A pharmaceutical composition comprising a selective estrogen receptor degrader and a method of preparing the same

Abstract

The present disclosure relates to a pharmaceutical composition comprising a selective estrogen receptor degrader and a preparation method thereof. Specifically, the present disclosure provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a filler comprising microcrystalline cellulose and anhydrous dibasic calcium phosphate, which has good dissolution and stability.

Description

A pharmaceutical composition comprising a selective estrogen receptor degrader and a preparation method thereof Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition comprising a selective estrogen receptor degrader (SERD) and a preparation method thereof. Specifically, the present disclosure relates to a composition comprising 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolano[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol or a pharmaceutically acceptable salt thereof and a filler comprising microcrystalline cellulose and anhydrous calcium hydrogen phosphate. Background Art

[0002] In the CSCO Breast Cancer Diagnosis and Treatment Guidelines (2020 edition), fulvestrant has been adjusted to a Class I recommendation for patients with hormone receptor-positive advanced breast cancer who have not undergone endocrine therapy, and fulvestrant + CDK4 / 6 inhibitors have been newly added as a Class II recommendation. In addition, fulvestrant combined with a CDK4 / 6 inhibitor has become a Class I recommendation for patients who have failed non-steroidal AI (NSAI) treatment and steroidal AI (SAI) treatment. As the only currently approved SERD, fulvestrant is approved in the form of an injection, which brings inconvenience to patients. Therefore, the search for new and more effective SERDs not only has huge market value but also brings drug options and convenience to breast cancer patients. Currently, Sanofi's SAI439859, a new generation of oral SERD inhibitors, is currently in Phase III clinical trials. In addition, Roche's GDC-9545, AstraZeneca's AZD-9833, and Radius's RAD1901 have all entered Phase III.

[0003] WO2021139756A1 discloses a selective estrogen receptor degrader (SERD), such as a compound shown in formula (I), whose compound name is 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolan-[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol. This compound exhibits a significant degradation effect on ERα.

[0004] In order to meet the medication needs of patients, the compound of formula (I) 2,2-difluoro-3-((5S,7R)-5-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-7-methyl-7,8-dihydro-[1,3]dioxolano[4,5-g]isoquinolin-6(5H)-yl-2,2-d2)propan-1-ol or a pharmaceutically acceptable salt thereof needs to be prepared into a suitable formulation. For solid preparations, the formulation needs to have good dissolution characteristics and formulation stability. For tablets, the tablet appearance should be complete and smooth, with uniform color, and have appropriate hardness and wear resistance. Summary of the Invention

[0005] The present disclosure provides a pharmaceutical composition comprising an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a filler, wherein the filler comprises microcrystalline cellulose and anhydrous calcium hydrogen phosphate.

[0006] In some embodiments, the weight ratio of the microcrystalline cellulose to anhydrous calcium hydrogen phosphate is 1:2 to 2:1.

[0007] In some specific embodiments, the weight ratio of the microcrystalline cellulose to anhydrous calcium hydrogen phosphate is 1:2 to 1:1.

[0008] In some embodiments, the content of the active ingredient is 0.1%-40% based on the total weight of the pharmaceutical composition.

[0009] In some embodiments, the content of the active ingredient is 1%-35% based on the total weight of the pharmaceutical composition. Optional contents include: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35% or any value between two points.

[0010] In some embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is selected from 1 mg to 500 mg (in free base form), specifically 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 1 05mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170 mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg , 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 37 0mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg or 500mg.

[0011] In some embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is selected from 25 mg to 200 mg (calculated as free base).

[0012] In some embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is selected from 50 mg, 75 mg, 100 mg, 150 mg or 200 mg (calculated as free base).

[0013] In some specific embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is 50 mg (calculated as free base).

[0014] In some specific embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is 75 mg (calculated as free base).

[0015] In some specific embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is 100 mg (calculated as free base).

[0016] In some specific embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is 150 mg (calculated as free base).

[0017] In some specific embodiments, the content of the compound represented by formula (I) in the unit dosage form of the pharmaceutical composition is 200 mg (calculated as free base).

[0018] In some embodiments, the filler content is 20%-95% based on the total weight of the pharmaceutical composition.

[0019] In some embodiments, the filler content is 50%-95% based on the total weight of the pharmaceutical composition. Optional contents include: 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or any value between two points.

[0020] In some embodiments, the content of the microcrystalline cellulose is 10%-50% based on the total weight of the pharmaceutical composition.

[0021] In some embodiments, the content of microcrystalline cellulose is 15%-45% based on the total weight of the pharmaceutical composition, and optional contents include 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45% or any value between two points.

[0022] In some embodiments, the content of anhydrous calcium hydrogen phosphate is 10%-50% based on the total weight of the pharmaceutical composition.

[0023] In some embodiments, the content of anhydrous calcium hydrogen phosphate is 15%-45% based on the total weight of the pharmaceutical composition, and optional contents include 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45% or any value between two points.

[0024] In some embodiments, the pharmaceutical composition further comprises one or more of a disintegrant, a binder, a glidant, a lubricant, and a coating agent.

[0025] In some embodiments, the content of the disintegrant is 1%-5% based on the total weight of the pharmaceutical composition.

[0026] In some embodiments, the content of the disintegrant is 1.5%-5% based on the total weight of the pharmaceutical composition, and optional contents include 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0% or any value between two points.

[0027] In some specific embodiments, the disintegrant is croscarmellose sodium.

[0028] In some embodiments, the content of the binder is 0.1%-10% based on the total weight of the pharmaceutical composition.

[0029] In some embodiments, the content of the binder is 0.2%-5% based on the total weight of the pharmaceutical composition, and optional contents include 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0% or any value between two points.

[0030] In some specific embodiments, the binder is hydroxypropyl cellulose.

[0031] In some embodiments, the content of the glidant is 0.1%-10% based on the total weight of the pharmaceutical composition.

[0032] In some embodiments, the content of the glidant is 0.2%-5% based on the total weight of the pharmaceutical composition, and optional contents include 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0% or any value between two points.

[0033] In some specific embodiments, the glidant is colloidal silicon dioxide.

[0034] In some embodiments, the content of the lubricant is 0.1%-10% based on the total weight of the pharmaceutical composition.

[0035] In some embodiments, the content of the lubricant is 0.2%-5% based on the total weight of the pharmaceutical composition, and optional contents include 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0% or any value between two points.

[0036] In some specific embodiments, the lubricant is magnesium stearate.

[0037] In some embodiments, the coating agent is a film coating premix (gastric soluble).

[0038] In some embodiments, the coating weight gain is 2%-4% based on the total weight of the pharmaceutical composition.

[0039] In some embodiments, the coating weight gain is 2.5%-3.5% based on the total weight of the pharmaceutical composition, and optional coating weight gains include 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5% or any value between two points.

[0040] In some embodiments, the pharmaceutically acceptable salt of the active ingredient is a triphosphate salt.

[0041] In some specific embodiments, the pharmaceutical composition comprises, based on the total weight of the pharmaceutical composition,

[0042] 1%-35% of the active ingredient, wherein the active ingredient is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0043] Filler 50%-95%, the filler is microcrystalline cellulose and anhydrous calcium hydrogen phosphate,

[0044] Disintegrant 1.5%-5%, the disintegrant is cross-linked carboxymethyl cellulose sodium,

[0045] 0.2%-5% binder, wherein the binder is hydroxypropyl cellulose,

[0046] 0.2%-5% of glidant, wherein the glidant is colloidal silicon dioxide,

[0047] Lubricant 0.2%-5%, the lubricant is magnesium stearate,

[0048] The coating agent is a film coating premix (gastric soluble type), and the coating weight gain is 2.5%-3.5% based on the total weight of the pharmaceutical composition.

[0049] The content of the compound represented by formula (I) in the unit dosage form is selected from 50 mg, 75 mg, 100 mg, 150 mg or 200 mg (calculated as free base).

[0050] In some embodiments, the weight ratio of the microcrystalline cellulose to anhydrous calcium hydrogen phosphate is 1:2 to 2:1.

[0051] In some specific embodiments, the weight ratio of the microcrystalline cellulose to anhydrous calcium hydrogen phosphate is 1:2 to 1:1.

[0052] In some embodiments, the composition is in the form of a tablet.

[0053] In some embodiments, the composition is subjected to dissolution testing according to the second method (paddle method) of dissolution testing method 0931 of the fourth part of the 2020 edition of the Chinese Pharmacopoeia, and the cumulative dissolution of the active ingredient in 30 minutes is ≥85%, including ≥85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%.

[0054] In some embodiments, the cumulative dissolution of the active ingredient in 45 minutes is ≥90%, including ≥90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%.

[0055] In some specific embodiments, the cumulative dissolution rate of the active ingredient in 45 minutes is ≥94%, including ≥94%, 95%, 96%, 97%, 98%, 99%, and 100%.

[0056] The present disclosure also provides a method for preparing the pharmaceutical composition of the present disclosure, comprising:

[0057] 1) mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with a filler and at least one pharmaceutical excipient selected from the group consisting of a disintegrant, a binder, a glidant, and a lubricant;

[0058] 2) The mixture obtained in step 1) is dry granulated and then tableted.

[0059] In some embodiments, the method further comprises coating the tablet obtained in step 2).

[0060] In some specific embodiments, the step of coating the tablets obtained in step 2) comprises coating the tablets obtained in step 2) with a film coating premix (gastric soluble) and water.

[0061] The present disclosure also provides a use of the pharmaceutical composition of the present disclosure in preparing a selective estrogen receptor degrader (SERD).

[0062] The present disclosure also provides a use of the pharmaceutical composition described in the present disclosure in the preparation of a medicament for preventing and / or treating cancer, wherein the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.

[0063] In some embodiments, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

[0064] In some embodiments, the cancer is breast cancer.

[0065] The present disclosure also provides a method for treating cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition of the present disclosure to a patient in need thereof, wherein the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, hemophilia and leukemia.

[0066] In some embodiments, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

[0067] In some embodiments, the cancer is breast cancer.

[0068] The present disclosure also provides a pharmaceutical composition according to the present disclosure, which is used as a drug for treating cancer, wherein the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.

[0069] In some embodiments, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer.

[0070] In some embodiments, the cancer is breast cancer.

[0071] Explanation of terms

[0072] In order to make the present disclosure more easily understood, certain technologies and sciences are specifically defined below. Unless otherwise explicitly defined in the present disclosure, all other technologies and sciences used in the present disclosure have the meanings commonly understood by those skilled in the art in the art to which the present disclosure belongs.

[0073] A "pharmaceutical composition" refers to a mixture containing one or more active ingredients described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0074] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0075] The "based on the total weight of the pharmaceutical composition" and "calculated by the total weight of the pharmaceutical composition" mentioned in the present disclosure are the numerical ranges for the amount of active ingredients or other types of pharmaceutical excipients used calculated based on the weight of the tablet core excluding the coating agent.

[0076] The term "mixing" in the present disclosure does not limit the order in which the components are added. For example, mixing A into B can mean either adding A into B or adding B into A. Mixing A and B can mean either adding A into B or adding B into A.

[0077] "Treatment" means administering a therapeutic agent, such as a fusion protein or insulin analog comprising any of the present disclosure, to a subject who has, is suspected of having, or is predisposed to having one or more diabetes or hyperglycemia-related diseases or symptoms thereof, and for which the therapeutic agent is known to have a therapeutic effect. Typically, a therapeutic agent is administered in an amount effective to alleviate one or more symptoms of a disease in a treated subject or population, by preventing or delaying the onset of symptoms or complications, alleviating symptoms or complications, or eliminating the disease, condition, or disorder to any clinically measurable extent. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can vary according to a variety of factors, such as the disease state, age, and weight of the subject, and the ability of the drug to produce the desired therapeutic effect in the subject. Whether the symptoms of the disease have been alleviated can be evaluated by any clinical test method commonly used by a physician or other health care professional to evaluate the severity or progression of the symptoms. Although the embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating the symptoms of the target disease in a subject, they should alleviate the symptoms of the target disease in a statistically significant number of subjects as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test. The patient to be treated is a mammal, and preferably a human.

[0078] "Prevent" or "prevent" means reducing the risk or incidence, or eliminating or slowing the progression of one or more conditions, symptoms, complications, or disorders.

[0079] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0080] "Subject" or "patient" refers to a mammal, particularly a primate, and especially a human.

[0081] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to." BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1. Appearance of the coated tablets of Formulation 1 of Example 1.

[0083] Figure 2. Appearance of the coated tablets of Formulation 2 of Example 1.

[0084] Figure 3. Appearance of the coated tablets of Formulation 3 of Example 1.

[0085] Figure 4 is a comparison of the appearance of the coated tablets of Prescriptions 1-3 in Example 1, wherein from right to left are the coated tablets of Prescriptions 1, 2, and 3. DETAILED DESCRIPTION

[0086] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure.

[0087] Experimental methods in the embodiments or test examples disclosed herein that do not specify specific conditions are generally performed under conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are commercially available reagents.

[0088] Example 1: Tablet Preparation

[0089] Table 1. Pharmaceutical composition prescription

[0090] The materials were weighed according to the above table, and the triphosphate salt of the compound of formula (I), microcrystalline cellulose, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, part of croscarmellose sodium, and part of magnesium stearate were mixed and granules were prepared using a dry granulator.

[0091] The remaining cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide are added to the above granules, and then the remaining magnesium stearate is added and mixed to form a total mixed granule. The total mixed granule is compressed into tablets.

[0092] The tablets obtained by compression in the previous step are coated with a film coating premix (gastric soluble type) and water to obtain coated tablets.

[0093] According to the above scheme, 300 coated tablets of each of Prescription 1, Prescription 2, and Prescription 3 were prepared and their appearance was observed. As shown in Figures 1 and 2, among the 300 coated tablets prepared, the coated tablets of Prescription 1 and Prescription 2 all had smooth surfaces without obvious depressions, with a pass rate of 100%. As shown in Figures 3 and 4, compared with the coated tablets of Prescription 1 and Prescription 2, among the 300 coated tablets prepared, the coated tablets of Prescription 3 all had obvious depressions on their surfaces, with a pass rate of 0.

[0094] Example 2: Dissolution Test

[0095] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method), use 900 ml of pH 4.5 acetate buffer as the dissolution medium, the rotation speed is 75 revolutions per minute, and take appropriate amounts of solution at 5, 10, 15, 30, 45, and 60 minutes, filter, and use as the test solution.

[0096] Reference solution: Take an appropriate amount of triphosphate salt of the compound of formula (I), add dissolution medium to dissolve it and quantitatively dilute it to prepare a reference solution.

[0097] Inject the test solution and reference solution into the liquid chromatograph respectively, record the chromatogram, measure the peak area, and calculate the dissolution amount of each tablet at different times (see Table 2).

[0098] Table 2. Dissolution of different tablets

[0099] Example 3: Accelerated experiment

[0100] Coated tablets of Formulations 1 and 3 were prepared according to the tablet preparation method of Example 1, placed in high-density polyethylene bottles, and stored at 40°C and 75% RH for 3 months. The total impurity content in the coated tablets of Formulations 1 and 3 was determined by HPLC. The test results are shown in Table 3.

[0101] Table 3. Stability of different tablets

Claims

1. A pharmaceutical composition comprising an active ingredient which is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a filler, wherein the filler comprises microcrystalline cellulose and anhydrous calcium hydrogen phosphate, Preferably, the weight ratio of the microcrystalline cellulose to the anhydrous calcium hydrogen phosphate is 1:2 to 2:1; More preferably, the weight ratio of the microcrystalline cellulose to the anhydrous calcium hydrogen phosphate is 1:2 to 1:

1.

2. The pharmaceutical composition according to claim 1, wherein the content of the active ingredient is 0.1%-40% based on the total weight of the pharmaceutical composition; Preferably, the content of the active ingredient is 1%-35% based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1 or 2, wherein the content of the filler is 20%-95% based on the total weight of the pharmaceutical composition; Preferably, the content of the filler is 50%-95% based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the content of the compound represented by formula (I) in the unit dosage form is selected from 1 mg-500 mg (calculated as the free base); Preferably, the content of the compound represented by formula (I) in the unit dosage form is selected from 25 mg-200 mg (calculated as the free base); More preferably, the content of the compound represented by formula (I) in the unit dosage form is selected from 50 mg, 75 mg, 100 mg, 150 mg or 200 mg (calculated as the free base).

5. The pharmaceutical composition according to any one of claims 1-4, wherein the content of the microcrystalline cellulose is 10%-50% based on the total weight of the pharmaceutical composition; Preferably, the content of the microcrystalline cellulose is 15%-45% based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the content of the anhydrous calcium hydrogen phosphate is 10%-50% based on the total weight of the pharmaceutical composition; Preferably, the content of the anhydrous calcium hydrogen phosphate is 15%-45% based on the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1-6, which further comprises one or more of a disintegrant, a binder, a glidant, a lubricant, and a coating agent.

8. The pharmaceutical composition according to claim 7, wherein the content of the disintegrant is 1%-5% based on the total weight of the pharmaceutical composition; Preferably, the content of the disintegrant is 1.5%-5% based on the total weight of the pharmaceutical composition.

9. The pharmaceutical composition according to claim 7 or 8, wherein the disintegrant is croscarmellose sodium.

10. The pharmaceutical composition according to claim 7, wherein the content of the binder is 0.1%-10% based on the total weight of the pharmaceutical composition; Preferably, the content of the binder is 0.2%-5% based on the total weight of the pharmaceutical composition.

11. The pharmaceutical composition according to claim 7 or 10, wherein the binder is hydroxypropyl cellulose.

12. The pharmaceutical composition according to claim 7, wherein the content of the glidant is 0.1%-10% based on the total weight of the pharmaceutical composition; Preferably, the content of the glidant is 0.2%-5% based on the total weight of the pharmaceutical composition.

13. The pharmaceutical composition according to claim 7 or 12, wherein the glidant is colloidal silicon dioxide.

14. The pharmaceutical composition according to claim 7, wherein the content of the lubricant is 0.1%-10% based on the total weight of the pharmaceutical composition; Preferably, the content of the lubricant is 0.2%-5% based on the total weight of the pharmaceutical composition.

15. The pharmaceutical composition according to claim 7 or 14, wherein the lubricant is magnesium stearate.

16. The pharmaceutical composition according to claim 7, wherein the coating agent is a film coating premix (gastrosoluble type).

17. The pharmaceutical composition according to claim 7 or 16, wherein the coating weight gain is 2%-4% based on the total weight of the pharmaceutical composition; Preferably, the coating weight gain is 2.5%-3.5% based on the total weight of the pharmaceutical composition.

18. The pharmaceutical composition according to any one of claims 1-17, wherein the pharmaceutically acceptable salt of the active ingredient is triphosphate.

19. The pharmaceutical composition according to any one of claims 1-18, which comprises, based on the total weight of the pharmaceutical composition, The active ingredient is 1% - 35%, and the active ingredient is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 50%-95% of a filler, and the filler is microcrystalline cellulose and anhydrous calcium hydrogen phosphate, 1.5%-5% of a disintegrant, and the disintegrant is croscarmellose sodium, 0.2%-5% of a binder, and the binder is hydroxypropyl cellulose, 0.2%-5% of a glidant, and the glidant is colloidal silicon dioxide, 0.2%-5% of a lubricant, and the lubricant is magnesium stearate, the coating agent is a film coating premix (gastrosoluble type), and the coating weight gain is 2.5%-3.5% based on the total weight of the pharmaceutical composition, the content of the compound shown in formula (I) in the unit dosage form is selected from 50 mg, 75 mg, 100 mg, 150 mg or 200 mg (calculated as the free base); Preferably, the weight ratio of the microcrystalline cellulose to the anhydrous calcium hydrogen phosphate is 1:2 to 2:1; More preferably, the weight ratio of the microcrystalline cellulose to the anhydrous calcium hydrogen phosphate is 1:2 to 1:

1.

20. The pharmaceutical composition according to any one of claims 1-17, wherein the composition is in the form of tablets.

21. The pharmaceutical composition according to any one of claims 1-18, wherein the dissolution of the composition is determined by the second method (paddle method) of dissolution determination in General Chapter 0931 of the Fourth Part of Chinese Pharmacopoeia 2020 Edition, and the cumulative dissolution of the active ingredient at 30 minutes is ≥85%.

22. The pharmaceutical composition according to claim 21, wherein the cumulative dissolution of the active ingredient at 45 minutes is ≥90%; Preferably, the cumulative dissolution of the active ingredient at 45 minutes is ≥94%.

23. A method for preparing the pharmaceutical composition according to any one of claims 1-22, comprising: 1) Mixing the compound of formula (I) or its pharmaceutically acceptable salt with a filler and at least one pharmaceutical excipient selected from a disintegrant, a binder, a glidant, and a lubricant; 2) Dry granulating the mixture obtained from step 1) and then tabletting; Preferably, it further comprises the step of coating the tablets obtained in step 2).

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