Pharmaceutical formulations of piperazine derivatives, methods for producing the same, and their uses.

Abstract

The present invention relates to pharmaceutical formulations containing piperazine derivatives, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, methods for preparing such pharmaceutical formulations, and their use in pharmaceuticals. In particular, the invention relates to formulations containing compounds represented by formula (I). [Formula 1] JPEG2026528917000082.jpg30169

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical formulations containing piperazine derivatives, their stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts thereof, methods for producing the same, and their uses in pharmaceuticals. [Background technology]

[0002] Adenosine diphosphate ribosylation (ADP-ribosylation) is a post-translational protein modification process in which one or more adenosine diphosphate ribose (ADP-ribose) groups are added to amino acid residues of proteins. ADP-ribosylation is a reversible process and is involved in physiological regulation such as cell signaling, DNA damage repair, transcription, gene expression regulation, and apoptosis. The enzymes that mediate the addition of ADP-ribose for modification are called ADP-ribosyltransferases. ADP-ribosyltransferases can catalyze two types of modifications: mono-ADP-ribosylation and poly-ADP-ribosylation. When DNA is damaged or cells are stressed, PARP (poly-ADP-ribose polymerase) is activated, increasing the amount of poly-ADP-ribose and decreasing the amount of NAD+. To date, scientists have identified 17 different types of PARP. Mono-PARPs constitute the majority of the PARP family and mediate important biological functions and various stress responses (e.g., unfolded protein responses, NF-κB signaling, antiviral responses, cytokine signaling, etc.). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced poly(ADP-ribose) polymerase (PARP-7) is a member of the mono-PARP family, and its expression is regulated by the aryl hydrocarbon receptor (AHR), which is activated by TCDD. AHR is a ligand-activated transcription factor that mediates toxic activity from many xenobiotics. AHR upregulates PARP-7 expression, which interacts with the kinase TBK1 to cause ADP-ribosylation of TBK1. This inhibits TBK1 activity, downregulating the IFN-I (type I interferon) response and ultimately suppressing the body's antiviral and antitumor immune responses.

[0003] The patent (PCT publication number: WO 2022242750) describes a novel PARP7 inhibitor represented by formula (I). This inhibitor exhibits good inhibitory effects on PARP7 activity and has potential for use in the preparation of antitumor drugs. [ka] It is important to prepare a pharmaceutical preparation containing a PARP7 inhibitor that exhibits excellent drug dissolution effect and stability.

Summary of the Invention

[0004] An object of the present invention is to provide a pharmaceutical preparation containing a PARP7 inhibitor, a method for producing the same, and its use in the production of an antitumor drug. Here, the PARP7 inhibitor is a piperazine derivative, or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof.

[0005] One or more embodiments of the present invention provide a pharmaceutical preparation of a piperazine derivative, or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical preparation contains a piperazine derivative with a content of 1 to 1000 mg, and the piperazine derivative is selected from the compounds of formula (I):

Chemical formula

[0006] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by the following: X1 is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from NH, O, or N and O; X2 is O or bond; X3 and X4 are independently C or N; R 1a and R 1b These are H, D, or C, respectively, independently. 1-6 It is alkyl; R 2a and R 2b These are H, D, or C, respectively, independently. 1-6 Alkyl; or R 2a and R 2b teeth 、 Together with the carbon atoms bonded to these, they form a 3- to 5-membered cycloalkyl ring; R3 is H, D, C 1-6 It is an alkyl, halogen, or cyano, where C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are independently H, D, or C 1-6 It is alkyl; or R4 and R5 are 、 Together with the carbon atoms bonded to these, they form a 3- to 5-membered cycloalkyl ring; R6 and R7 are independently H, D, or C 1-6 It is alkyl; R8 and R9 can be independently set to H, D, or C1-6 It is alkyl; or R8 and R9, together with the carbon atoms bonded to them, form =O; Each R 10 C is independent 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b Halogen, cyanoacrylate, S(O)2R 10c , SR 10d Or a cycloalkyl group with 3-5 members, where C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with one to three halogens; R 10a , R 10b , R 10c and R 10d These are H, D, or C, respectively, independently. 1-6 It is alkyl; A is [ka] and; R a C 1-6 Alkyl, C 3-5 It is a cycloalkyl, halogen, or cyano, where C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; C is a heterocycle of 5-6 members containing 1-3 N heteroatoms; m is 1, 2, or 3; n is 0, 1, 2, or 3; and p is 0, 1, 2, or 3.

[0007] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the piperazine derivative is selected from the compounds of formula (I-1): [ka] Here: X1 is a 4- to 6-membered heterocycle containing 1-3 heteroatoms selected from NH, or N and O; X2 is O; X3 and X4 are independently C or N; R 1a and R 1b These are H, D, or C, respectively, independently. 1-6 It is alkyl; R 2a and R 2b These are H, D, or C, respectively, independently. 1-6 It is alkyl; R3 is H, D, C 1-6 It is an alkyl or halogen, where C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are independently H, D, or C 1-6 It is alkyl; R6 and R7 are independently H, D, or C 1-6 It is alkyl; R8 and R9 can be independently set to H, D, or C 1-6 It is alkyl; or R8 and R9, together with the carbon atoms bonded to them, form =O; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano, or SR 10d And here C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with one to three halogens; R 10d is H, D, or C 1-6 It is alkyl; A is [ka] and; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms; m is 1, 2 or 3; and n is 0, 1, 2 or 3.

[0008] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the piperazine derivative is selected from the compounds of formula (I-2):

Chemical formula

[0009] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by the following: X1 is NH; X2 is O; R 1a and R 1b These are H, D, or C, respectively, independently. 1-6 It is alkyl; R 2a and R 2b These are H, D, or C, respectively, independently. 1-6 It is alkyl; R3 is H, D, C 1-6 It is an alkyl or halogen, where C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are independently H, D, or C 1-6 It is alkyl; R6 and R7 are independently H, D, or C 1-6 It is alkyl; R8 and R9 can be independently set to H, D, or C 1-6 It is alkyl; or R8 and R9, together with the carbon atoms bonded to them, form =O; R 10 C 1-6 Alkyl, cyano, or SR 10d And here C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R 10d is H, D, or C1-6 It is alkyl; A is [ka] and; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; m is 1, 2, or 3; and n is 0, 1, 2, or 3.

[0010] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by the following: X1 is selected from NH; X2 is selected from O; R 1a and R 1b teeth 、 Each is independent of H, D, or C 1-6 Selected from alkyl groups; R 2a and R 2b teeth 、 Each is independent of H, D, or C 1-6 Selected from alkyl groups; R3 is H, D, C 1-6 It is an alkyl or halogen, where C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are independently either H or D; R6 and R7 are independently either H or D; R8 and R9 are independently either H or D; R 10 CF3 or SR 10d and; R 10d is H, D, or C 1-6 It is alkyl; A is [ka] and; B is [ka] and; m is 1, 2, or 3; and n is 0, 1, 2, or 3.

[0011] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by the following: X1 is selected from NH; X2 is selected from O; R 1a and R 1b teeth 、 Each is independent of H, D, or C 1-3 Selected from alkyl groups; R 2a and R 2b teeth 、 Each is independent of H, D, or C 1-3 Selected from alkyl groups; R3 is selected from H, D, or CF3; R4 and R5 are each independently selected from H or D; R6 and R7 are each independently selected from H or D; R8 and R9 are each independently selected from H or D; R 10 is CF3; A is [ka] and; B is [ka] and; m is 1, 2, or 3; and n is 0, 1, or 2.

[0012] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the piperazine derivative is selected from compounds of formula (I-3): [ka] Here: X1 is a 4- to 6-membered heterocycle containing 1-3 heteroatoms selected from NH, or N and O; X2 is O; R 1a and R 1b These are H, D, or C, respectively, independently. 1-6 It is alkyl; R 2a and R 2b These are H, D, or C, respectively, independently. 1-6 It is alkyl; R4 and R5 are independently H, D, or C 1-6 It is alkyl; R6 and R7 are independently H, D, or C 1-6 It is alkyl; R8 and R9 can be independently set to H, D, or C 1-6 It is alkyl; or R8 and R9, together with the carbon atoms bonded to them, form =O; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano, or SR 10d And here C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with one to three halogens; R 10d is H, D, or C 1-6 It is alkyl; A is [ka] and; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; m is 1, 2, or 3; and n is 0, 1, 2, or 3.

[0013] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by the following: X1 is a 4- to 6-membered heterocycle containing 1-3 heteroatoms selected from NH, or N and O; X2 is O; R 1a and R 1b These are H, D, or C, respectively, independently. 1-3 It is alkyl; R 2a and R 2b These are H, D, or C, respectively, independently. 1-3 It is alkyl; R4 and R5 are independently H, D, or C 1-3 It is alkyl; R6 and R7 are independently H, D, or C 1-3 It is alkyl; R8 and R9 can be independently set to H, D, or C 1-3 It is alkyl; or R8 and R9, together with the carbon atoms bonded to them, form =O; R 10 C 1-6 Alkyl, cyano, or SR 10d And here C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R 10d is H, D, or C 1-6 It is alkyl; A is [ka] and; B is [ka] and; m is 1, 2, or 3; and n is 0, 1, or 2.

[0014] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by the following: X1 is NH; X2 is O; R 1a and R 1b These are H, D, or C, respectively, independently. 1-3 It is alkyl; R 2a and R 2b These are independently H or D; R4 and R5 are independently either H or D; R6 and R7 are independently either H or D; R8 and R9 are independently either H or D; R 10 is CF3; A is [ka] and; B is [ka] and; m is 1, 2, or 3; and n is 0, 1, or 2.

[0015] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that a piperazine derivative, or a stereoisomer thereof, a tautomer thereof, a deuterated compound, or a pharmaceutically acceptable salt thereof, is selected from the following: [ka] [ka] [ka] [ka] [ka]

[0016] In one or more embodiments, the pharmaceutical formulation of the present invention contains a piperazine derivative, or its stereoisomer, tautomer, deuterated compound, or a pharmaceutically acceptable salt thereof, in doses of 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, and 70-80 mg. It is characterized by containing the following amounts: 80-90 mg, 90-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, or 900-1000 mg.

[0017] In one or more embodiments, the pharmaceutical formulation of the present invention contains a piperazine derivative, or its stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof, in an amount of 5% to 90% (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or any weight percentage range) of the total weight of the pharmaceutical formulation, preferably 20% to 80%, more preferably 30% to 70%.

[0018] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that its dosage form is selected from tablets, capsules, or granules.

[0019] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by further comprising one or more of the following: a diluent, a disintegrant, a solvent, a flow promoter, and a lubricant.

[0020] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the diluent is selected from one or more combinations thereof of microcrystalline cellulose, starch, mannitol, lactose, pregelled starch, dextrin, sucrose, calcium hydrogen phosphate, and calcium phosphate; the content of the diluent is 10% to 80% of the total weight of the pharmaceutical formulation (e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or any weight percentage range).

[0021] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the disintegrant is selected from one or more combinations thereof of microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polariphosphate potassium, pregelled starch, and starch; the content of the disintegrant is 1% to 60% of the total weight of the pharmaceutical formulation (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or any weight percentage range), preferably 3% to 20%.

[0022] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the solvent is selected from either poloxamer or sodium dodecyl sulfate, or a combination thereof; the content of the solvent is 2% to 10% of the total weight of the pharmaceutical formulation (e.g., about 1%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or any weight percentage range).

[0023] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the flow promoter is selected from either colloidal silica or talc, or a combination thereof; the content of the flow promoter is 0.5% to 5% of the total weight of the pharmaceutical formulation (e.g., about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, or any weight percentage range).

[0024] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the lubricant is selected from one or more combinations thereof of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oil, magnesium lauryl sulfate, polyethylene glycol, glyceryl behenate, and sucrose esters; the lubricant content is 0.5% to 5% of the total weight of the pharmaceutical formulation (e.g., about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, or any weight percentage range).

[0025] One or more embodiments of the present invention provide a method for preparing a pharmaceutical formulation of a piperazine derivative. This preparation method includes the steps of: micronizing a piperazine derivative to control its particle size to 5 to 100 μm, preferably 5 to 70 μm, and more preferably 5 to 40 μm; mixing the micronized piperazine derivative with a diluent, a disintegrant, and / or a solvent to obtain a mixture; dry granulating the mixture and adding a flow promoter and / or lubricant to the resulting granules to obtain intermediate granules; then forming the intermediate granules into tablets, capsules, or granules; and optionally coating the tablets.

[0026] One or more embodiments of the present invention provide a method for preparing a pharmaceutical formulation of a piperazine derivative. This preparation method includes the steps of: micronizing a piperazine derivative to control its particle size to 5 to 100 μm, preferably 5 to 70 μm, and more preferably 5 to 40 μm; mixing the micronized piperazine derivative with a disintegrant and / or a solubilizer, then adding a diluent, a flow promoter and / or a lubricant and mixing to obtain a mixture; dry granulating the mixture and adding a flow promoter and / or a lubricant to the resulting granules to obtain intermediate granules; then forming the intermediate granules into tablets, capsules, or granules; and optionally coating the tablets.

[0027] One or more embodiments of the present invention provide a method for preparing a pharmaceutical formulation of a piperazine derivative. This preparation method includes the steps of: micronizing a piperazine derivative to control its particle size to 5 to 100 μm, preferably 5 to 70 μm, more preferably 5 to 40 μm; mixing the micronized piperazine derivative with a diluent and / or disintegrant, then adding and mixing the diluent, and further adding and mixing a flow promoter and / or lubricant to obtain a mixture; then forming this mixture into tablets, capsules, or granules; and optionally coating the tablets.

[0028] One or more embodiments of the present invention provide the use of pharmaceutical formulations of piperazine derivatives of the present invention in the preparation of agents for the treatment and / or prevention of cancer.

[0029] One or more embodiments of the present invention provide a method for the prevention and / or treatment of cancer. This method comprises administering to a patient a therapeutically effective dose of a pharmaceutical formulation of a piperazine derivative of the present invention.

[0030] The cancer described in the present invention is selected from solid tumors, which are selected from breast cancer, central nervous system cancer, uterine cancer, cervical cancer, kidney cancer, adrenal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, testicular cancer, gastric cancer, head and neck cancer, laryngeal cancer, urinary tract cancer, bladder cancer, colon cancer, rectal cancer, thyroid cancer, bone cancer, epithelial cancer, bile duct cancer, gallbladder cancer, skin cancer, mesothelioma, basal cell carcinoma, adenoid cystic carcinoma, leiomyosarcoma, gastrointestinal stromal tumor, Ewing's sarcoma, Kaposi's sarcoma, or progressive solid tumors with PARP7 amplification.

[0031] In one or more embodiments, the cancer referred to in the present invention is selected from hematological malignancies, which are selected from leukemia, myeloma, and lymphoma. Examples of hematological malignancies include Hodgkin lymphoma or non-Hodgkin lymphoma, multiple myeloma, B-cell lymphoma, small lymphocytic lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

[0032] For lung cancer, non-small cell lung cancer or neuroendocrine lung cancer is preferred. For non-small cell lung cancer, squamous cell carcinoma or adenocarcinoma of the lung is preferred. For breast cancer, hormone receptor-positive (HR+) breast cancer is preferred. For esophageal cancer, squamous cell carcinoma of the esophagus or adenocarcinoma of the esophagus is preferred. For head and neck cancer, head and neck squamous cell carcinoma is preferred. For uterine cancer, endometrial cancer is preferred. For central nervous system cancer, glioma is preferred. For liver cancer, hepatocellular carcinoma is preferred. For B-cell lymphoma, diffuse large B-cell lymphoma is preferred.

[0033] Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0034] "Stereoisomers" refer to isomers that arise from differences in the spatial arrangement of atoms within a molecule, and include cis / trans isomers, enantiomers, and conformers.

[0035] A "tautomer" or "tautomer form" refers to a structural isomer with a different energy that can be interconverted across a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. This specification includes all tautomers of the compound in question.

[0036] "Medically acceptable salt" or "the medicamentally acceptable salt" means a salt of the compound of this application which maintains the biological efficacy and properties of the free acid or free base and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, or by reacting the free base with a non-toxic inorganic acid or organic acid.

[0037] The terms "optional," "optional," "selective," or "selectively" mean that the events or situations described below may occur but do not necessarily occur, and the descriptions include both cases in which the events or situations occur and cases in which they do not. For example, "a heterocycle that may be substituted with alkyl" means that alkyl may or may not be present, and this description includes both cases in which the heterocycle is substituted with alkyl and cases in which it is not. [Modes for carrying out the invention]

[0038] The technical solutions of the present invention will be described in detail by the following embodiments. However, the scope of protection of the present invention is not limited to these embodiments.

[0039] The piperazine derivatives of the present invention can be prepared by the method described in patent WO 2022242750, and in particular, compound A used in the examples of the present invention is selected from compound 1 described in patent WO 2022242750. Its structure is as follows:

[0040] [ka]

[0041] [Table 1]

[0042] Preparation method: 1) Compound A was pulverized by jet pulverization to a particle size of X90 = 37.69 μm. Predetermined amounts of compound A, lactose, and croscarmellose sodium were weighed, sieved twice through a 40-mesh sieve, and mixed for 5 minutes to obtain mixture 1.

[0043] 2) A predetermined amount of microcrystalline cellulose was added to mixture 1 and mixed for 5 minutes to obtain mixture 2.

[0044] 3) A predetermined amount of colloidal silica and magnesium stearate was added to mixture 2 and mixed for 5 minutes to obtain an intermediate powder.

[0045] 4) Tablets containing 200 mg were produced by compressing them using a φ10 mm die. The tablet weight was controlled to 440 mg ± 5%.

[0046] [Table 2]

[0047] Preparation method: The procedure is the same as in Example 1, with a particle size X90 = 26.16 μm.

[0048] [Table 3]

[0049] Preparation method: The procedure is the same as in Example 1, with a particle size X90 = 12.07 μm.

[0050] [Table 4]

[0051] Preparation method: The particle size X90 is set to 72.98 μm, similar to Example 1.

[0052] [Table 5]

[0053] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Microcrystalline cellulose, croscarmellose sodium, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0054] 2) A predetermined amount of compound A, microcrystalline cellulose, and croscarmellose sodium was weighed, sieved twice using a 40-mesh sieve, and mixed for 5 minutes to obtain mixture 1.

[0055] 3) Mixture 1 was dried and granulated. The roller compression speed was 3-5 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg / cm². 2 This was controlled to obtain granule 1.

[0056] 4) A predetermined amount of colloidal silica and magnesium stearate was added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. When intermediate granule 2 was analyzed by HPLC, the content of compound A was found to be 43.0% to 48.0%. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0057] 5) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0058] [Table 6]

[0059] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Microcrystalline cellulose, lactose, croscarmellose sodium, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0060] 2) A predetermined amount of compound A, microcrystalline cellulose, lactose, and croscarmellose sodium was weighed, sieved twice through a 40-mesh sieve, and mixed for 5 minutes to obtain mixture 1.

[0061] 3) Mixture 1 was dried and granulated. The roller compression speed was 3-5 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg. / cm 2 The control was adjusted to obtain granule 1.

[0062] 4) Predetermined amounts of colloidal silica and magnesium stearate were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 43.0% to 48.0% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material. Mobile phase: Water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62. Column temperature: 45°C. Flow rate: 1 mL / min. Detection wavelength: 221 nm.

[0063] 5) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0064] [Table 7]

[0065] Preparation method: The procedure was the same as in Example 5. Intermediate granule 2 was analyzed by HPLC, and the content of compound A was found to be 54.3% to 59.3%. HPLC conditions: Octadecylsilane-bonded silica gel was used as the packing material. Mobile phase: Water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62. Column temperature: 45°C. Flow rate: 1 mL / min. Detection wavelength: 221 nm.

[0066] [Table 8]

[0067] Preparation method: The procedure was the same as in Example 5. Intermediate granule 2 was analyzed by HPLC, and the content of compound A was found to be 48.0% to 53.0%. HPLC conditions: Octadecylsilane-bonded silica gel was used as the packing material. Mobile phase: Water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62. Column temperature: 45°C. Flow rate: 1 mL / min. Detection wavelength: 221 nm.

[0068] [Table 9]

[0069] Preparation method: 1) Compound A was pulverized by jet pulverization to control the X90 particle size to 40 μm or less, and then sieved through a 60-mesh sieve. Microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0070] 2) Predetermined amounts of compound A, microcrystalline cellulose, and crospovidone were weighed, sieved twice through a 40-mesh sieve, and mixed for 5 minutes to obtain mixture 1.

[0071] 3) Mixture 1 was dried and granulated. The roller compression speed was 3-5 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg / cm². 2に The control was applied. This resulted in obtaining granule 1.

[0072] 4) A predetermined amount of colloidal silica and magnesium stearate was added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. When intermediate granule 2 was analyzed by HPLC, the content of compound A was found to be 43.0% to 48.0%. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0073] 5) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0074] [Table 10]

[0075] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Microcrystalline cellulose, carboxymethyl sodium starch, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0076] 2) A predetermined amount of compound A, microcrystalline cellulose, and sodium carboxymethyl starch were weighed, sieved twice through a 40-mesh sieve, and mixed for 5 minutes to obtain mixture 1.

[0077] 3) Mixture 1 was dried and granulated. The roller compression speed was 3-5 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg. / cm 2 The control was adjusted to obtain granule 1.

[0078] 4) A predetermined amount of colloidal silica and magnesium stearate was added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 43.0% to 48.0% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material. Mobile phase: Water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62. Column temperature: 45°C. Flow rate: 1 mL / min. Detection wavelength: 221 nm.

[0079] 5) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0080] [Table 11]

[0081] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0082] 2) A predetermined amount of compound A and poloxamer were weighed and sieved twice through a 40-mesh sieve. A predetermined amount of crospovidone was added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0083] 3) A specified amount of microcrystalline cellulose was added to mixture 1 and mixed for 10 minutes. Next, half of the specified amount of magnesium stearate and half of the specified amount of colloidal silica were added and mixed for 5 minutes to obtain mixture 2.

[0084] 4) Mixture 2 was dried and granulated. The roller compression speed was 4-6 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg / cm². 2 As a result, granule 1 was obtained.

[0085] 5) The remaining specified amounts of magnesium stearate and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 43.0% to 48.0% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0086] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0087] [Table 12]

[0088] Preparation method: The procedure was the same as in Example 11. When intermediate granule 2 was analyzed by HPLC, the content of compound A was found to be 47.5% to 52.5%. HPLC conditions: Octadecylsilane-bonded silica gel was used as the packing material. Mobile phase: Water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62. Column temperature: 45°C. Flow rate: 1 mL / min. Detection wavelength: 221 nm.

[0089] [Table 13]

[0090] Preparation method: The procedure was the same as in Example 11. HPLC analysis of intermediate granule 2 revealed that the compound A content was 47.5% to 52.5%. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material. Mobile phase: Water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62. Column temperature: 45°C. Flow rate: 1 mL / min. Detection wavelength: 221 nm.

[0091] [Table 14]

[0092] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0093] 2) A predetermined amount of compound A and poloxamer was weighed and sieved twice through a 40-mesh sieve. A predetermined amount of crospovidone was added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0094] 3) A specified amount of microcrystalline cellulose was added to mixture 1 and mixed for 10 minutes. Next, half of the specified amount of magnesium stearate and half of the specified amount of colloidal silica were added and mixed for 5 minutes to obtain mixture 2.

[0095] 4) Mixture 2 was dried and granulated. The roller compression speed was 4-6 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg / cm². 2 As a result, granule 1 was obtained.

[0096] 5) The remaining specified amounts of magnesium stearate and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 47.5% to 52.5% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0097] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0098] 7) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0099] [Table 15]

[0100] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0101] 2) A predetermined amount of compound A and poloxamer was weighed and sieved twice through a 40-mesh sieve. A predetermined amount of crospovidone was added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0102] 3) A specified amount of microcrystalline cellulose was added to mixture 1 and mixed for 10 minutes. Next, half of the specified amount of magnesium stearate and half of the specified amount of colloidal silica were added and mixed for 5 minutes to obtain mixture 2.

[0103] 4) Mixture 2 is compressed with a roller at a speed of 4-6 Hz, granulation at a speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm². 2 Dry granulation was performed to obtain granule 1.

[0104] 5) The remaining specified amounts of magnesium stearate and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 47.5% to 52.5% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0105] 6) Based on the content of the intermediate granule 2, tableting was carried out using a φ6 mm die to produce tablets with a content of 50 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 50 - 80 N.

[0106] 7) The prepared tablets were coated at a coating weight gain rate of about 2.0 - 5.0%.

[0107]

Table 16

[0108] Preparation method: 1) Compound A was micronized by jet milling, and after controlling the X90 particle size to be 40 μm or less, it was sieved through a 60 - mesh sieve. Also, poloxamer was sieved through a 60 - mesh sieve. Moreover, microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved through a 40 - mesh sieve.

[0109] 2) A predetermined amount of compound A and poloxamer were weighed and sieved twice through a 40 - mesh sieve. Also, a predetermined amount of crospovidone was added and sieved twice through a 40 - mesh sieve to obtain mixture 1.

[0110] 3) A specified amount of microcrystalline cellulose was added to mixture 1 and mixed for 10 minutes. Next, a specified amount of 1 / 2 of magnesium stearate and a specified amount of 1 / 2 of colloidal silica were added and mixed for 5 minutes to obtain mixture 2.

[0111] 4) Mixture 2 was subjected to dry granulation. The roller compression speed was 4 - 6 Hz, the granulation speed was 15 - 20 Hz, and the oil pump pressure was 30 - 80 kg / cm 2 to obtain granule 1.

[0112] 5) The remaining specified amounts of magnesium stearate and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 47.5% to 52.5% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0113] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ8 mm die to produce tablets with a content of 100 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 60-100 N.

[0114] 7) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0115] [Table 17]

[0116] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0117] 2) A predetermined amount of compound A and poloxamer was weighed and sieved twice through a 40-mesh sieve. A predetermined amount of crospovidone was added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0118] 3) A predetermined amount of microcrystalline cellulose was added to mixture 1 and mixed for 10 minutes to obtain mixture 2.

[0119] 4) Mixture 2 was dried and granulated. The roller compression speed was 4-6 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg / cm².2 As a result, granule 1 was obtained.

[0120] 5) A specified amount of magnesium stearate and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 27.5% to 32.5% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0121] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 120 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0122] 7) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0123] [Table 18]

[0124] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0125] 2) A predetermined amount of compound A and poloxamer was weighed and sieved twice through a 40-mesh sieve. A predetermined amount of crospovidone was added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0126] 3) A specified amount of microcrystalline cellulose was added to Mixture 1 and mixed for 10 minutes. Next, half of the specified amount of magnesium stearate and half of the specified amount of colloidal silica were added and mixed for 5 minutes to obtain Mixture 2.

[0127] 4) Mixture 2 was dry granulated at a roller compression speed of 4 - 6 Hz, a granulation speed of 15 - 20 Hz, and an oil pump pressure of 30 - 80 kg / cm 2 to obtain Granule 1.

[0128] 5) The remaining specified amounts of magnesium stearate and colloidal silica were added to Granule 1 and mixed for 5 minutes to obtain Intermediate Granule 2. When Intermediate Granule 2 was analyzed by HPLC, the content of Compound A was 67.5% - 72.5%. HPLC conditions: Octadecylsilane-bonded silica gel was used as the filler; Mobile phase: water (adjusted to pH 3.5 with phosphoric acid) / methanol = 38 / 62; Column temperature: 45°C; Flow rate: 1 mL / min; Detection wavelength: 221 nm.

[0129] 6) Based on the content of Intermediate Granule 2, tableting compression was performed using a φ10 mm die to produce tablets with a content of 280 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70 - 110 N.

[0130] 7) The prepared tablets were coated at a coating weight increase rate of approximately 2.0 - 5.0%.

[0131]

Table 19

[0132] Preparation method: The same as Example 14.

[0133]

Table 20

[0134] Preparation method: The same as Example 14.

[0135] [Table 21]

[0136] Preparation method: This is the same as in Example 14.

[0137] [Table 22]

[0138] Preparation method: This is the same as in Example 14.

[0139] [Table 23]

[0140] Preparation method: 1) Compound A was pulverized by jet pulverization to control the particle size X90 to 40 μm or less, and then sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Starch, microcrystalline cellulose, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0141] 2) A predetermined amount of compound A and poloxamer was weighed and sieved twice through a 40-mesh sieve. A predetermined amount of microcrystalline cellulose was added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0142] 3) A predetermined amount of starch was added to mixture 1 and mixed for 10 minutes. Next, half of the predetermined amount of magnesium stearate and half of the predetermined amount of colloidal silica were added and mixed for 5 minutes to obtain mixture 2.

[0143] 4) Mixture 2 is compressed with a roller at a speed of 4-6 Hz, granulation at a speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm². 2 Dry granulation was performed to obtain granule 1.

[0144] 5) The remaining specified amounts of magnesium stearate and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 47.5% to 52.5% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0145] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0146] 7) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0147] [Table 24]

[0148] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Mannitol, low-substituted hydroxypropyl cellulose, colloidal silica, and magnesium stearate were each sieved through a 40-mesh sieve.

[0149] 2) A predetermined amount of compound A and poloxamer was weighed and sieved twice through a 40-mesh sieve. A predetermined amount of low-substituted hydroxypropyl cellulose was added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0150] 3) A specified amount of mannitol was added to mixture 1 and mixed for 10 minutes. Next, half of the specified amount of magnesium stearate and half of the specified amount of colloidal silica were added and mixed for 5 minutes to obtain mixture 2.

[0151] 4) Mixture 2 was dried and granulated. The roller compression speed was 4-6 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg / cm². 2 As a result, granule 1 was obtained.

[0152] 5) The remaining specified amounts of magnesium stearate and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 47.5% to 52.5% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0153] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0154] 7) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0155] [Table 25]

[0156] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Sodium dodecyl sulfate was also sieved through a 60-mesh sieve. Microcrystalline cellulose, crospovidone, talc, and sodium stearyl fumarate were each sieved through a 40-mesh sieve.

[0157] 2) A predetermined amount of compound A and sodium dodecyl sulfate were weighed and sieved twice through a 40-mesh sieve. A predetermined amount of crospovidone was also added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0158] 3) A specified amount of microcrystalline cellulose was added to mixture 1 and mixed for 10 minutes. Half of the specified amount of sodium stearyl fumarate and half of the specified amount of talc were added and mixed for 5 minutes to obtain mixture 2.

[0159] 4) Mixture 2 is compressed with a roller at a speed of 4-6 Hz, granulation at a speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm². 2 Dry granulation is performed to obtain granule 1.

[0160] 5) The remaining specified amounts of sodium stearyl fumarate and talc were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC, and the content of compound A was found to be 47.5% to 52.5%. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material. Mobile phase: Water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62. Column temperature: 45°C. Flow rate: 1 mL / min. Detection wavelength: 221 nm.

[0161] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0162] 7) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0163] [Table 26]

[0164] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Poloxamer was also sieved through a 60-mesh sieve. Pregelated starch, starch, colloidal silica, and stearic acid were each sieved through a 40-mesh sieve.

[0165] 2) A predetermined amount of compound A and poloxamer was weighed and sieved twice through a 40-mesh sieve. A predetermined amount of starch was then added and sieved twice through a 40-mesh sieve to obtain mixture 1.

[0166] 3) A predetermined amount of pregelled starch was added to mixture 1 and mixed for 10 minutes. Next, half of the predetermined amount of stearic acid and half of the predetermined amount of colloidal silica were added and mixed for 5 minutes to obtain mixture 2.

[0167] 4) Mixture 2 is compressed with a roller at a speed of 4-6 Hz, granulation at a speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm². 2 Dry granulation was performed to obtain granule 1.

[0168] 5) The remaining specified amount of stearic acid and colloidal silica were added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. Intermediate granule 2 was analyzed by HPLC and found to contain 47.5% to 52.5% of compound A. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0169] 6) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0170] 7) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0171] [Table 27]

[0172] Preparation method: 1) Compound A was pulverized using a jet pulverization method, and after controlling the particle size X90 to 40 μm or less, it was sieved using a 60-mesh sieve. Microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate were each sieved using a 40-mesh sieve.

[0173] 2) Predetermined amounts of compound A, microcrystalline cellulose, and crospovidone were weighed, sieved twice through a 40-mesh sieve, and mixed for 5 minutes to obtain mixture 1.

[0174] 3) Mixture 1 was dried and granulated. The roller compression speed was 3-5 Hz, the granulation speed was 15-20 Hz, and the oil pump pressure was 30-80 kg / cm². 2 This was controlled to obtain granule 1.

[0175] 4) A predetermined amount of colloidal silica and magnesium stearate was added to granule 1 and mixed for 5 minutes to obtain intermediate granule 2. When intermediate granule 2 was analyzed by HPLC, the content of compound A was found to be 47.5% to 52.5%. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0176] 5) Based on the content of intermediate granule 2, tablets were compressed using a φ10 mm die to produce tablets with a content of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0177] 6) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0178] [Table 28]

[0179] Preparation method: 1) Compound A was pulverized by jet pulverization, and the X90 particle size was controlled to 40 μm or less, after which it was sieved through a 60-mesh sieve. Microcrystalline cellulose, lactose, crospovidone, colloidal silica, and magnesium stearate were also sieved through a 40-mesh sieve.

[0180] 2) A predetermined amount of compound A, lactose, and crospovidone was weighed and mixed for 5 minutes to obtain mixture 1.

[0181] 3) A predetermined amount of microcrystalline cellulose was added to mixture 1 and mixed for 5 minutes to obtain mixture 2.

[0182] 4) A predetermined amount of colloidal silica and magnesium stearate were added to mixture 2 and mixed for 5 minutes to obtain an intermediate powder. The intermediate powder was analyzed by HPLC and found that the content of compound A was 47.5% to 52.5%. HPLC conditions: Octadecylsilane-bonded silica gel was used as packing material; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0183] 5) Based on the content of the intermediate powder, tablets were compressed using a φ10 mm die to produce tablets with a strength of 200 mg. The tablets were controlled to have a weight variation of ±5% and a hardness of 70-110 N.

[0184] 6) The prepared tablets were coated with a coating weight increase rate of approximately 2.0-5.0%.

[0185] [Table 29]

[0186] Preparation method: 1) Compound A was pulverized by jet pulverization to control the X90 particle size to 40 μm or less, and then sieved through a 60-mesh sieve. Microcrystalline cellulose, croscarmellose sodium, and colloidal silica were also sieved through a 60-mesh sieve.

[0187] 2) A predetermined amount of compound A was weighed, a predetermined amount of croscarmellose sodium was added, and the mixture was mixed for 5 minutes to obtain mixture 1.

[0188] 3) A predetermined amount of microcrystalline cellulose was added to mixture 1, mixed for 10 minutes, and then sieved through a 60-mesh sieve to obtain mixture 2.

[0189] 4) A predetermined amount of colloidal silica was added to mixture 2 and mixed for 5 minutes to obtain the contents powder.

[0190] 5) The contents of the powder were filled into capsules. The net weight was 120 mg / granule (content 50 mg).

[0191] [Table 30]

[0192] Preparation method: 1) Compound A was pulverized by jet pulverization to control the X90 particle size to 40 μm or less, and then sieved through a 60-mesh sieve. Microcrystalline cellulose, croscarmellose sodium, and colloidal silica were also sieved through a 60-mesh sieve.

[0193] 2) A predetermined amount of compound A was weighed, a predetermined amount of croscarmellose sodium was added, and the mixture was mixed for 5 minutes to obtain mixture 1.

[0194] 3) A predetermined amount of microcrystalline cellulose was added to mixture 1, mixed for 10 minutes, and then sieved through a 60-mesh sieve to obtain mixture 2.

[0195] 4) A predetermined amount of colloidal silica was added to mixture 2 and mixed for 5 minutes to obtain the contents powder.

[0196] 5) The contents of the powder were filled into capsules. The contents weight was 240 mg per capsule (containing 100 mg).

[0197] Dissolution test I. Dissolution Test Method: Based on the dissolution test method (Chinese Pharmacopoeia 2020 Edition Volume IV 0931, Method 2), 900 ml of hydrochloric acid solution (pH=1.2) containing 0.1% sodium dodecyl sulfate was added to the samples of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, respectively. Sampling was performed at a rotation speed of 75 revolutions per minute after 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes, and the dissolution rate was measured.

[0198] II. Elution Results and Conclusions: [Table 31]

[0199] Conclusion: The formulation of the present invention showed good drug dissolution effect within 120 minutes.

[0200] Stability testing I. Examination conditions: The samples were placed on clean, open watch glass and exposed to high-temperature (60±2°C), high-humidity (75%±1% relative humidity), and light irradiation (4500±500 lux) conditions. Test samples were taken on days 5 and 10, respectively.

[0201] II. Results and Conclusions [Table 32]

[0202] Conclusion: In the influence factor tests of the formulation of the present invention, no significant differences were observed in any of the tested indicators compared to day 0, demonstrating that the formulation of the present invention possesses stable quality.

[0203] Pharmacokinetic studies in beacon dogs The test substance tablets were prepared for oral administration. Healthy male beagle dogs (provided by the Sichuan Musk Deer Breeding Research Institute) were used, with each beagle weighing 10 kg. Three dogs were administered one tablet of each type, with a dosage of one tablet per dog. Blood samples were collected from the forelimb veins of all three dogs at each time point. The test substance was administered orally, and blood samples were collected 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. After anticoagulation treatment with EDTA-K2, the blood samples were centrifuged at 3200 g at 4°C for 10 minutes to separate the plasma. All plasma samples were stored at -70°C and used for testing. The concentration of the test drug in plasma was measured by LC-MS / MS (using gliclazide as an internal standard), and the major pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartment model.

[0204] Conclusion: The formulation of the present invention exhibited good pharmacokinetic properties.

[0205] Although this specification describes specific embodiments in detail, those skilled in the art should understand that the above embodiments are illustrative and should not be construed as limiting the invention. Those skilled in the art can make several improvements and modifications to the invention without departing from the principles of the invention, and the technical solutions obtained by these improvements and modifications are also within the scope of protection of the claims of the invention.

Claims

1. A pharmaceutical formulation comprising a piperazine derivative, or a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical formulation contains the piperazine derivative in an amount of 1 to 1000 mg, and the piperazine derivative is selected from compounds of formula (I): 【Chemistry 1】 Here: X １ It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from NH, O, or N and O; X ２ is O or bond; X ３ and X ４ Each is independently either C or N; R １ａ and R １ｂ are each independently H, D or C １－６ alkyl; or R １ａ and R １ｂ are 、 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl; R ２ａ and R ２ｂ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ２ａ and R ２ｂ teeth 、 Together with the carbon atoms bonded to these, they form a 3- to 5-membered cycloalkyl ring; R ３ H, D, C １－６ It is an alkyl, halogen, or cyano, where C １－６ The alkyl group is optionally substituted with one to three halogens; R ４ and R ５ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ４ and R ５ teeth 、 Together with the carbon atoms bonded to these, they form a 3- to 5-membered cycloalkyl ring; R ６ and R ７ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ６ and R ７ teeth 、 Together with the carbon atoms bonded to them, they form =O; R ８ and R ９ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ８ and R ９ These, together with the carbon atoms bonded to them, form =O; or R ８ and R ９ These, together with the carbon atoms bonded to them, form a 3- to 5-membered cycloalkyl ring; Each R １０ C is independent １－６ Alkyl, C １－６ Alkoxy, CONR １０ａ R １０ｂ Halogen, cyanoacrylate, S(O) ２ R １０ｃ , SR １０ｄ Or a cycloalkyl group with 3 to 5 members, where C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with one to three halogens; R １０ａ , R １０ｂ , R １０ｃ and R １０ｄ These are H, D, or C, respectively, independently. １－６ It is alkyl; A is 【Chemistry 2】 And; R ａ C １－６ Alkyl, C ３－５ It is a cycloalkyl, halogen, or cyano, where C １－６ The alkyl group is optionally substituted with one to three halogens; B is a 5- to 10-membered carbon ring or heteroring, where the heteroring contains 1 to 3 heteroatoms selected from N, O, and S; C is a heterocycle with 5-6 membered rings containing 1-3 N heteroatoms; m is 1, 2, or 3; n is 0, 1, 2 or 3; and A pharmaceutical preparation in which p is 0, 1, 2, or 3.

2. X １ It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from NH, O, or N and O; X ２ is O or bond; X ３ and X ４ Each is independently either C or N; R １ａ and R １ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ２ａ and R ２ｂ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ２ａ and R ２ｂ teeth 、 Together with the carbon atoms bonded to these, they form a 3- to 5-membered cycloalkyl ring; R ３ H, D, C １－６ It is an alkyl, halogen, or cyano, where C １－６ The alkyl group is optionally substituted with one to three halogens; R ４ and R ５ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ４ and R ５ teeth 、 Together with the carbon atoms bonded to these, they form a 3- to 5-membered cycloalkyl ring; R ６ and R ７ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ８ and R ９ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ８ and R ９ These, together with the carbon atoms bonded to them, form =O; Each R １０ is independently C １－６ alkyl, C １－６ alkoxy, CONR １０ａ R １０ｂ , halogen, cyano, S(O) ２ R １０ｃ , SR １０ｄ or 3- to 5-membered cycloalkyl, where C １－６ alkyl and C １－６ alkoxy are optionally substituted with 1 to 3 halogens; R １０ａ , R １０ｂ , R １０ｃ and R １０ｄ These are H, D, or C, respectively, independently. １－６ It is alkyl; A is 【Transformation 3】 And; R ａ C １－６ Alkyl, C ３－５ It is a cycloalkyl, halogen, or cyano, where C １－６ The alkyl group is optionally substituted with one to three halogens; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; C is a heterocycle with 5-6 membered rings containing 1-3 N heteroatoms; m is 1, 2, or 3; n is 0, 1, 2 or 3; and The pharmaceutical preparation according to claim 1, wherein p is 0, 1, 2, or 3.

3. The piperazine derivative is selected from compounds of formula (I-1): 【Chemistry 4】 Here: X １ It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from NH, or N and O; X ２ is O; X ３ and X ４ Each is independently either C or N; R １ａ and R １ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ２ａ and R ２ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ３ H, D, C １－６ It is an alkyl or halogen, where C １－６ The alkyl group is optionally substituted with one to three halogens; R ４ and R ５ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ６ and R ７ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ８ and R ９ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ８ and R ９ These, together with the carbon atoms bonded to them, form =O; R １０ C １－６ Alkyl, C １－６ Alkoxy, cyano, or SR １０ｄ And here C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with one to three halogens; R １０ｄ is H, D, or C １－６ It is alkyl; A is 【Transformation 5】 And; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; C is a heterocycle with 5-6 membered rings containing 1-3 N heteroatoms; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 1, wherein n is 0, 1, 2, or 3.

4. The piperazine derivative is selected from the compounds of formula (I-2): 【Transformation 6】 Here: X １ is NH; X ２ is O; R １ａ and R １ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ２ａ and R ２ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ３ H, D, C １－６ It is an alkyl or halogen, where C １－６ The alkyl group is optionally substituted with one to three halogens; R ４ and R ５ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ６ and R ７ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ８ and R ９ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ８ and R ９ These, together with the carbon atoms bonded to them, form =O; R １０ C １－６ Alkyl, C １－６ Alkoxy, cyano, or SR １０ｄ And here C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with one to three halogens; R １０ｄ is H, D, or C １－６ It is alkyl; A is 【Transformation 7】 And; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 1, wherein n is 0, 1, 2, or 3.

5. X １ is NH; X ２ is O; R １ａ and R １ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ２ａ and R ２ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ３ H, D, C １－６ It is an alkyl or halogen, where C １－６ The alkyl group is optionally substituted with one to three halogens; R ４ and R ５ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ６ and R ７ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ８ and R ９ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ８ and R ９ These, together with the carbon atoms bonded to them, form =O; R １０ C １－６ Alkyl, cyano, or SR １０ｄ And here C １－６ The alkyl group is optionally substituted with one to three halogens; R １０ｄ is H, D, or C １－６ It is alkyl; A is 【Transformation 8】 And; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 4, wherein n is 0, 1, 2, or 3.

6. X １ It is selected from NH; X ２ is selected from O; R １ａ and R １ｂ teeth 、 Each is independently H, D, or C １－６ Selected from alkyl groups; R ２ａ and R ２ｂ teeth 、 Each is independently H, D, or C １－６ Selected from alkyl groups; R ３ H, D, C １－６ It is an alkyl or halogen, where C １－６ The alkyl group is optionally substituted with one to three halogens; R ４ and R ５ Each is independently either H or D; R ６ and R ７ Each is independently either H or D; R ８ and R ９ Each is independently either H or D; R １０ CF ３ Or SR １０ｄ And; R １０ｄ is H, D, or C １－６ It is alkyl; A is 【Chemistry 9】 And; B is 【Chemistry 10】 And; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 5, wherein n is 0, 1, 2, or 3.

7. X １ It is selected from NH; X ２ is selected from O; R １ａ and R １ｂ teeth 、 Each is independently H, D, or C １－３ Selected from alkyl groups; R ２ａ and R ２ｂ teeth 、 Each is independently H, D, or C １－３ Selected from alkyl groups; R ３ is H, D, or CF ３ Selected from; R ４ and R ５ Each is independently selected from H or D; R ６ and R ７ Each is independently selected from H or D; R ８ and R ９ Each is independently selected from H or D; R １０ CF ３ And; A is 【Chemistry 11】 And; B is 【Chemistry 12】 And; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 6, wherein n is 0, 1, or 2.

8. The piperazine derivative is selected from the compounds of formula (I-3): 【Chemistry 13】 Here: X １ It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from NH, or N and O; X ２ is O; R １ａ and R １ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ２ａ and R ２ｂ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ４ and R ５ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ６ and R ７ These are H, D, or C, respectively, independently. １－６ It is alkyl; R ８ and R ９ These are H, D, or C, respectively, independently. １－６ Alkyl; or R ８ and R ９ These, together with the carbon atoms bonded to them, form =O; R １０ C １－６ Alkyl, C １－６ Alkoxy, cyano, or SR １０ｄ And here C １－６ Alkyl and C １－６ The alkoxy is optionally substituted with one to three halogens; R １０ｄ is H, D, or C １－６ It is alkyl; A is 【Chemistry 14】 And; B is a 5-6 membered carbon ring or heterocycle, where the heterocycle contains 1-3 heteroatoms selected from N, O, and S; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 1, wherein n is 0, 1, 2, or 3.

9. X １ It is a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from NH, or N and O; X ２ is O; R １ａ and R １ｂ These are H, D, or C, respectively, independently. １－３ It is alkyl; R ２ａ and R ２ｂ These are H, D, or C, respectively, independently. １－３ It is alkyl; R ４ and R ５ These are H, D, or C, respectively, independently. １－３ It is alkyl; R ６ and R ７ These are H, D, or C, respectively, independently. １－３ It is alkyl; R ８ and R ９ These are H, D, or C, respectively, independently. １－３ Alkyl; or R ８ and R ９ These, together with the carbon atoms bonded to them, form =O; R １０ C １－６ Alkyl, cyano, or SR １０ｄ And here C １－６ The alkyl group is optionally substituted with one to three halogens; R １０ｄ is H, D, or C １－６ It is alkyl; A is 【Chemistry 15】 And; B is 【Chemistry 16】 And; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 8, wherein n is 0, 1, or 2.

10. X １ is NH; X ２ is O; R １ａ and R １ｂ These are H, D, or C, respectively, independently. １－３ It is alkyl; R ２ａ and R ２ｂ Each is independently either H or D; R ４ and R ５ Each is independently either H or D; R ６ and R ７ Each is independently either H or D; R ８ and R ９ Each is independently either H or D; R １０ CF ３ And; A is 【Chemistry 17】 And; B is [Chemistry 18] And; m is 1, 2, or 3; and The pharmaceutical preparation according to claim 9, wherein n is 0, 1, or 2.

11. The pharmaceutical preparation according to any one of claims 1 to 10, characterized in that the piperazine derivative, or its stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof, is selected from the following: 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】

12. The piperazine derivative or its stereoisomer, tautomer, deuterated compound, or a pharmaceutically acceptable salt thereof, is administered in doses of 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, and 100-1 A pharmaceutical preparation according to any one of claims 1 to 11, characterized in that it contains 50 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, or 900-1000 mg.

13. The pharmaceutical preparation according to any one of claims 1 to 12, characterized in that the content of a piperazine derivative, or a stereoisomer thereof, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof in the pharmaceutical preparation is 5% to 90%, preferably 20% to 80%, and more preferably 30% to 70% of the total weight of the pharmaceutical preparation.

14. The pharmaceutical preparation according to claims 1 to 13, characterized in that the dosage form of the pharmaceutical preparation is selected from tablets, capsules, or granules.

15. A pharmaceutical preparation according to claims 1 to 14, further comprising one or more of a diluent, a disintegrant, a solvent, a flow promoter, and a lubricant.

16. The pharmaceutical preparation according to claim 15, characterized in that the diluent is selected from one of microcrystalline cellulose, starch, mannitol, lactose, pregelled starch, dextrin, sucrose, calcium hydrogen phosphate, and calcium phosphate, or a combination of several thereof; the content of the diluent is 10% to 80% of the total weight of the pharmaceutical preparation.

17. The pharmaceutical preparation according to claim 15, characterized in that the disintegrant is selected from one or more of the following: microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polariline potassium, pregelled starch, and starch; and the content of the disintegrant is 1% to 60%, preferably 3% to 20%, of the total weight of the pharmaceutical preparation.

18. The pharmaceutical preparation according to claim 15, characterized in that the solubilizer is selected from one of poloxamer and sodium dodecyl sulfate, or a combination of the two; and the content of the solubilizer is 2% to 10% of the total weight of the pharmaceutical preparation.

19. The pharmaceutical preparation according to claim 15, characterized in that the flow promoter is selected from either colloidal silica or talc, or a combination of the two; and the content of the flow promoter is 0.5% to 5% of the total weight of the pharmaceutical preparation.

20. The pharmaceutical formulation according to claim 15, characterized in that the lubricant is selected from one or more of the following: stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oil, magnesium lauryl sulfate, polyethylene glycol, glyceryl behenate, and sucrose esters; and the content of the lubricant is 0.5% to 5% of the total weight of the pharmaceutical formulation.

21. A method for preparing a pharmaceutical formulation of a piperazine derivative according to any one of claims 1 to 20, comprising the steps of: micronizing the piperazine derivative and controlling its particle size to 5 to 100 μm, preferably 5 to 70 μm, more preferably 5 to 40 μm; mixing the micronized piperazine derivative with a diluent, a disintegrant and / or a solvent to obtain a mixture; dry granulating the mixture and adding a flow promoter and / or lubricant to the obtained granules to obtain intermediate granules; then forming the intermediate granules into tablets, capsules, or granules; and optionally coating the tablets.

22. A method for preparing a pharmaceutical formulation of a piperazine derivative according to any one of claims 1 to 20, comprising the steps of: micronizing the piperazine derivative and controlling its particle size to 5 to 100 μm, preferably 5 to 70 μm, more preferably 5 to 40 μm; mixing the micronized piperazine derivative with a disintegrant and / or a solubilizer, then adding a diluent, a flow promoter and / or a lubricant and mixing to obtain a mixture; dry granulating the mixture and adding the flow promoter and / or the lubricant to the obtained granules to obtain intermediate granules; then forming the intermediate granules into tablets, capsules, or granules; and optionally coating the tablets.

23. A method for preparing a pharmaceutical formulation of a piperazine derivative according to any one of claims 1 to 20, comprising the steps of: micronizing the piperazine derivative and controlling its particle size to 5 to 100 μm, preferably 5 to 70 μm, more preferably 5 to 40 μm; mixing the micronized piperazine derivative with a diluent and / or disintegrant, then adding and mixing the diluent, and further adding and mixing a flow promoter and / or lubricant to obtain a mixture; then forming the mixture into tablets, capsules, or granules; and optionally coating the tablets.

24. Use of a pharmaceutical formulation of a piperazine derivative according to any one of claims 1 to 20 in the preparation of a drug for the treatment and / or prevention of cancer.

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