PHARMACEUTICAL COMPOSITION AND ITS APPLICATION

Abstract

The present invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition and the use thereof. The pharmaceutical composition comprises 1wt%-70wt% of a compound of formula (I) or a pharmaceutically acceptable salt, crystal form and isomer thereof, and at least one pharmaceutical adjuvant. By means of research, the present invention develops the pharmaceutical composition which can be prepared into final dosage forms, such as tablets, capsules and particles. When the pharmaceutical composition is prepared into a tablet, the pharmaceutical composition has good compressibility, good dissolution rate and good particle fluidity when compared to other pharmaceutical combination modes.

Description

Pharmaceutical composition and use thereof 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 novel mechanism. It 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 material in order to obtain a stable and pharmaceutically usable drug preparation.

[0004] Summary of the Invention

[0005] The present invention studies the following pharmaceutical composition, comprising 1 wt% to 70 wt% of an active ingredient, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, or isomer thereof, and at least one pharmaceutical excipient;

[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 a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, or isomer thereof; 10wt%-90wt% of a filler; 0.1wt%-10wt% of a binder; 1wt%-10wt% of a disintegrant; and 0.1wt%-2wt% of a lubricant.

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

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

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

[0012] Preferably, the pharmaceutical composition of the present invention further contains 0.5 wt% to 1 wt% 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 1 wt%-5 wt%, 2 wt%-5 wt% or 2.5 wt%-5 wt% of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form or isomer thereof.

[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 type of microcrystalline cellulose is microcrystalline cellulose 101.

[0019] In some embodiments, the mass ratio of the lactose monohydrate to the 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 the lactose monohydrate to the 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, hypromellose, 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 model of the 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, such as water, may 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, or 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, or isomer has a particle size distribution range D90 < 59.7 μm.

[0033] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, or 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, or 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≤59 μm, for example, D90≤58 μm, D90≤57 μm, D90≤56 μm, D90≤55 μm, D90≤54 μm, D90≤53 μm, D90≤52 μm, D90≤51 μm; including but not limited to: 0 μm <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 compound of formula (I) or its pharmaceutically acceptable salt, crystal form, or isomer has a particle size distribution range of 18.1 μm ≤ D90 < 59.7 μm.

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

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

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

[0041] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, or isomer has a particle size distribution range of 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, crystalline form, or isomer is 1-20 mg. 1-20 mg includes any value between 1-20, for example, 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, and 20 mg.

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

[0044] In some embodiments, the pharmaceutical formulation 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 further provides use of any one of the pharmaceutical compositions or pharmaceutical preparations described in any one of the embodiments 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 cancer, lung cancer, endometrial cancer, breast cancer, thyroid cancer, ovarian cancer, peritoneal cancer, kidney cancer, B-cell malignancies, oral cancer, or 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 pre-mixed with the disintegrant and the active ingredient, and then wet-granulated with the binder and dried to obtain dry granules.

[0051] In some embodiments, the wet granulation step further includes a final mixing 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 percentage by mass (weight). BRIEF DESCRIPTION OF THE DRAWINGS

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

[0055] Figure 2 shows an example of tablets that stick during the compressibility evaluation.

[0056] Beneficial effects of the present 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 prepared into tablets, the pharmaceutical composition has good compressibility and dissolution properties compared to other drug combinations, as well as good granular 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 an appropriate range, thereby avoiding the impact of inappropriate particle size on drug dissolution, and thus avoiding the impact on drug bioavailability. Furthermore, the present invention's control of the particle size of the active ingredient can also avoid the problem of inconsistent dissolution of different batches of drugs produced by the same prescription process, ensuring that the drug can be dissolved stably during the preparation process and with good reproducibility between batches. Studies have found that by controlling the D 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] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention is described in further detail below. It is apparent that the embodiments described herein are merely a portion of the embodiments of the present invention, and not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall 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, the compound of formula (I), was air-flow ground to a particle size D90 ≤ 50 μm. The fillers, lactose monohydrate 200M, microcrystalline cellulose 101, corn starch, and mannitol 160°C, were sieved. During the initial mixing, the active ingredient was first thoroughly mixed with a portion of the lactose monohydrate 200M, and then the remaining lactose monohydrate 200M, other fillers, and low-substituted hydroxypropyl cellulose were added and mixed evenly. A solution of povidone K30 and water was sprayed and added for granulation. After oven drying, the granules were granulated. During the final mixing, colloidal silicon dioxide, magnesium stearate, and the granules were sieved, mixed evenly, and compressed into tablets using a tablet press.

[0063] Table 1

[0064] According to the prescription ratio in Table 2, the active ingredient, the compound of formula (I), was air-flow milled to a particle size D90 ≤ 50 μm. The fillers, lactose monohydrate 200M, microcrystalline cellulose 101, and fully pregelatinized starch, were sieved. During the initial mixing, the active ingredient was thoroughly mixed with the fillers, lactose monohydrate (or fully pregelatinized starch), microcrystalline cellulose 101, and sodium starch glycolate. A solution of povidone K30 and water was added for granulation. After oven drying, the granules were granulated. During the final mixing, the colloidal silicon dioxide, magnesium stearate, and granules were sieved, mixed uniformly, and compressed into tablets using a tablet press.

[0065] Table 2

[0066] According to the prescription ratio in Table 3, the active ingredient, the compound of formula (I), was air-flow ground to a particle size D90 ≤ 50 μm. The fillers, lactose monohydrate 200M and microcrystalline cellulose 101, were sieved. During the initial mixing, the active ingredient was first thoroughly mixed with a portion of the lactose monohydrate 200M, and then the remaining lactose monohydrate, microcrystalline cellulose 101, and sodium starch glycolate were added and mixed evenly. A solution of povidone K30 and water was sprayed and added for granulation. After oven drying, the granules were granulated. During the final mixing, colloidal silicon dioxide, magnesium stearate, and the granules were sieved, mixed evenly, and compressed into tablets using a tablet press.

[0067] Table 3

[0068] According to the prescription ratio in Table 4, the active ingredient formula (I) compound was air-flow milled to a particle size D90 ≤ 50 μm. Lactose monohydrate 200M, microcrystalline cellulose 101, and hydroxypropyl cellulose EXF were sieved. During the initial mixing, the active ingredient was first thoroughly mixed with part of the lactose monohydrate 200M, and then the remaining lactose monohydrate 200M, microcrystalline cellulose 101, and cross-linked polyvinylpolypyrrolidone XL-10 were added and mixed evenly. When hydroxypropyl cellulose EXF was used as a binder, it was added to the dry powder and mixed. When povidone K30 was used as a binder, it was prepared into a solution with water and added for wet granulation. After oven drying, the granules were granulated. During the final mixing, colloidal silicon dioxide, magnesium stearate, and the granules were sieved, mixed evenly, and compressed into tablets using a tablet press.

[0069] Table 4

[0070] According to the prescription ratio in Table 5, the active ingredient, the compound of formula (I), was air-flow milled to a particle size D90 ≤ 50 μm. Lactose monohydrate 200M and microcrystalline cellulose 101 were sieved. During the initial mixing, the active ingredient was first thoroughly mixed with a portion of the lactose monohydrate 200M, and then the remaining lactose monohydrate 200M and microcrystalline cellulose 101 were added and mixed evenly. The disintegrants, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpolypyrrolidone XL-10, were added separately and mixed evenly. A solution of povidone K30 and water was added for wet granulation. After oven drying, the granules were granulated. During the final mixing, colloidal silicon dioxide, magnesium stearate, and the granules were sieved, mixed evenly, and compressed into tablets using a tablet press.

[0071] Table 5

[0072] According to the prescription ratio in Table 6, the active ingredient was air-flow milled to a particle size D90 ≤ 50 μm. The fillers lactose monohydrate 200M and microcrystalline cellulose 101 were sieved. During the initial mixing, the active ingredient was first thoroughly mixed with a portion of the lactose monohydrate 200M, 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. After oven drying, the granules were granulated. During the final mixing, colloidal silicon dioxide and / or magnesium stearate were added and sieved with the granules. After mixing evenly, the granules were compressed into tablets using a tablet press.

[0073] Table 6

[0074] Experimental Example 1: Compressibility Comparison

[0075] During the tablet preparation process for Examples 1-14 and Comparative Examples 1-4, the tablet compression process was observed and their compressibility was evaluated. If the tablets were easy to form, could be compressed to a suitable hardness under moderate pressure, and had a smooth and intact surface, the compressibility was good, as shown in Figure 1. If the tablets became loose, cracked, sticky, or astringent during compression, the compressibility was poor. The results are shown in Table 7.

[0076] Table 7

[0077] Sticking: It refers to the phenomenon that fine powder on the surface of the tablet is adhered to the punch and die during tableting, resulting in the tablet surface being rough, uneven and with dents, as shown in Figure 2.

[0078] Astringent punch: When the tablet press is running, the upper and lower punches cannot move normally.

[0079] Experimental Example 2: Dissolution Comparison

[0080] Dissolution test: According to the dissolution and release test method (Chinese Pharmacopoeia 2015 edition Part IV General Chapter 0931 Method 2, USP <711> ), the tablets of Examples 1-13 were subjected to dissolution tests 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 lauryl sulfate was added, and the mixture was stirred to dissolve), and the dissolution test was performed at 37.0 ± 0.5 ° C with a paddle speed of 50 rpm.

[0081] The dissolution comparison under the sample setting condition (0 day) is shown in Table 8:

[0082] Table 8

[0083] The dissolution comparison under the sample setting conditions (60°C for 10 days) is shown in Table 9:

[0084] Table 9

[0085] The dissolution results show that the tablets of Examples 1-13 of the present invention dissolve rapidly 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.

[0086] Experimental Example 3: Angle of Repose and Carr's Coefficient Test

[0087] The Carle coefficient and angle of repose are measured by a powder comprehensive property tester.

[0088] 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.

[0089] Carr coefficient: 1. Bulk density: The density measured when the powder is filled in a measuring container without applying 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 vibrated and compacted. The volume 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.

[0090] The test results are shown in Table 10:

[0091] Table 10

[0092] From the results in Table 10, it can be seen that the tablets of the present invention have good granule flowability.

[0093] Examples 15-1 to 15-8

[0094] According to the prescription ratio of Example 15 in Table 11, the active ingredient compound of formula (I) was prepared into particle sizes as shown in Table 12. Then, according to the following steps, 200M lactose monohydrate and 101 microcrystalline cellulose were sieved. During the initial mixing, the compound of formula (I) was first thoroughly mixed with a portion of the 200M lactose monohydrate, and then the remaining 200M lactose monohydrate, 101 microcrystalline cellulose, and sodium starch glycolate were added and mixed evenly. A solution of povidone K30 and water was added and wet granulated. After oven drying, the particles were granulated. During the final mixing, colloidal silicon dioxide, magnesium stearate, and the particles were sieved, mixed evenly, and compressed into tablets using a tablet press.

[0095] Table 11

[0096] Table 12

[0097] Dissolution test

[0098] According to the dissolution and release test method (Chinese Pharmacopoeia 2015 edition Part IV General Chapter 0931 Method 2, USP <711> ), the dissolution test of Examples 15-1 to 15-8 was carried out 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, 1.0 g of sodium lauryl sulfate was added, and the mixture was stirred to dissolve), and the dissolution experiment was carried out at 37.0±0.5°C and a paddle speed of 75 revolutions per minute.

[0099] Table 12

[0100] The results showed that the dissolution rate of the compound of formula (I) in the tablets of Examples 15-2 to 15-7 was relatively fast, reaching over 90% dissolution in 45 minutes, and the dissolution similarity factor f2 was greater than 50, indicating that dissolution was generally consistent between batches. However, the dissolution rate of the tablet of Example 15-8 was relatively slow, with only 82.8% dissolution in 45 minutes and a similarity factor f2 of less than 50, indicating inconsistent dissolution between batches.

[0101] Friability: Refer to the Tablet Friability Test Method in Part IV General Chapter 0923 of the 2015 edition of the Chinese Pharmacopoeia.

[0102] 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 containing 1-70% by weight of an active ingredient, which is a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form or isomer thereof, and at least one pharmaceutical excipient; (I).

2. A pharmaceutical composition according to claim 1, characterized in that the pharmaceutical excipient may include a filler, a binder, a disintegrant, or a lubricant.

3. The pharmaceutical composition according to claim 2, characterized in that the pharmaceutical excipient additionally includes a glidant.

4. The pharmaceutical composition according to paragraph 3, containing 1-30% by weight of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form or isomer thereof; 10-90% by weight of a filler; 0.1-10% by weight of a binder; 1-10% by weight of a disintegrant; and 0.1-2% by weight of a lubricant; and 0.1-2% by weight of a glidant; preferably comprising 1-10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form or isomer thereof; 80-90% by weight of a filler; 2-5% by weight of a binder; 2-8% by weight of a disintegrant; 0.6-1% by weight of a lubricant; and 0.5-1% by weight of a glidant.

5. The pharmaceutical composition according to claim 3, characterized in that the filler is selected from one or more of the following substances: 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 the following substances: povidone, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose and sodium carboxymethylcellulose; 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 the following substances: sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and sodium croscarmellose; 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 and sodium stearyl fumarate; the glidant is selected from colloidal silicon dioxide and talc.

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

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

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

12. A dosage form characterized in that it is prepared from a pharmaceutical composition according to any of paragraphs 1-11.

13. The dosage form according to paragraph 12, characterized in that it is a tablet.

14. A kit containing a dosage form according to item 12 and instructions for use.

15. Use of a pharmaceutical composition according to any of paragraphs 1-11 or a dosage form according to paragraph 12 in the manufacture of a medicinal product for the treatment of malignant neoplasms.

16. The use according to claim 15, wherein the malignant neoplasms include cholangiocarcinoma, 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, renal cancer, malignant B-cell neoplasms, oral cancer and nasopharyngeal cancer.

17. A method for preparing a pharmaceutical composition according to any of paragraphs 1-11 or a dosage form according to paragraph 12 or 13, in which the preparation is carried out by wet granulation.