method for preparing the pharmaceutical composition according to any one of claims 1 to 11 or the pharmaceutical preparation according to claim 12 or 13, characterized in that: The preparation was carried out by wet granulation method.

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