Pharmaceutical compositions of cdks inhibitors and methods of preparation

Abstract

The application belongs to the technical field of medicine, and particularly relates to a pharmaceutical composition of a CDKs inhibitor compound of formula (I), a preparation method of the pharmaceutical composition, and application in preparing a medicine for treating cancer. The pharmaceutical composition provided by the application has good performance and stable quality, the production process is stable and robust, the quality is stable and controllable, the repeatability is high, and the needs of industrial production can be met.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a composition of CDKs kinase inhibitors, a method for preparing the composition, and the use of the composition in the preparation of a drug for treating cancer. Background Technology

[0002] The development of tumors is related to an imbalance of various oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes ultimately converge on the cell cycle. Therefore, tumors can be considered a type of cell cycle disease (CCD), and regulating or blocking the cell cycle is one approach to treating tumors. Currently, many molecules related to cell cycle regulation have been discovered, among which cyclin-dependent kinases (CDKs) are the core molecules of the cell cycle regulatory network. CDKs are catalytic subunits, a class of serine (Ser) / threonine (Thr) kinases, and as important intracellular signal transduction molecules, they participate in different phases of the cell cycle. Studies have shown that abnormalities in any part of the cell cycle regulatory network centered on CDKs will cause cell cycle abnormalities, ultimately leading to tumorigenesis. The CDK family currently has 21 subtypes, which function by binding to their regulatory subunits cyclins. In addition to their role in the cell cycle, the functions of various CDK subtypes also include the regulation of transcription, DNA repair, differentiation, and programmed cell death. Based on the key role of CDKs in regulating the proliferation and death of tumor cells, the CDK kinase family has provided opportunities and new fields for the discovery and development of anti-tumor drugs.

[0003] Among the CDK subtypes involved in the cell cycle, CDK4 / 6 plays an irreplaceable role. Cancer-related cell cycle mutations mainly occur during the G1 phase and G1 / S phase transition. The complex formed by CDK4 / 6 and Cyclin D, through phosphorylation of the tumor suppressor gene Rb product pRb, releases the bound transcription factor E2F, initiating the transcription of genes related to the S phase, prompting cells to pass the checkpoint and metastasize from the G1 phase to the S phase. Approximately 80% of human tumors exhibit abnormalities in the cyclin D-CDK4 / 6-INK4-Rb pathway. Alterations in this pathway accelerate the G1 phase progression, leading to faster tumor cell proliferation and a survival advantage. Therefore, intervention in this pathway has become a therapeutic strategy, and CDK4 / 6 has emerged as a highly promising anti-tumor target.

[0004] PCT / CN2014 / 095615 discloses the following compound formula (I). Studies have shown that this compound possesses excellent CDK4 / 6 kinase inhibitory activity, exhibits good blood-brain barrier permeability, and offers the possibility of using CDKs inhibitors as tumor treatment, while also demonstrating good safety.

[0005] Summary of the Invention

[0006] This invention provides a pharmaceutical composition of a compound of formula (I) and a method for its preparation. The technical problem solved is to provide a pharmaceutical composition suitable for the physicochemical properties of a compound of formula (I) and possessing good pharmaceutical properties such as disintegration, dissolution, release, and stability. Specifically, this invention provides a pharmaceutical composition comprising a compound of formula (I), a filler, a binder, and a disintegrant; optionally, it further comprises a lubricant and / or a flow aid.

[0007]

[0008] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant, and optionally, a lubricant and / or a flow aid.

[0009]

[0010] The filler is selected from microcrystalline cellulose / lactose monohydrate or microcrystalline cellulose / pregelatinized starch.

[0011] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant, and optionally, a lubricant and / or a flow aid.

[0012]

[0013] The filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate, starch, and dextrin.

[0014] The adhesive is selected from one or more of copovidone VA64, hydroxypropyl cellulose, povidone K30, sodium carboxymethyl cellulose, methyl cellulose, or hydroxypropyl methyl cellulose;

[0015] The disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or croscarmellose.

[0016] The lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, and glyceryl behenate.

[0017] The flow aid is selected from silica or talc.

[0018] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant.

[0019]

[0020] The filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, anhydrous dicalcium phosphate, starch, and dextrin.

[0021] The adhesive is selected from one or more of hydroxypropyl cellulose, povidone K30, or hydroxypropyl methylcellulose;

[0022] The disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, or croscarmellose.

[0023] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant, and optionally, a lubricant and / or a flow aid.

[0024]

[0025] The filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, anhydrous dicalcium phosphate, starch, and dextrin.

[0026] The adhesive is selected from one or more of hydroxypropyl cellulose, povidone K30, or hydroxypropyl methylcellulose;

[0027] The disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch or croscarmellose.

[0028] The lubricant is selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate.

[0029] The flow aid is selected from silica or talc.

[0030] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant, and optionally, a lubricant and / or a flow aid.

[0031] The filler is selected from one or two of microcrystalline cellulose, lactose monohydrate, and pregelatinized starch;

[0032] The adhesive is selected from hydroxypropyl cellulose or povidone K30;

[0033] The disintegrant is selected from croscarmellose sodium or croscarmellose polyvinylpyrrolidone;

[0034] The lubricant is magnesium stearate; the flow aid is silicon dioxide.

[0035] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant, and optionally, a lubricant and / or a flow aid.

[0036] The filler is selected from microcrystalline cellulose / lactose monohydrate or microcrystalline cellulose / pregelatinized starch;

[0037] The adhesive is polyvinylpyrrolidone K30 or hydroxypropyl cellulose;

[0038] The disintegrant is croscarmellose sodium;

[0039] The lubricant is magnesium stearate; the flow aid is silicon dioxide.

[0040] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant.

[0041] The filler is selected from microcrystalline cellulose / lactose monohydrate or microcrystalline cellulose / pregelatinized starch;

[0042] The adhesive is polyvinylpyrrolidone K30;

[0043] The disintegrant is croscarmellose sodium.

[0044] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant, and optionally, a lubricant and / or a flow aid.

[0045] The filler is selected from microcrystalline cellulose PH101 / lactose monohydrate or microcrystalline cellulose PH101 / pregelatinized starch;

[0046] The adhesive is polyvinylpyrrolidone K30;

[0047] The disintegrant is croscarmellose sodium;

[0048] The lubricant is magnesium stearate; the flow aid is silica. In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder, and a disintegrant, optionally further comprising a lubricant and / or a flow aid.

[0049]

[0050] Furthermore, the weight percentages of each component are as follows:

[0051]

[0052] In some embodiments, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, anhydrous dicalcium phosphate, starch, and dextrin.

[0053] In some embodiments, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and anhydrous dicalcium phosphate.

[0054] In some embodiments, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, and pregelatinized starch.

[0055] In some embodiments, the filler is selected from one or more of microcrystalline cellulose PH101, lactose monohydrate, pregelatinized starch, and anhydrous dicalcium phosphate.

[0056] In some embodiments, the filler is selected from one or two of microcrystalline cellulose PH101, lactose monohydrate, and pregelatinized starch.

[0057] In some embodiments, the filler is selected from 30% to 70% by weight.

[0058] In some embodiments, the filler is selected from 40% to 70% by weight.

[0059] In some embodiments, the filler is selected from 50% to 65% by weight.

[0060] In some embodiments, the adhesive is selected from one or more of copovidone VA64, hydroxypropyl cellulose, povidone K30, sodium carboxymethyl cellulose, or hydroxypropyl methylcellulose.

[0061] In some embodiments, the adhesive is selected from one or more of hydroxypropyl cellulose, povidone K30, or hydroxypropyl methylcellulose.

[0062] In some embodiments, the adhesive is selected from one or more of copovidone VA64, hydroxypropyl cellulose, and povidone K30.

[0063] In some embodiments, the adhesive is selected from copovidone VA64, hydroxypropyl cellulose, or povidone K30.

[0064] In some embodiments, the adhesive is selected from hydroxypropyl cellulose or povidone K30.

[0065] In some embodiments, the adhesive is polyvinylpyrrolidone K30.

[0066] In some embodiments, the adhesive is selected from 1% to 5% by weight.

[0067] In some embodiments, the adhesive is selected from 2% to 5% by weight.

[0068] In some embodiments, the adhesive is selected from 2% to 4% by weight.

[0069] In some embodiments, the adhesive is selected from 3% to 5% by weight.

[0070] In some embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or croscarmellose.

[0071] In some embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, or croscarmellose.

[0072] In some embodiments, the disintegrant is selected from croscarmellose sodium, carboxymethyl starch sodium, or croscarmellose.

[0073] In some embodiments, the disintegrant is selected from croscarmellose sodium or carboxymethyl starch sodium.

[0074] In some embodiments, the disintegrant is selected from croscarmellose sodium or croscarmellose polyvinylpyrrolidone.

[0075] In some embodiments, the disintegrant is croscarmellose sodium.

[0076] In some embodiments, the weight percentage of the disintegrant is selected from 2% to 8%.

[0077] In some embodiments, the weight percentage of the disintegrant is selected from 2% to 6%.

[0078] In some embodiments, the weight percentage of the disintegrant is selected from 4% to 6%.

[0079] In some implementations, the disintegrant may be added all at once or in two separate additions, one inside and one outside.

[0080] In some embodiments, the disintegrant is added in two separate additions, one internal and one external, with a weight ratio of 5:1 to 1:3, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, or 1:3.

[0081] In some embodiments, the disintegrant is added in two separate additions, one internal and one external, with a weight ratio of 2:1 to 1:2, for example, 2:1, 1:1, or 1:2.

[0082] In some embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, and glyceryl behenate.

[0083] In some embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate.

[0084] In some embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, and sodium stearate fumarate.

[0085] In some embodiments, the lubricant is selected from magnesium stearate or stearic acid.

[0086] In some embodiments, the lubricant is magnesium stearate.

[0087] In some embodiments, the weight percentage of the lubricant is selected from 0-3%.

[0088] In some embodiments, the weight percentage of the lubricant is selected from 0.01% to 3%.

[0089] In some embodiments, the weight percentage of the lubricant is selected from 0.5% to 3%.

[0090] In some embodiments, the weight percentage of the lubricant is selected from 1% to 3%.

[0091] In some embodiments, the weight percentage of the lubricant is selected from 1% to 2%.

[0092] In some embodiments, the flow aid is selected from silica or talc.

[0093] In some embodiments, the flow aid is silicon dioxide.

[0094] In some embodiments, the weight percentage of the gliding agent is selected from 0-4%.

[0095] In some embodiments, the weight percentage of the gliding agent is selected from 0.01% to 4%.

[0096] In some embodiments, the weight percentage of the gliding agent is selected from 0.5-4%.

[0097] In some embodiments, the weight percentage of the gliding agent is selected from 0-3%.

[0098] In some embodiments, the weight percentage of the gliding agent is selected from 0.5-3%.

[0099] In some embodiments, the weight percentage of the gliding agent is selected from 0-2%.

[0100] In some embodiments, the weight percentage of the gliding agent is selected from 0.5-2%.

[0101] In some embodiments, the weight percentage of the gliding agent is selected from 0-1%.

[0102] In some embodiments, the weight percentage of the gliding agent is selected from 0.01-1%.

[0103] In some embodiments, the weight percentage of the gliding agent is selected from 0.5-1%.

[0104] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 20%-50% of the compound of formula (I), 50%-65% of the filler, 1%-5% of the binder, 2%-8% of the disintegrant, 1%-3% of the lubricant, and 0.01-1% of the flow aid.

[0105] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 20%-50% of a compound of formula (I), 50%-65% of a filler, 1%-5% of a binder, 2%-8% of a disintegrant, 1%-3% of a lubricant, and 0.01-1% of a flow aid.

[0106] The filler is selected from one or two of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and anhydrous dicalcium phosphate;

[0107] The adhesive is selected from hydroxypropyl cellulose or povidone K30;

[0108] The disintegrant is selected from croscarmellose sodium or croscarmellose polyvinylpyrrolidone;

[0109] The lubricant is magnesium stearate; the flow aid is silicon dioxide.

[0110] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 20%-50% of a compound of formula (I), 40%-60% of a filler, 3%-5% of a binder, 4%-6% of a disintegrant, 1%-3% of a lubricant, and 0.01-1% of a flow aid.

[0111] The filler is selected from one or two of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and anhydrous dicalcium phosphate;

[0112] The adhesive is polyvinylpyrrolidone K30;

[0113] The disintegrant is croscarmellose sodium;

[0114] The lubricant is magnesium stearate; the flow aid is silicon dioxide.

[0115] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 20%-50% of a compound of formula (I), 50%-65% of a filler, 3%-5% of a binder, 4%-6% of a disintegrant, 1%-3% of a lubricant, and 0.01-1% of a flow aid.

[0116] The filler is selected from microcrystalline cellulose / lactose monohydrate, microcrystalline cellulose / pregelatinized starch, or microcrystalline cellulose / anhydrous calcium phosphate;

[0117] The adhesive is polyvinylpyrrolidone K30;

[0118] The disintegrant is croscarmellose sodium;

[0119] The lubricant is magnesium stearate; the flow aid is silicon dioxide.

[0120] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 20%-50% of a compound of formula (I), 50%-65% of a filler, 3%-5% of a binder, 4%-6% of a disintegrant, 1%-3% of a lubricant, and 0.01-1% of a flow aid.

[0121] The filler is selected from microcrystalline cellulose PH101 / lactose monohydrate, microcrystalline cellulose PH101 / pregelatinized starch, or microcrystalline cellulose PH101 / anhydrous calcium hydrogen phosphate;

[0122] The adhesive is polyvinylpyrrolidone K30;

[0123] The disintegrant is croscarmellose sodium;

[0124] The lubricant is magnesium stearate; the flow aid is silicon dioxide.

[0125] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 20%-40% of the compound of formula (I), 50%-60% of the filler, 3%-5% of the binder, 4%-6% of the disintegrant, 1%-3% of the lubricant, and 0.01-1% of the flow aid.

[0126] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 30%-40% of the compound of formula (I), 50%-60% of the filler, 3%-4% of the binder, 4%-6% of the disintegrant, 1%-3% of the lubricant, and 0.01-1% of the flow aid.

[0127] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 30%-40% of the compound of formula (I), 50%-60% of the filler, 3%-3.5% of the binder, 4%-6% of the disintegrant, 1%-3% of the lubricant, and 0.01-1% of the flow aid.

[0128] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 30%-40% of the compound of formula (I), 50%-60% of the filler, 3%-3.5% of the binder, 4%-6% of the disintegrant, 1%-2% of the lubricant, and 0.01-1% of the flow aid.

[0129] In some embodiments, the filler is selected from one or two of microcrystalline cellulose, lactose monohydrate, and pregelatinized starch. In some embodiments, the filler is selected from microcrystalline cellulose / lactose monohydrate, microcrystalline cellulose / pregelatinized starch, or microcrystalline cellulose / anhydrous calcium phosphate.

[0130] In some embodiments, the filler is selected from microcrystalline cellulose / lactose monohydrate or microcrystalline cellulose / pregelatinized starch.

[0131] In some embodiments, the weight ratio of microcrystalline cellulose / lactose monohydrate is selected from 7:1 to 1:2, for example 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

[0132] In some embodiments, the weight ratio of microcrystalline cellulose to pregelatinized starch is selected from 7:1 to 1:2, for example 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

[0133] In some embodiments, the weight ratio of microcrystalline cellulose / anhydrous dicalcium phosphate is selected from 7:1 to 1:2, for example 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

[0134] In some embodiments, the filler is selected from microcrystalline cellulose PH101 / lactose monohydrate, microcrystalline cellulose PH101 / pregelatinized starch, or microcrystalline cellulose PH101 / anhydrous dicalcium phosphate.

[0135] In some embodiments, the filler is selected from microcrystalline cellulose PH101 / lactose monohydrate or microcrystalline cellulose PH101 / pregelatinized starch.

[0136] In some embodiments, the weight ratio of microcrystalline cellulose PH101 / lactose monohydrate is selected from 7:1 to 1:2, for example 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

[0137] In some embodiments, the weight ratio of microcrystalline cellulose PH101 to pregelatinized starch is selected from 7:1 to 1:2, for example 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

[0138] In some embodiments, the weight ratio of microcrystalline cellulose PH101 / anhydrous dicalcium phosphate is selected from 7:1 to 1:2, for example 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

[0139] In some embodiments, the weight ratio of microcrystalline cellulose PH101 / lactose monohydrate is selected from 5:1 to 1:1.

[0140] In some embodiments, the weight ratio of microcrystalline cellulose PH101 to pregelatinized starch is selected from 5:1 to 1:1.

[0141] In some embodiments, the weight ratio of microcrystalline cellulose PH101 / anhydrous dicalcium phosphate is selected from 5:1 to 1:1.

[0142] In some embodiments, the weight ratio of microcrystalline cellulose PH101 / lactose monohydrate is selected from 4:1 to 1:1.

[0143] In some embodiments, the weight ratio of microcrystalline cellulose PH101 to pregelatinized starch is selected from 5:1 to 2:1.

[0144] In some embodiments, the weight ratio of microcrystalline cellulose PH101 / anhydrous dicalcium phosphate is selected from 4:1 to 1:1.

[0145] In some embodiments, the disintegrant is croscarmellose sodium.

[0146] In some implementations, the disintegrant may be added all at once or in two separate additions, one inside and one outside.

[0147] In some embodiments, the disintegrant is added in two separate additions, one internal and one external, with a weight ratio of 5:1 to 1:3, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, or 1:3.

[0148] In some embodiments, the disintegrant is added in two separate additions, one internal and one external, with a weight ratio of 2:1 to 1:2, for example, 2:1, 1:1, or 1:2.

[0149] In some embodiments, the disintegrant is added in two separate applications, one internal and one external, with a weight ratio of 1:1 between the two applications.

[0150] In some embodiments, the lubricant is 1% by weight.

[0151] In some embodiments, the flow aid is 0.5% by weight.

[0152] In some embodiments, the composition optionally contains a suitable amount of a wetting agent selected from anhydrous ethanol or water.

[0153] In some embodiments, the composition optionally includes a suitable amount of a wetting agent, wherein the wetting agent is water.

[0154] In some embodiments, the pharmaceutical composition may be prepared as tablets or capsules.

[0155] On the other hand, the present invention also provides a method for preparing tablets of the pharmaceutical composition as described above, comprising the following steps:

[0156] (1) Mix the compound of formula (I) with a filler and an internally added disintegrant to obtain a premix;

[0157] (2) Prepare the adhesive solution;

[0158] (3) Mix the adhesive solution obtained in step (2) with the premix in step (1) and granulate;

[0159] (4) Dry the granules obtained in step (3) and perform dry granulation;

[0160] (5) The granules obtained after dry granulation in step (4) are mixed with an added disintegrant, optional lubricant, and optional flow aid to obtain a final mixture;

[0161] (6) Press the final mixture obtained in step (5) to obtain a core sheet;

[0162] (7) Coating the core obtained in step (6).

[0163] In some implementations, anhydrous ethanol or water is used as a wetting agent when preparing the adhesive solution.

[0164] In some implementations, water is used as a wetting agent when preparing the adhesive solution.

[0165] In some embodiments, the coating powder used in the coating process is selected from gastrointestinal film coating premixes, with a coating weight gain of 2%-8%, preferably 2%-6%.

[0166] In some embodiments, the coating dispersant used in the coating process is selected from anhydrous ethanol or water.

[0167] In some embodiments, the coating dispersant used in the coating process is water.

[0168] In another aspect, the present invention also relates to the use of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of cancer-related diseases mediated by CDK4 / 6 kinases in subjects.

[0169] The present invention also provides a method for treating and / or preventing cancer-related diseases mediated by CDK4 / 6 kinases in mammals in need, the method comprising administering to the mammals in need a therapeutically and / or preventively effective amount of the pharmaceutical composition of the present invention.

[0170] In some embodiments, the CDK4 / 6 kinase-mediated cancer-related diseases are selected from: brain tumors, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma, melanoma, glioma, and sarcoma.

[0171] In another aspect, the present invention also provides a kit comprising:

[0172] (a) the aforementioned pharmaceutical composition,

[0173] (b) an effective amount of one or more anticancer agents.

[0174] Terminology Explanation

[0175] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this invention, definitions of some terms are provided below. When the definitions and interpretations of the terms provided in this invention differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this invention shall prevail.

[0176] The fillers described in this invention include, but are not limited to, microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate, starch, and dextrin.

[0177] The adhesives described in this invention include, but are not limited to, copovidone VA64, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, povidone K30, copovidone, maltodextrin, and maltose.

[0178] The wetting agent described in this invention refers to a solvent used to prepare the adhesive solution, which is gradually removed during the preparation of the pharmaceutical composition. It includes, but is not limited to, 90% or more ethanol and water; specific examples include, but are not limited to, 90% ethanol, 95% ethanol, anhydrous ethanol, and water.

[0179] The term "appropriate amount" in "appropriate amount of wetting agent" as used in this invention refers to adjusting the amount of wetting agent according to the amount of adhesive used. It is mainly determined based on the percentage of adhesive used (in the formulation) and the mass fraction of adhesive. The commonly used mass fraction of adhesive (mass ratio to wetting agent) is selected from 2% to 10% (w / w), including but not limited to 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%.

[0180] The disintegrants described in this invention include, but are not limited to, croscarmellose sodium, hydroxymethyl cellulose, calcium hydroxymethyl cellulose, low-substituted hydroxypropyl methyl cellulose, croscarmellose, sodium hydroxymethyl starch, and hydroxypropyl starch.

[0181] The lubricants described in this invention include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and magnesium lauryl sulfate.

[0182] The flow aids described in this invention include, but are not limited to, talc, micronized silica gel, and silica.

[0183] The dispersant described in this invention refers to a solvent used to dissolve the coating powder, which is gradually removed during the core coating process. The dispersant includes, but is not limited to, anhydrous ethanol and water.

[0184] The pharmaceutical composition of the present invention can be packaged in any packaging that does not affect the stability of the pharmaceutical formulation. For example, the inner packaging can be PVC aluminum-plastic blister packaging, double aluminum packaging, PVDC aluminum-plastic blister packaging, etc., and the outer packaging can be a composite film bag.

[0185] The "effective dose" as described in this invention refers to a drug dose capable of preventing, alleviating, delaying, inhibiting, or curing the subject's condition. The dosage is related to the route of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual characteristics (gender, weight, height, age), etc.

[0186] The "microcrystalline cellulose / lactose monohydrate" mentioned in this invention refers to a mixture of microcrystalline cellulose and lactose monohydrate in any possible ratio, including but not limited to 100:1-1:100, 10:1-1:10, 7:1-1:2, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, and 1:4. Both microcrystalline cellulose and lactose monohydrate include various product types for industrial applications. The definitions of "microcrystalline cellulose / pregelatinized starch" and "microcrystalline cellulose / anhydrous dicalcium phosphate" in this invention are the same as above.

[0187] In the pharmaceutical composition of the present invention, the sum of the weight percentages of its various components is less than or equal to 100%.

[0188] Beneficial effects of the invention

[0189] 1. The pharmaceutical composition of the present invention has good disintegration and dissolution properties.

[0190] 2. The pharmaceutical composition of the present invention is stable and can provide a long shelf life.

[0191] 3. The pharmaceutical composition of the present invention has a stable process, controllable cost, and strong repeatability, which can meet the requirements of industrial production. Detailed Implementation Plan

[0192] The technical solution of the present invention will be described below with reference to specific embodiments, and the above-mentioned content of the present invention will be further explained in detail. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following embodiments. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention.

[0193] The compounds of formula (I) used in the following examples or experimental cases can be prepared by referring to existing methods.

[0194] It should be noted that in the embodiments below, formulations with identical compositions are assigned the same formulation number. However, since production batches may not be entirely identical, for formulations with the same number, there may be slight differences in the basic properties of the particles, dissolution rate, particle size distribution, etc., in different embodiments. Those skilled in the art will understand that this is a normal error in the experimental process.

[0195] Example 1: Investigation of the types of fillers

[0196] 1. Preparation process:

[0197] 1) Weighing: Weigh out the compound of formula (I), filler, internal disintegrant and other internal raw materials and excipients according to the amount required, and set aside for later use;

[0198] 2) Mixing: Weigh the raw and auxiliary materials and place them in a wet granulation machine, then mix them evenly;

[0199] 3) Preparation of adhesive solution: Weigh the adhesive according to the required amount and prepare the adhesive solution using water as a wetting agent;

[0200] 4) Granulation and wet granulation: Add the prepared adhesive solution to the raw and auxiliary materials mixed in step (2), adjust the granulator to the appropriate parameters, and granulate;

[0201] 5) Drying and dry granulation: The obtained wet granules are dried in a fluidized bed granulator and then dry granulated.

[0202] 6) Additives and final mixing: Add disintegrants, lubricants and gliding agents according to the particle yield to obtain the final mixture;

[0203] 7) Tableting: The final mixture obtained in step (6) is pressed on a tablet press to obtain tablet cores;

[0204] 8) Coating the tablet cores obtained in step (7) (the coating powder is selected from gastric-soluble film coating premix, and the coating weight gain is 2%-8%).

[0205] 2. Prescription design

[0206] Table 1 Formulation Design for Filler Screening

[0207]

[0208] Table 2 Formulation Design for Filler Screening

[0209]

[0210] 3. Results of the investigation

[0211] Table 3. Results of Filler Screening

[0212]

[0213] Table 4. Examination of Filler Screening Results

[0214]

[0215] Table 5. Results of the evaluation of filler type selection – related substances and content

[0216]

[0217] 4. Conclusion of the investigation:

[0218] As shown in Table 3, except for the combination of microcrystalline cellulose PH101 and pregelatinized starch (2:1), the formulations using microcrystalline cellulose PH101 and mannitol (2:1) or mannitol and pregelatinized starch (2:1) as fillers all exhibited sticking and disintegration phenomena. Moreover, the formulation using microcrystalline cellulose PH101 and pregelatinized starch (2:1) as fillers was superior to other formulations in terms of soft material properties, whether it sticks to the screen, and disintegration time, and there were no significant differences in other key test results.

[0219] The results in Tables 4 and 5 show that the soft material prepared by the combination of microcrystalline cellulose PH101 / mannitol (4:1) is slightly moist, and the wet granules are easy to clump together. The soft material, wet granules, and dry granules prepared by the combinations of microcrystalline cellulose PH101 / lactose monohydrate (4:1), microcrystalline cellulose PH101 / anhydrous calcium hydrogen phosphate (4:1), and microcrystalline cellulose PH101 / pregelatinized starch (4:1) all have good properties. In addition, none of the four filler combinations in Formulas 4-7 showed sticking or clumping, and there was no significant difference in the related substances and their stability.

[0220] Example 2: Selection of Filler Type

[0221] The type of filler was examined, mainly focusing on its impact on the key quality attribute of dissolution.

[0222] 1. Preparation process

[0223] The prescription was prepared according to the preparation process of Example 1.

[0224] 2. Prescription design

[0225] Table 6. Filler Type Selection – Formulation Design

[0226]

[0227]

[0228] 3. Results of the investigation

[0229] Table 7 Results of the evaluation of filler type selection - dissolution rate

[0230]

[0231] 4. Conclusion of the Investigation

[0232] The results show that the combination of microcrystalline cellulose and lactose monohydrate dissolves rapidly and completely, while the combination of microcrystalline cellulose and anhydrous dicalcium phosphate dissolves slowly and incompletely, and the combination of pregelatinized starch and mannitol dissolves relatively slowly.

[0233] Example 3: Investigation on filler dosage and ratio

[0234] 1. Preparation process

[0235] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0236] 2. Prescription design

[0237] Table 8. Formulation Design for Filler Dosage

[0238]

[0239]

[0240] Table 9 Formulation Design for Filler Dosage

[0241]

[0242] 3. Results of the investigation

[0243] Table 10 Results of the optimization study on filler dosage

[0244]

[0245] Table 11 Results of Filler Dosage Optimization Study – Particle Size Distribution

[0246]

[0247] Table 12 Results of the optimization study on filler dosage

[0248]

[0249]

[0250] Table 13 Results of Filler Dosage Optimization Study - Dissolution

[0251]

[0252] 4. Conclusion of the Investigation

[0253] The above experimental results show that different ratios of microcrystalline cellulose PH101 and pregelatinized starch (2:1, 3:1, 5:1) have no significant effect on whether the mixture sticks together, the particle ratio, or the dissolution rate.

[0254] Adjusting the ratio of microcrystalline cellulose PH101 to lactose monohydrate from 4:1 to 2:1 or 1:1 had no significant effect on the particle size, compactness, brittleness, disintegration, and dissolution of the dry granules.

[0255] Example 4: Investigation into the selection of adhesive types

[0256] 1. Preparation process

[0257] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0258] 2. Prescription design

[0259] Table 14 Adhesive Type Selection - Formulation Design

[0260]

[0261]

[0262] 3. Results of the investigation

[0263] Table 15 Results of the Examination on Adhesive Type Selection - Basic Items for Tablets

[0264]

[0265] Table 16 Results of the Examination on Adhesive Type Selection - Basic Items for Tablets

[0266]

[0267] 4. Conclusion of the Investigation

[0268] The results above show that copovidone VA64, used as a binder, produces softer granules with more fine powder. This makes the granules easily ground during compression, increasing the risk of powder leakage and making tablet extrusion difficult due to excessive fine powder. In contrast, povidone K30 or hydroxypropyl cellulose, used as binders, produce granules with superior strength compared to copovidone VA64. There were no significant differences among the three binders in other key indicators such as dissolution curves and stability.

[0269] Example 5: Selection of Adhesive Type

[0270] 1. Preparation process

[0271] The prescription was prepared according to the preparation process of Example 1.

[0272] 2. Prescription design

[0273] Table 17 Adhesive Type Selection – Formulation Design

[0274]

[0275]

[0276] 3. Results of the investigation

[0277] Table 18 Results of the Adhesive Type Selection Study – Basic Items

[0278] Soft material properties Moderate moisture content, small amount of pellets Moderate moisture content, partially formed into balls Moderate moisture content, partially formed into balls wet granular properties Good particle size Particle Aggregates serious clustering Dry granule properties Medium firmness Slightly hard harder Is it sticky or not? Non-stick punching trend Non-stick punching trend Non-stick punching trend Tablet hardness / kg 14.18-16.99 14.68-17.10 14.38-16.94 Disintegration timeout / min 5 7 20

[0279] Table 19 Results of Adhesive Type Selection Investigation - Dissolution Rate

[0280]

[0281] 4. Conclusion of the Investigation

[0282] The results show that the soft material, wet granules, and dry granules prepared by replacing the binder with methylcellulose or sodium carboxymethylcellulose are all inferior to those of povidone K30. Furthermore, the tablets prepared by using methylcellulose as a binder have a slightly delayed disintegration time and slow and incomplete dissolution, while the tablets prepared by using sodium carboxymethylcellulose as a binder have a significantly delayed disintegration time and slow dissolution.

[0283] Based on the results of the investigation in Examples 4 and 5, selecting povidone K30 or hydroxypropyl cellulose with suitable viscosity can improve the compactness of the particles, ensure the normal and efficient operation of the tableting process, and at the same time ensure that the tablets can be quickly and completely dissolved.

[0284] Example 6: Optimization Study of Adhesive Dosage

[0285] 1. Preparation process

[0286] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0287] 2. Prescription design

[0288] Table 20 Adhesive Dosage Optimization - Formulation Design

[0289]

[0290] 3. Results of the investigation

[0291] Table 21 Results of the Optimization Study on Adhesive Dosage - Basic Items for Tablets

[0292] Is it sticky or not? Non-stick punching trend Non-stick punching trend Non-stick punching trend Tablet hardness / kg 7～9 7～9 7～8 Disintegration timeout / min 4 2 4

[0293] Table 22 Results of Adhesive Dosage Optimization Study - Dissolution

[0294]

[0295] 4. Conclusion of the Investigation

[0296] No sticking or punching tendency was observed when the binder dosage was 4%, 3.5%, and 3%. There were no significant differences in tablet hardness, disintegration time, and dissolution among the three formulations.

[0297] Example 7: Selection of Disintegrant Type

[0298] 1. Preparation process

[0299] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0300] 2. Prescription design

[0301] Table 23 Selection of Disintegrant Types - Formulation Design

[0302]

[0303] 3. Results of the investigation

[0304] Table 24 Results of the Study on the Selection of Disintegrant Types - Basic Items for Tablets

[0305] Tablet hardness / kg 7～9 7～9 Disintegration timeout / min 2 4

[0306] Table 25 Results of the Study on the Selection of Disintegrant Types - Dissolution Rate

[0307]

[0308] 4. Conclusion of the Investigation

[0309] The data above show that, under similar hardness conditions, croscarmellose sodium as a disintegrant is significantly superior to croscarmellose XL-10 as a disintegrant in terms of disintegration time, dissolution rate, and dissolution stability.

[0310] Example 8: Selection of Disintegrant Type

[0311] 1. Preparation process

[0312] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0313] 2. Prescription design

[0314] Table 26 Selection of Disintegrant Types – Formulation Design

[0315]

[0316]

[0317] 3. Results of the investigation

[0318] Table 27 Results of the Study on the Selection of Disintegrant Types – Basic Items

[0319] Tablet hardness / kg 14.18-16.99 13.93-17.23 14.78-17.38 Disintegration timeout / min 5 22 6

[0320] Table 28 Results of the Study on the Selection of Disintegrant Types - Dissolution Rate at 120mg

[0321]

[0322] 4. Conclusion of the Investigation

[0323] The results show that tablets made with low-substituted hydroxypropyl cellulose as a disintegrant dissolve slowly and incompletely, while tablets made with sodium carboxymethyl starch as a disintegrant dissolve slowly. The disintegrant effects of both are inferior to those of croscarmellose sodium.

[0324] Example 9: Investigation on the Dosage of Disintegrant

[0325] 1. Preparation process

[0326] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0327] 2. Prescription design

[0328] Table 29 Analysis of Disintegrant Dosage - Formulation Design

[0329]

[0330]

[0331] 3. Results of the investigation

[0332] Table 30 Results of the Optimization Study on Disintegrant Dosage - Basic Items for Tablets

[0333] Tablet hardness / kg 7～9 7～9 7～9 Disintegration timeout / min 2 1 3

[0334] Table 31 Results of the optimization study on disintegrant dosage - dissolution

[0335]

[0336] 4. Conclusion of the Investigation

[0337] The optimal method for using croscarmellose sodium as a disintegrant is a combination of internal and external application. When the disintegrant dosages are 3% internal and 2% external, and 1% internal and 1% external, with consistent tablet hardness, the different disintegrant ratios result in slight differences in disintegration time, but have minimal overall impact on the dissolution profile.

[0338] Example 10: Selection of Lubricant / Groothing Agent

[0339] To address the issue of easy sticking and punching during tablet compression and ensure the normal operation of the production process, the types of lubricants were screened.

[0340] 1. Preparation process

[0341] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0342] 2. Prescription design

[0343] Table 32 Selection of Lubricant / Glider Types – Formulation Design

[0344]

[0345]

[0346] 3. Results of the investigation

[0347] Table 33 Lubricant / Groothing Agent Selection – Sticking / Fluidation Conditions

[0348] Prescription 20 magnesium stearate Unbonded Prescription 27 Sodium stearate Adhesive punch

[0349] 4. Conclusion of the Investigation

[0350] The results of the investigation show that when sodium stearate fumarate was used as a lubricant, obvious sticking and punching occurred, while when magnesium stearate was used as a lubricant, no sticking and punching occurred, ensuring the smooth progress of the tableting process.

[0351] Example 11: Investigation of Lubricant Dosage

[0352] 1. Preparation process

[0353] According to the prescription, the prescription was prepared according to the preparation process of Example 1.

[0354] 2. Prescription design

[0355] Table 34 Lubricant Dosage Investigation - Recipe Design

[0356]

[0357] 3. Results of the investigation

[0358] Table 35 Results of Lubricant Dosage Optimization Study – Particle Size Distribution

[0359]

[0360] Table 36 Results of Lubricant Dosage Optimization Study - Basic Tablet Items

[0361] Dry granule properties Medium firmness Medium firmness Is it sticky or not? The surface smoothness decreases, posing a risk of sticking and impact. Non-stick punching trend Tablet hardness / kg 7～9 7～8 Disintegration timeout / min 2 4

[0362] 4. Conclusion of the Investigation

[0363] The experiment showed that, under the condition that the particle size, properties and tablet hardness were basically consistent, the tablets made with the 0.5% magnesium stearate formulation had reduced surface smoothness and a risk of sticking and punching; the tablets made with the 1% magnesium stearate formulation did not have a sticking and punching tendency and could meet the quality standard requirements.

Claims

1. A pharmaceutical composition comprising a compound of formula (I), a filler, a binder, and a disintegrant, further comprising a lubricant and / or a flow aid, （I）， The weight percentages of each component are as follows: Compound (I) 20%-50% Filler 50%-65% Adhesive 1%-5% Disintegrant 2%-8% Lubricant 1%-3% Flow aid 0.01-1%, The filler is selected from one or two of microcrystalline cellulose, lactose monohydrate, and pregelatinized starch; The adhesive is selected from hydroxypropyl cellulose or povidone K30; The disintegrant is selected from croscarmellose sodium; The lubricant is magnesium stearate; The flow aid is silicon dioxide; The pharmaceutical composition is in the form of tablets.

2. The pharmaceutical composition of claim 1, wherein the weight percentage of the disintegrant is selected from 2% to 6%.

3. The pharmaceutical composition of claim 1, by weight percentage, comprises 30%-40% of the compound of formula (I), 50%-60% of the filler, 3%-4% of the binder, 4%-6% of the disintegrant, 1%-3% of the lubricant, and 0.01-1% of the flow aid.

4. The pharmaceutical composition of claim 1, wherein the disintegrant is added in two portions.

5. The pharmaceutical composition of claim 4, wherein the weight ratio of the two additions of the disintegrant is 5:1 to 1:

3.

6. The pharmaceutical composition of claim 4, wherein the weight ratio of the two additions of the disintegrant is 2:1 to 1:

2.

7. The pharmaceutical composition of claim 4, wherein the weight ratio of the two additions of the disintegrant is 1:

1.

8. The pharmaceutical composition of claim 1, wherein the lubricant is 1% by weight.

9. The pharmaceutical composition of claim 1, wherein the gliding agent comprises 0.5% by weight.

10. The pharmaceutical composition of claim 1, wherein the filler is selected from microcrystalline cellulose / lactose monohydrate and microcrystalline cellulose / pregelatinized starch.

11. The pharmaceutical composition of claim 10, wherein the weight ratio of microcrystalline cellulose / lactose monohydrate is selected from 7:1 to 1:2, and the weight ratio of microcrystalline cellulose / pregelatinized starch is selected from 7:1 to 1:

2.

12. The pharmaceutical composition of claim 10, wherein the weight ratio of the microcrystalline cellulose / lactose monohydrate is selected from 5:1 to 1:

1.

13. The pharmaceutical composition of claim 10, wherein the weight ratio of the microcrystalline cellulose / lactose monohydrate is selected from 4:1 to 1:

1.

14. The pharmaceutical composition of claim 10, wherein the weight ratio of the microcrystalline cellulose / pregelatinized starch is selected from 5:1 to 2:

1.

15. A method for preparing a tablet of the pharmaceutical composition according to any one of claims 1-14, characterized in that, Includes the following steps: (1) The compound of formula (I) is mixed with a filler and an internally added disintegrant to obtain a premix; (2) Prepare the adhesive solution; (3) The adhesive solution obtained in step (2) is mixed with the premixed mixture in step (1) and granulated; (4) Dry the granules obtained in step (3) and perform dry granulation; (5) The granules obtained after dry granulation in step (4) are mixed with the added disintegrant, lubricant and gliding agent to obtain the final mixture; (6) Press the final mixture obtained in step (5) to obtain a core sheet; (7) Coating the core obtained in step (6).

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