WO2024104448A1 - Pharmaceutical composition of cdks inhibitor and preparation method therefor - Google Patents

Abstract

A pharmaceutical composition of a CDKs inhibitor compound of formula (I), a preparation method for the pharmaceutical composition, and use of the pharmaceutical composition in the preparation of a drug for treating cancer. The provided pharmaceutical composition is good in performance and has stable properties. The production process for the pharmaceutical composition is robust. The quality of the pharmaceutical composition is stable and controllable. The pharmaceutical composition exhibits strong reproducibility and meets the requirements for industrial production.

Description

Pharmaceutical composition of CDKs inhibitors and preparation method thereof Technical Field

The present invention belongs to the field of medical technology, and specifically relates to a composition of a class of CDKs kinase inhibitors, a preparation method of the composition, and use of the composition in preparing a drug for treating cancer.

Background technique

The occurrence of tumors is related to the imbalance of multiple oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes will eventually converge on the cell cycle. Therefore, it can be said that tumors are a type of cell cycle disease (CCD), and regulating or blocking the cell cycle is one of the ways to treat tumors. At present, 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 and are a type of serine (Ser)/threonine (Thr) kinases. As important signal transduction molecules in cells, they participate in different stages of the cell cycle. Studies have shown that any abnormality in the cell cycle regulatory network centered on CDKs will cause abnormal cell cycle and ultimately lead to the occurrence of tumors. The CDKs family currently has 21 subtypes, which work by binding to its regulatory subunit cyclins (cell cycle proteins). In addition to acting on the cell cycle, the functions of various subtypes of CDKs 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 CDKs kinase family provides opportunities and new areas for the discovery and development of anti-tumor drugs.

Among the CDKs subtypes involved in the cell cycle, CDK4/6 plays an irreplaceable role. Cancer-related cell cycle mutations mainly exist in the G1 phase and G1/S phase transition process. The complex formed by CDK4/6 and CyclinD releases the bound transcription factor E2F through the phosphorylation of the tumor suppressor gene Rb product pRb, initiates the transcription of genes related to the S phase, prompts cells to pass the checkpoint, and transfers from the G1 phase to the S phase. About 80% of human tumors have abnormalities in the cyclin D-CDK4/6-INK4-Rb pathway. Changes in this pathway accelerate the G1 phase process, allowing tumor cells to proliferate faster and gain a survival advantage. Therefore, intervention in this pathway has become a therapeutic strategy, and CDK4/6 has become a highly potential anti-tumor target.

PCT/CN2014/095615 discloses the following compound formula (I). Studies have shown that the compound has excellent CDK4/6 kinase inhibitory activity and exhibits good blood-brain barrier permeability, providing the possibility of CDKs inhibitors as tumor treatment, and has good safety.

Summary of the invention

The present invention provides a pharmaceutical composition of a compound of formula (I) and a preparation method thereof. The technical problem to be solved is to provide a pharmaceutical composition that is suitable for the physicochemical properties of the compound of formula (I) and has good pharmaceutical properties such as disintegration, dissolution, release, stability, etc. Specifically, the present invention provides a pharmaceutical composition, which includes a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant.

Wherein, the filler is selected from microcrystalline cellulose/lactose monohydrate or microcrystalline cellulose/pregelatinized starch.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant.

Wherein, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate, starch, and dextrin;

The binder is selected from one or more of copovidone VA64, hydroxypropyl cellulose, povidone K30, sodium carboxymethyl cellulose, methyl cellulose or hypromellose;

The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone;

The lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate;

The glidant is selected from silicon dioxide or talc.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant.

Wherein, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, anhydrous calcium hydrogen phosphate, starch, and dextrin;

The binder is selected from one or more of hydroxypropyl cellulose, povidone K30 or hypromellose;

The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium starch glycolate or cross-linked polyvinylpyrrolidone.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant.

Wherein, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, anhydrous calcium hydrogen phosphate, starch, and dextrin;

The binder is selected from one or more of hydroxypropyl cellulose, povidone K30 or hypromellose;

The disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone;

The lubricant is selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate;

The glidant is selected from silicon dioxide or talc.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant.

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 cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone;

The lubricant is magnesium stearate; the glidant is silicon dioxide.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant.

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

The adhesive is povidone K30 or hydroxypropyl cellulose;

The disintegrant is cross-linked carboxymethyl cellulose sodium;

The lubricant is magnesium stearate; the glidant is silicon dioxide.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant.

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

The adhesive is povidone K30;

The disintegrant is cross-linked sodium carboxymethyl cellulose.

In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant.

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

The adhesive is povidone K30;

The disintegrant is cross-linked carboxymethyl cellulose sodium;

The lubricant is magnesium stearate; the glidant is silicon dioxide. In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), a filler, a binder and a disintegrant, and optionally, further comprises a lubricant and/or a glidant.

And in terms of weight percentage, the weight ratio of each component is as follows:

In certain embodiments, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate, starch, and dextrin.

In certain embodiments, the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and anhydrous calcium hydrogen phosphate.

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

In certain embodiments, the filler is selected from one or more of microcrystalline cellulose PH101, lactose monohydrate, pregelatinized starch, and anhydrous calcium hydrogen phosphate.

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

In certain embodiments, the weight percentage of the filler is selected from 30%-70%.

In certain embodiments, the weight percentage of the filler is selected from 40%-70%.

In certain embodiments, the weight percentage of the filler is selected from 50%-65%.

In certain embodiments, the binder is selected from one or more of copovidone VA64, hydroxypropyl cellulose, povidone K30, sodium carboxymethyl cellulose or hypromellose.

In certain embodiments, the binder is selected from one or more of hydroxypropyl cellulose, povidone K30, or hypromellose.

In certain embodiments, the binder is selected from one or more of copovidone VA64, hydroxypropyl cellulose, and povidone K30.

In certain embodiments, the binder is selected from copovidone VA64, hydroxypropyl cellulose, or povidone K30.

In certain embodiments, the binder is selected from hydroxypropyl cellulose or povidone K30.

In certain embodiments, the binder is povidone K30.

In certain embodiments, the weight percentage of the binder is selected from 1% to 5%.

In certain embodiments, the weight percentage of the binder is selected from 2%-5%.

In certain embodiments, the weight percentage of the binder is selected from 2% to 4%.

In certain embodiments, the weight percentage of the binder is selected from 3%-5%.

In certain embodiments, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, low-substituted hydroxypropyl cellulose, or cross-linked polyvinylpyrrolidone.

In certain embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium starch glycolate, or crospovidone.

In certain embodiments, the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, or crospovidone.

In certain embodiments, the disintegrant is selected from croscarmellose sodium or sodium starch glycolate.

In certain embodiments, the disintegrant is selected from croscarmellose sodium or crospovidone.

In certain embodiments, the disintegrant is croscarmellose sodium.

In certain embodiments, the weight percentage of the disintegrant is selected from 2% to 8%.

In certain embodiments, the weight percentage of the disintegrant is selected from 2% to 6%.

In certain embodiments, the weight percentage of the disintegrant is selected from 4% to 6%.

In certain embodiments, the disintegrant can be added once or twice, internally and externally.

In certain embodiments, the disintegrant is added twice, and the weight ratio of the two additions is 5:1-1:3, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3.

In certain embodiments, the disintegrant is added twice, and the weight ratio of the two additions is 2:1-1:2, such as 2:1, 1:1, 1:2.

In certain embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate.

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

In certain embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, and sodium stearyl fumarate.

In certain embodiments, the lubricant is selected from magnesium stearate or stearic acid.

In certain embodiments, the lubricant is magnesium stearate.

In certain embodiments, the weight percentage of the lubricant is selected from 0-3%.

In certain embodiments, the weight percentage of the lubricant is selected from 0.01% to 3%.

In certain embodiments, the weight percentage of the lubricant is selected from 0.5% to 3%.

In certain embodiments, the weight percentage of the lubricant is selected from 1% to 3%.

In certain embodiments, the weight percentage of the lubricant is selected from 1% to 2%.

In certain embodiments, the glidant is selected from silicon dioxide or talc.

In certain embodiments, the glidant is silicon dioxide.

In certain embodiments, the weight percentage of the glidant is selected from 0-4%.

In certain embodiments, the weight percentage of the glidant is selected from 0.01%-4%.

In certain embodiments, the weight percentage of the glidant is selected from 0.5-4%.

In certain embodiments, the weight percentage of the glidant is selected from 0-3%.

In certain embodiments, the weight percentage of the glidant is selected from 0.5-3%.

In certain embodiments, the weight percentage of the glidant is selected from 0-2%.

In certain embodiments, the weight percentage of the glidant is selected from 0.5-2%.

In certain embodiments, the weight percentage of the glidant is selected from 0-1%.

In certain embodiments, the weight percentage of the glidant is selected from 0.01-1%.

In certain embodiments, the weight percentage of the glidant is selected from 0.5-1%.

In certain 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 glidant.

In certain embodiments, the pharmaceutical composition comprises 20%-50% by weight of the compound of formula (I) , 50%-65% filler, 1%-5% binder, 2%-8% disintegrant, 1%-3% lubricant, 0.01-1% glidant;

The filler is selected from one or two of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and anhydrous calcium hydrogen phosphate;

The adhesive is selected from hydroxypropyl cellulose or povidone K30;

The disintegrant is selected from cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone;

The lubricant is magnesium stearate; the glidant is silicon dioxide.

In certain 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 glidant;

The filler is selected from one or two of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, and anhydrous calcium hydrogen phosphate;

The adhesive is povidone K30;

The disintegrant is cross-linked carboxymethyl cellulose sodium;

The lubricant is magnesium stearate; the glidant is silicon dioxide.

In certain 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 glidant;

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

The adhesive is povidone K30;

The disintegrant is cross-linked carboxymethyl cellulose sodium;

The lubricant is magnesium stearate; the glidant is silicon dioxide.

In certain 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 glidant;

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

The adhesive is povidone K30;

The disintegrant is cross-linked carboxymethyl cellulose sodium;

The lubricant is magnesium stearate; the glidant is silicon dioxide.

In certain embodiments, the pharmaceutical composition comprises, by weight percentage, 20%-40% of a compound of formula (I), 50%-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 glidant.

In certain embodiments, the pharmaceutical composition comprises, by weight percentage, 30%-40% of a compound of formula (I), 50%-60% of a filler, 3%-4% of a binder, 4%-6% of a disintegrant, 1%-3% of a lubricant, and 0.01-1% of a glidant.

In certain embodiments, the pharmaceutical composition comprises, by weight percentage, 30%-40% of a compound of formula (I), 50%-60% of a filler, 3%-3.5% of a binder, 4%-6% of a disintegrant, 1%-3% of a lubricant, and 0.01-1% of a glidant.

In certain embodiments, the pharmaceutical composition comprises, by weight percentage, 30%-40% of a compound of formula (I), 50%-60% of a filler, 3%-3.5% of a binder, 4%-6% of a disintegrant, 1%-2% of a lubricant, and 0.01-1% of a glidant.

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 hydrogen phosphate.

In certain embodiments, the filler is selected from microcrystalline cellulose/lactose monohydrate, or microcrystalline cellulose/pregelatinized starch.

In certain embodiments, the weight ratio of microcrystalline cellulose/lactose monohydrate is selected from 7:1-1:2, such as 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

In certain embodiments, the weight ratio of microcrystalline cellulose/pregelatinized starch is selected from 7:1-1:2, such as 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

In certain embodiments, the weight ratio of microcrystalline cellulose/anhydrous calcium hydrogen phosphate is selected from 7:1-1:2, such as 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

In certain embodiments, the filler is selected from microcrystalline cellulose PH101/lactose monohydrate, microcrystalline cellulose PH101/pregelatinized starch, or microcrystalline cellulose PH101/anhydrous calcium hydrogen phosphate.

In certain embodiments, the filler is selected from microcrystalline cellulose PH101/lactose monohydrate, or microcrystalline cellulose PH101/pregelatinized starch.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/lactose monohydrate is selected from 7:1-1:2, such as 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/pregelatinized starch is selected from 7:1-1:2, such as 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/anhydrous calcium hydrogen phosphate is selected from 7:1-1:2, such as 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/lactose monohydrate is selected from 5:1-1:1.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/pregelatinized starch is selected from 5:1-1:1.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/anhydrous calcium hydrogen phosphate is selected from 5:1-1:1.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/lactose monohydrate is selected from 4:1-1:1.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/pregelatinized starch is selected from 5:1-2:1.

In certain embodiments, the weight ratio of microcrystalline cellulose PH101/anhydrous calcium hydrogen phosphate is selected from 4:1-1:1.

In certain embodiments, the disintegrant is croscarmellose sodium.

In certain embodiments, the disintegrant can be added once or twice, internally and externally.

In certain embodiments, the disintegrant is added twice, and the weight ratio of the two additions is 5:1-1:3, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3.

In certain embodiments, the disintegrant is added twice, and the weight ratio of the two additions is 2:1-1:2, such as 2:1, 1:1, 1:2.

In certain embodiments, the disintegrant is added twice, and the weight ratio of the two additions is 1:1.

In certain embodiments, the weight percentage of the lubricant is 1%.

In certain embodiments, the weight percentage of the glidant is 0.5%.

In certain embodiments, the composition optionally comprises an appropriate amount of a wetting agent selected from anhydrous ethanol or water.

In certain embodiments, the composition optionally comprises a suitable amount of a wetting agent, which is water.

In certain embodiments, the pharmaceutical composition can be prepared as a tablet or a capsule.

On the other hand, the present invention also provides a method for preparing a tablet of the pharmaceutical composition as described above, comprising the following steps: step:

(1) mixing the compound of formula (I) with a filler and an internal disintegrant to obtain a premix;

(2) preparing adhesive solution;

(3) mixing the binder solution obtained in step (2) with the premix of step (1) and granulating;

(4) drying the granules obtained in step (3) and performing dry granulation;

(5) mixing the granules obtained after dry granulation in step (4) with an external disintegrant, an optional lubricant, and an optional glidant to obtain a final mixture;

(6) compressing the final mixture obtained in step (5) to obtain a tablet core;

(7) coating the tablet core obtained in step (6).

In certain embodiments, anhydrous ethanol or water is used as a wetting agent when preparing the adhesive solution.

In certain embodiments, water is used as a wetting agent when preparing the adhesive solution.

In certain embodiments, the coating powder used in the coating process is selected from a gastric soluble film coating premix, and the coating weight gain is 2%-8%, preferably, the coating weight gain is 2%-6%.

In certain embodiments, the coating dispersant used in the coating process is selected from anhydrous ethanol or water.

In certain embodiments, the coating dispersant used in the coating process is water.

In another aspect, the present invention also relates to the use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cancer-related diseases mediated by CDK4/6 kinase in a subject.

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

In certain embodiments, the CDK4/6 kinase-mediated cancer-related disease is selected from the group consisting of 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 tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma.

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

(a) the aforementioned pharmaceutical composition,

and (b) an effective amount of one or more anticancer agents.

Explanation of terms

In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, but in order to better understand the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided by the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided by the present invention shall prevail.

The filler described in the present invention includes but is not limited to microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate, starch, and dextrin.

The adhesives described in the present invention include but are not limited to copovidone VA64, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, povidone K30, copovidone, maltodextrin, and maltose.

The wetting agent of the present invention refers to a solvent used to prepare the adhesive solution, which will be gradually removed during the preparation of the pharmaceutical composition, including but not limited to 90% or more ethanol and water, and specific examples include but are not limited to 90% ethanol, 95% ethanol, anhydrous ethanol, water, etc.

The "appropriate amount" in the "appropriate amount of wetting agent" described in the present invention means adjusting the amount of the wetting agent according to the amount of the adhesive, which is mainly determined according to the percentage of the adhesive dosage (in the prescription) and the mass fraction of the adhesive. The commonly used mass fraction of the adhesive (mass ratio to the wetting agent) is selected from 2%-10% (w/w), including but not limited to 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% and 10%.

The disintegrants described in the present invention include but are not limited to cross-linked sodium carboxymethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose calcium, low-substituted hydroxypropyl methyl cellulose, cross-linked polyvinylpyrrolidone, sodium hydroxymethyl starch, and hydroxypropyl starch.

The lubricant described in the present invention includes but is not limited to magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and magnesium lauryl sulfate.

The glidant described in the present invention includes but is not limited to talc, micro-powder silica gel, and silicon dioxide.

The dispersant of the present invention refers to a solvent used to dissolve the coating powder, which will be gradually removed during the tablet coating process. The dispersant includes but is not limited to anhydrous ethanol and water.

The pharmaceutical composition of the present invention can be packaged in any packaging that does not affect the stability of the pharmaceutical preparation. 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 is a composite film bag.

The "effective amount" of the present invention refers to the dosage of the drug that can prevent, alleviate, delay, inhibit or cure the subject's disease. The size of the dosage is related to the drug administration method, the pharmacokinetics of the drug, the severity of the disease, the individual characteristics of the subject (gender, weight, height, age), etc.

The "microcrystalline cellulose/lactose monohydrate" of the present invention refers to microcrystalline cellulose and lactose monohydrate mixed 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, 1:4, and microcrystalline cellulose and lactose monohydrate both include various product models for their industrial use. The "microcrystalline cellulose/pregelatinized starch" and "microcrystalline cellulose/anhydrous calcium hydrogen phosphate" of the present invention are defined as above.

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

Advantageous Effects of the Invention

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

2. The pharmaceutical composition of the present invention is stable in nature and can provide a longer shelf life.

3. The pharmaceutical composition of the present invention has stable process, controllable cost, strong repeatability, and can meet the requirements of industrial production.

Specific implementation plan

The technical solution of the present invention will be described below in conjunction with specific implementation methods, and the above content of the present invention will be further described in detail, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

The compounds of formula (I) used in the following examples or experimental examples can be prepared by referring to the methods of the prior art.

It should be noted that in the following examples, when the formulations are exactly the same, they are given the same formulation number. However, since the production batches may not be exactly the same, for the formulations with the same number, the basic properties, dissolution, particle size distribution and other data of the particles may be slightly different in different examples. Those skilled in the art will understand that this situation The shape belongs to the normal error in the experimental process.

Example 1: Investigation of filler types

1. Preparation process:

1) Weighing: Weigh the compound of formula (I), filler, internal disintegrant and other internal raw materials and auxiliary materials according to the required amount and set aside;

2) Mixing: The weighed raw and auxiliary materials are placed in a wet granulator and mixed evenly;

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

4) Granulation, wet granulation: adding the prepared binder solution to the raw and auxiliary materials mixed in step (2), adjusting the granulator to appropriate parameters, and granulating;

5) Drying and dry granulation: The obtained wet granules are dried in a fluidized bed granulator and dry granulated;

6) Adding excipients and total mixing: adding additional disintegrants, lubricants and glidants according to the particle yield to obtain a final mixture;

7) tableting: compressing the final mixture obtained in step (6) on a tablet press to obtain tablet cores;

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

2. Prescription design

Table 1 Prescription design for filler screening

Table 2 Prescription design for filler screening

3. Investigation results

Table 3 Filler screening results

Table 4 Filler screening results

Table 5 Results of investigation on filler type selection - related substances and contents

4. Conclusions of the investigation:

It can be seen from the results in Table 3 that, except for the combination of microcrystalline cellulose PH101 and pregelatinized starch (2:1), the combination of microcrystalline cellulose PH101 and mannitol (2:1) or mannitol and pregelatinized starch (2:1) as fillers all showed sticking phenomenon; and the combination of microcrystalline cellulose PH101 and pregelatinized starch (2:1) as fillers was also superior to other prescriptions in soft material properties, whether it sticks to the screen and disintegration time, and there was no significant difference in other key inspection results.

From the results in Tables 4 and 5, it can be seen that the soft material prepared by the combination of microcrystalline cellulose PH101/mannitol (4:1) is slightly wet, and the wet granules are easy to squeeze into a mass; 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, the four filler combinations of Formulations 4 to 7 did not cause sticking, and there was no obvious difference in the related substances and their stability.

Example 2: Filler Type Selection

The types of fillers were investigated, mainly focusing on the impact of filler types on the key quality attribute, dissolution.

1. Preparation process

According to the prescription, the preparation process of Example 1 is followed to prepare the prescription.

2. Prescription design

Table 6 Filler type selection - prescription design

3. Investigation results

Table 7 Results of investigation on filler type selection - dissolution

4. Conclusion

The results show that the combination of microcrystalline cellulose and lactose monohydrate dissolves quickly and completely, the combination of microcrystalline cellulose and anhydrous calcium hydrogen phosphate dissolves slowly and incompletely, and the combination of pregelatinized starch and mannitol dissolves relatively slowly.

Example 3: Investigation of filler dosage and ratio

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 8 Prescription design of filler dosage

Table 9 Prescription design of filler dosage

3. Investigation results

Table 10 Results of optimization study on filler dosage

Table 11 Results of optimization of filler dosage - particle size distribution

Table 12 Results of optimization study on filler dosage

Table 13 Results of optimization of filler dosage - dissolution

4. Conclusion

From the above test results, it can be seen that different dosages of microcrystalline cellulose PH101 and pregelatinized starch (2:1, 3:1, 5:1) have no obvious effect on stickiness, particle ratio, dissolution, etc.

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, friability, disintegration and dissolution of the dry granules.

Example 4: Selection of adhesive types

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 14 Adhesive type selection-formulation design

3. Investigation results

Table 15 Results of investigation on adhesive type selection - basic items for tablets

Table 16 Results of the selection of adhesive types - basic items for tablets

4. Conclusion

From the above results, it can be seen that when copolyvidone VA64 is used as a binder, the particles produced are softer and contain more fine powder. The particles are easily ground during tableting, which increases the risk of powder leakage during tableting and excessive fine powder leads to difficulty in tableting. When povidone K30 or hydroxypropyl cellulose is used as a binder, the particle strength is better than that of copolyvidone VA64. There is no significant difference among the three binders in other key indicators such as dissolution curve and stability.

Example 5: Adhesive Type Selection

1. Preparation process

According to the prescription, the preparation process of Example 1 is followed to prepare the prescription.

2. Prescription design

Table 17 Adhesive type selection - prescription design

3. Investigation results

Table 18 Results of adhesive type selection investigation - basic items

Table 19 Results of adhesive type selection investigation - dissolution

4. Conclusion

The results of the investigation show that the properties of soft materials, wet granules and dry granules prepared by using methyl cellulose or sodium carboxymethyl cellulose as binders are inferior to those of povidone K30, and the disintegration time of tablets prepared by using methyl cellulose as a binder is slightly delayed, and the dissolution is slow and incomplete. The disintegration time of tablets prepared by using sodium carboxymethyl cellulose as a binder is significantly delayed, and the dissolution is slow.

Based on the results of Examples 4 and 5, selecting polyvidone K30 or hydroxypropyl cellulose with appropriate viscosity can not only improve the compactness of the granules and ensure the normal and efficient tableting process, but also ensure that the tablets can be quickly and completely dissolved.

Example 6: Optimization of adhesive dosage

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 20 Optimization of adhesive dosage - prescription design

3. Investigation results

Table 21 Results of optimization of adhesive dosage - basic items of tablets

Table 22 Results of optimization study on adhesive dosage - dissolution

4. Conclusion

There was no sticking tendency when the binder dosage was 4%, 3.5% and 3%. There was no significant difference in tablet hardness, disintegration time and dissolution among the three proportions.

Example 7: Selection of disintegrant type

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 23 Disintegrant type selection optimization - prescription design

3. Investigation results

Table 24 Results of the selection of disintegrant types - basic items for tablets

Table 25 Disintegrant Type Selection Investigation Results - Dissolution

4. Conclusion

It can be seen from the above data that, under the condition of similar hardness, cross-linked carboxymethyl cellulose sodium as a disintegrant is significantly superior to cross-linked polyvinylpyrrolidone XL-10 as a disintegrant in terms of disintegration time, dissolution rate and dissolution stability.

Example 8: Selection of disintegrant type

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 26 Disintegrant Type Selection - Formulation Design

3. Investigation results

Table 27 Results of the selection of disintegrant types - basic items

Table 28 Disintegrant Type Selection Investigation Results - 120mg Dissolution

4. Conclusion

The results of the investigation show that the tablets prepared with low-substituted hydroxypropyl cellulose as a disintegrant dissolve slowly and incompletely, and the tablets prepared with sodium carboxymethyl starch as a disintegrant dissolve slowly, and the disintegration effects of both are inferior to that of cross-linked sodium carboxymethyl cellulose.

Example 9: Study on the dosage of disintegrant

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 29 Disintegrant dosage investigation - prescription design

3. Investigation results

Table 30 Results of optimization of disintegrant dosage - basic items of tablets

Table 31 Disintegrant dosage optimization results - dissolution

4. Conclusion

The best way to use crosslinked carboxymethyl cellulose sodium as a disintegrant is to use it in combination with granules and internal and external addition. When the dosage of disintegrant is 3% for internal and external addition, 2% for internal and external addition, and 1% for internal and external addition, under the condition of consistent tablet hardness, the prescriptions with different disintegrant ratios have slight differences in disintegration time, but have little effect on the overall dissolution curve.

Example 10: Selection of lubricant/glidant type

In order to solve the problem of easy sticking during tableting and ensure the normal progress of the production process, the types of lubricants are screened.

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 32 Lubricant/glidant type selection - prescription design

3. Investigation results

Table 33 Lubricant/glidant type selection - sticking situation

4. Conclusion

The results of the investigation show that when sodium stearyl fumarate is selected as the lubricant, obvious sticking phenomenon occurs, while when magnesium stearate is selected as the lubricant, no sticking phenomenon occurs, which ensures the smooth progress of the tableting process.

Example 11: Lubricant dosage study

1. Preparation process

According to the prescription, the preparation process of Example 1 is used to prepare the

2. Prescription design

Table 34 Lubricant dosage investigation-prescription design

3. Investigation results

Table 35 Lubricant dosage optimization results - particle size distribution

Table 36 Lubricant dosage optimization results - basic items for tablets

4. Conclusion

The experiment shows that when the particle size, properties and tablet hardness are basically controlled the same, the tablet surface smoothness of the tablets prepared with the 0.5% magnesium stearate prescription decreases, and there is a risk of sticking; the tablets prepared with the 1% magnesium stearate prescription have no sticking tendency and can meet the quality standard requirements.

Claims (10)

A pharmaceutical composition comprising a compound of formula (I), a filler, a binder and a disintegrant, and optionally, a lubricant and/or a glidant,
Preferably, in terms of weight percentage, the weight ratios of the components are as follows:
The pharmaceutical composition according to claim 1, wherein the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, pregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate, starch, and dextrin; preferably, the weight percentage of the filler is selected from 30%-70%, more preferably 50%-65%. The pharmaceutical composition according to any one of claims 1 to 2, wherein the binder is selected from one or more of povidone VA64, hydroxypropyl cellulose, povidone K30, sodium carboxymethyl cellulose or hypromellose; preferably, the weight percentage of the binder is selected from 1% to 5%. The pharmaceutical composition according to any one of claims 1 to 3, wherein the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone; preferably, the disintegrant is added twice; more preferably, the weight ratio of the two additions of the disintegrant is 5:1-1:3, preferably 2:1-1:2. The pharmaceutical composition according to any one of claims 1 to 4, wherein the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate; preferably, the weight percentage of the lubricant is selected from 0-3%, more preferably 1%-3%. The pharmaceutical composition according to any one of claims 1 to 5, wherein the glidant is selected from silicon dioxide or talc; preferably, the weight percentage of the glidant is selected from 0-3%, more preferably 0-1%. The pharmaceutical composition according to claim 1, comprising, by weight percentage, 20%-50% of the 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 0-1% of a glidant; Preferably, the filler is selected from microcrystalline cellulose, lactose monohydrate, pregelatinized starch, anhydrous calcium hydrogen phosphate One or two; The adhesive is selected from hydroxypropyl cellulose or povidone K30; The disintegrant is selected from cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone; The lubricant is magnesium stearate; the glidant is silicon dioxide. The pharmaceutical composition according to claim 7, wherein the filler is selected from microcrystalline cellulose/lactose monohydrate, microcrystalline cellulose/pregelatinized starch, or microcrystalline cellulose/anhydrous calcium hydrogen phosphate, preferably, the weight ratio of microcrystalline cellulose/lactose monohydrate is selected from 7:1-1:2, the weight ratio of microcrystalline cellulose/pregelatinized starch is selected from 7:1-1:2, and the weight ratio of microcrystalline cellulose/anhydrous calcium hydrogen phosphate is selected from 7:1-1:2. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that the pharmaceutical composition is prepared as a tablet or a capsule. A method for preparing a tablet of the pharmaceutical composition according to any one of claims 1 to 9, characterized in that it comprises the following steps: (1) mixing the compound of formula (I) with a filler and an internal disintegrant to obtain a premix; (2) preparing adhesive solution; (3) mixing the binder solution obtained in step (2) with the premix of step (1) and granulating; (4) drying the granules obtained in step (3) and performing dry granulation; (5) mixing the granules obtained after dry granulation in step (4) with an external disintegrant, an optional lubricant, and an optional glidant to obtain a final mixture; (6) compressing the final mixture obtained in step (5) to obtain a tablet core; (7) coating the tablet core obtained in step (6).