Pharmaceutical composition of fluorine-substituted cyclic amine compound or salt thereof, and preparation method therefor

Abstract

The present application relates to a pharmaceutical composition and preparation of a compound represented by formula (I) or a salt thereof, and a preparation method therefor. Specifically, the present application discloses a pharmaceutical composition using the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition contains the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition of the present application has good drug stability and safety, involves a simple and convenient preparation method, and is suitable for industrial production.

Description

A pharmaceutical composition of a fluorine-substituted cyclic amine compound or its salt and a preparation method thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202311206152.2 filed with the State Intellectual Property Office of China on September 18, 2023, and the contents disclosed in said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of pharmaceutical preparations. Specifically, the present application relates to pharmaceutical compositions, preparations and preparation methods of indanone compounds. Background Art

[0004] Alzheimer's disease (AD) is a fatal primary neurodegenerative disorder of the central nervous system and the most common type of Alzheimer's disease. Acetylcholinesterase inhibitors (AChEIs) are currently the main drugs for the treatment of AD. AChE inhibitors can inhibit cholinesterase activity, increase acetylcholine neurotransmitters in the cerebral cortex and hippocampus, and improve neuro-neuronal synaptic dysfunction and the reduction of acetylcholine transmitters caused by cell death or functional degeneration, thereby improving cognitive function and enhancing memory and thinking abilities. Currently, the main AChE inhibitors on the market are donepezil, huperzine A, and galantamine. According to a survey, among the main anti-dementia drug varieties in sample hospitals in 22 cities in China, Japan's Eisai Co., Ltd.'s AChE inhibitor donepezil accounted for nearly 57% of the market share; my country's independently developed natural product drug huperzine A only accounted for 25% of the market share.

[0005] CN103787954A discloses 2-(4-fluoro-(1-(2-fluorobenzyl))piperidin-4-methyl)-5,6-dimethoxy-2,3-dihydro-1-indanone (hereinafter referred to as the compound of formula (I)). Its specific structure is as follows. It is a new and highly effective acetylcholinesterase inhibitor with high affinity / slow dissociation and high selectivity. It has strong in vitro and in vivo selective inhibitory activity against AChE and can improve learning and memory disorders. Studies have shown that 2-(4-fluoro-(1-(2-fluorobenzyl))piperidin-4-methyl)-5,6-dimethoxy-2,3-dihydro-1-indanone has high oral bioavailability, good blood-brain barrier passage, and high drug concentration in brain tissue (4.4 times the plasma drug concentration). It has strong in vitro and in vivo selective inhibitory activity against AChE and good safety performance, with no hERG or genotoxicity.

[0006] However, the compound of formula (I) or its pharmaceutically acceptable salt is unstable under hot and humid conditions. Therefore, there is still a need to develop a formulation that can provide a stable compound of formula (I) and can be produced on a large scale.

[0007] Summary of the Invention

[0008] In order to solve the above technical problems, the present application adopts a process combining dry mixing and powder tableting to prepare a preparation of the compound of formula (I) with stable drug quality and capable of large-scale production.

[0009] The present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which has the advantages of high solubility, good stability, low total impurity content, excellent content uniformity, simple operation, and ease of industrial production. The present application also provides a method for preparing the pharmaceutical composition.

[0010] The chemical name of the compound of formula (I) is 2-(4-fluoro-(1-(2-fluorobenzyl))piperidin-4-methyl)-5,6-dimethoxy-2,3-dihydro-1-indanone.

[0011] In one aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which further comprises one or more of a filler, a disintegrant, and a lubricant.

[0012] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 0.50 wt% to 20.00 wt%, preferably 0.50 wt% to 5.00 wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof having a particle size (D90) of 5 to 50 μm, preferably 8 to 12 μm.

[0013] In some embodiments, the filler is selected from pharmaceutical excipients with good compressibility. In some embodiments, the filler is selected from fillers comprising microcrystalline cellulose. In terms of weight percentage, the filler accounts for 55.00 wt% to 97.00 wt% of the weight of the pharmaceutical composition, preferably 90.00 wt% to 96.00 wt%.

[0014] In some embodiments, the disintegrant accounts for 0.50 wt%-7.00 wt% of the weight of the pharmaceutical composition, preferably 2.00 wt%-5.50 wt%.

[0015] In some embodiments, the lubricant is selected from one or more of micropowdered silica gel, sodium stearyl fumarate, and magnesium stearate. In terms of weight percentage, the lubricant accounts for 0.10wt%-5.00wt% of the weight of the pharmaceutical composition, preferably 0.20wt%-2.00wt%.

[0016] In some embodiments, the pharmaceutical composition comprises, by weight percentage: 0.5wt%-20wt%, preferably 0.50wt%-5.00wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 55.00wt%-97.00wt%, preferably 90.00wt%-96.00wt% of a filler; 0.50wt%-7.00wt%, preferably 2.00wt%-5.50wt% of a disintegrant; and 0.10wt%-5.00wt%, preferably 0.20wt%-2.00wt% of a lubricant. Preferably, the pharmaceutical composition comprises, by weight percentage: 0.50 wt%-4.00 wt% of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; 92.00 wt%-96.00 wt% of a filler; 2.00 wt%-5.50 wt% of a disintegrant; and 0.20 wt%-2.00 wt% of a lubricant. Most preferably, the pharmaceutical composition comprises, by weight percentage: 0.50 wt%-2.50 wt% of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; 92.00 wt%-96.00 wt% of a filler; 2.00 wt%-5.50 wt% of a disintegrant; and 0.20 wt%-2.00 wt% of a lubricant.

[0017] In a preferred embodiment, the pharmaceutical composition is in a dosage form for oral administration, for example, a tablet.

[0018] In another aspect, the present application provides a method for preparing the pharmaceutical composition according to the present application, wherein the method adopts dry mixing and then powder tableting.

[0019] In another aspect, the present application provides use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating acetylcholinesterase-related nervous system diseases, such as Alzheimer's disease, Parkinson's syndrome, epilepsy, schizophrenia and the like.

[0020] In another aspect, the present application provides a pharmaceutical composition as described herein for treating a neurological disease associated with acetylcholinesterase. In some embodiments, the neurological disease associated with acetylcholinesterase is such as Alzheimer's disease, Parkinson's syndrome, epilepsy, schizophrenia, etc.

[0021] In another aspect, the present application provides a method for treating a neurological disease associated with acetylcholinesterase, the method comprising administering a therapeutically effective amount of the pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the neurological disease associated with acetylcholinesterase is, for example, Alzheimer's disease, Parkinson's syndrome, epilepsy, schizophrenia, etc.

[0022] Compared with the existing technology, the present application has the following advantages and excellent technical effects: the present application adopts a combination of dry mixing and powder tableting technology, the preparation method is simple, the operation is simple, and it is easy to scale up production; the pharmaceutical composition of the present application has good stability, excellent content uniformity, and slow growth of total impurities, which is conducive to the production and storage of the product. DETAILED DESCRIPTION

[0023] Hereinafter, exemplary embodiments of the present application will be described, but the protection scope of the present application is not limited thereto.

[0024] The pharmaceutical composition of the present application

[0025] The present application provides a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0026] In some embodiments, the pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant, and a lubricant.

[0027] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more of a filler, a disintegrant, and a lubricant. The compound of formula (I), 2-(4-fluoro-(1-(2-fluorobenzyl))piperidin-4-methyl)-5,6-dimethoxy-2,3-dihydro-1-indanone, is a novel, highly selective small molecule acetylcholinesterase (AChE) inhibitor used to treat acetylcholinesterase-related neurological diseases, such as Alzheimer's disease.

[0028] In some embodiments, the pharmaceutical composition is a unit-dose pharmaceutical composition. In some embodiments, the mass of the compound of formula (I) or a pharmaceutically acceptable salt thereof in each unit-dose composition is 0.1 mg-4.0 mg. In some embodiments, the mass of the compound of formula (I) in each unit dose of the composition is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg or 4.0 mg; or a range consisting of any of the foregoing values ​​as endpoints. In some embodiments, the mass of the compound of formula (I) in each unit dose of the composition is 0.1 mg-4.0 mg, 0.5 mg-4.0 mg, 1.0 mg-4.0 mg, 1.0 mg-3.0 mg, for example, 1.0 mg, 2.0 mg, 3.0 mg or 4.0 mg.

[0029] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present application is selected from 0.50wt%-20.00wt%, preferably 0.50wt%-5.00wt%, more preferably 0.50wt%-2.50wt%. In some embodiments, in the pharmaceutical composition of the present application, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.50wt%, 0.60wt%, 0.70wt%, 0.80wt%, 0.90wt%, 1.00wt%, 1.50wt%, 2.00wt%, 2.50wt%, 3.00wt%, 3.50wt%, 4.00wt%, 4.50wt%, 5.00wt%, 5.50wt%, 6.00wt%, 6.50wt%, 7.00wt%, 7.50wt%, 8.00wt%, 8.50wt%, 9.00wt% %, 9.50wt%, 10.00wt%, 10.50wt%, 11.00wt%, 11.50wt%, 12.00wt%, 12.50wt%, 13.00wt%, 13.50wt%, 14.00wt%, 14.50wt%, 15.00wt%, 15.50wt%, 16.00wt%, 16.50wt%, 17.00wt%, 17.50wt%, 18.00wt%, 18.50wt%, 19.00wt%, 19.50wt%, or 20.00wt%; or any of the foregoing values ​​as endpoints. In some embodiments, in the pharmaceutical composition of the present application, the amount of the compound of formula (I) is selected from 0.50wt%-5.00wt%. In some embodiments, in the pharmaceutical composition of the present application, the amount of the compound of formula (I) is 0.50wt%, 0.60wt%, 0.70wt%, 0.80wt%, 0.90wt%, 1.00wt%, 1.10wt%, 1.20wt%, 1.30wt%, 1.40wt%, 1.50wt%, 1.60wt%, 1.70wt%, 1.80wt%, 1.90wt%, 2.00wt%, 2.10wt%, 2.20wt%, 2.30wt%, 2.40wt% or 2.50wt%, for example, 0.50wt%-2.50wt%.

[0030] In some embodiments, the filler is selected from pharmaceutical excipients with good compressibility. In some embodiments, the filler can be selected from one or more of microcrystalline cellulose and pregelatinized starch. In some embodiments, the filler accounts for 55.00 wt% to 97.00 wt% of the weight of the pharmaceutical composition, preferably 90.00 wt% to 96.00 wt%.

[0031] In a preferred embodiment, at least 50% or more (eg, 55% or more, 60% or more, or 65% or more) of the filler is a water-insoluble filler.

[0032] In some embodiments, the filler is microcrystalline cellulose, preferably 55.00 wt% to 97.00 wt% of microcrystalline cellulose based on the amount of the pharmaceutical composition.

[0033] In some embodiments, the filler is a filler comprising microcrystalline cellulose, preferably 55.00 wt% to 80.00 wt% of microcrystalline cellulose, preferably 60.00 wt% to 80.00 wt% of microcrystalline cellulose based on the amount of the pharmaceutical composition.

[0034] In some embodiments, the filler comprises pregelatinized starch, preferably 15.00 wt% to 20.00 wt% of pregelatinized starch, preferably 16.00 wt% to 17.00 wt% of pregelatinized starch based on the amount of the pharmaceutical composition.

[0035] In some embodiments, the filler is a combination of microcrystalline cellulose and pregelatinized starch. In a preferred embodiment, the mass ratio of microcrystalline cellulose to pregelatinized starch is 5:1 to 1:1, for example, 5:1 to 1.5:1.

[0036] In some embodiments, the disintegrant is selected from one or more of starch and its derivatives (e.g., dry starch, sodium carboxymethyl starch), low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinyl pyrrolidone. In some embodiments, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl cellulose. For example, the disintegrant is low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose; or low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose.

[0037] In some embodiments, in the pharmaceutical composition according to the present application, the amount of the disintegrant is selected from 0.50wt%-7.00wt%, preferably 2.00wt%-5.50wt%. In some embodiments, in the pharmaceutical composition according to the present application, the amount of the disintegrant is selected from 0.50wt%, 0.60wt%, 0.70wt%, 0.80wt%, 0.90wt%, 1.00wt%, 1.10wt%, 1.20wt%, 1.30wt%, 1.40wt%, 1.50wt%, 1.60wt%, 1.70wt%, 1.80wt%, 1.90wt%, 2.00wt%, 2.10wt%, 2.20wt%, 2.30wt%, 2.40wt%, 2.50wt%, 2.60wt%, 2.70wt%, 2.80wt%, 2.90wt%. %, 3.00wt%, 3.10wt%, 3.20wt%, 3.30wt%, 3.40wt%, 3.50wt%, 3.60wt%, 3.70wt%, 3.80wt%, 3.90wt%, 4.00wt%, 4.10wt%, 4.20wt%, 4.30wt%, 4.40wt%, 4.50wt%, 4.60wt%, 4.70wt%, 4.80wt%, 4.90wt%, 5.00wt%, 5.50wt%, 6.00wt%, 6.50wt% or 7.00wt%; or any range consisting of the aforementioned values ​​as endpoints. In some embodiments, in the pharmaceutical composition of the present application, the amount of the disintegrant is selected from 2.00wt%-4.50wt%.

[0038] In one embodiment, the disintegrant is low-substituted hydroxypropyl cellulose and / or cross-linked sodium carboxymethyl cellulose. In one embodiment, the disintegrant is low-substituted hydroxypropyl cellulose. In one embodiment, the disintegrant is cross-linked sodium carboxymethyl cellulose. In one embodiment, the disintegrant is a combination of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose.

[0039] When the disintegrants are low-substituted hydroxypropyl cellulose and croscarmellose sodium, the two can be combined in any ratio. For example, the mass ratio of low-substituted hydroxypropyl cellulose to croscarmellose sodium can be 10:1 to 1:10, for example, 10:1, 5:1, 1:1, 1:2, 1:3, 1:5 or 1:10.

[0040] In some embodiments, the lubricant is selected from one or more of micropowdered silica gel, sodium stearyl fumarate, and magnesium stearate. In some embodiments, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, and magnesium stearate and micropowdered silica gel.

[0041] In some embodiments, the amount of the lubricant in the pharmaceutical composition according to the present application is selected from 0.10 wt% to 5.00 wt%, preferably 0.20 wt% to 2.00 wt%, by weight percentage. In some embodiments, in the pharmaceutical composition of the present application, the amount of the lubricant is selected from 0.10wt%, 0.20wt%, 0.30wt%, 0.40wt%, 0.50wt%, 0.60wt%, 0.70wt%, 0.80wt%, 0.90wt%, 1.00wt%, 1.10wt%, 1.20wt%, 1.30wt%, 1.40wt%, 1.50wt%, 1.60wt%, 1.70wt%, 1.80wt%, 1.90wt%, 2.00wt%, 2.10wt%, 2.20wt%, 2.30wt%, 2.40wt%, 2.50wt%, 2.60wt%, 2.70wt%, 2.80wt%, 2.90wt%, 3.00wt%, 3.10wt%, 3.20wt%, 3.30wt%, 3.40wt%, 3.50wt%, 3.60wt%, 3.70wt%, 3.80wt%, 3.90wt%, 4.00wt%, 4.10wt%, 4.20wt%, 4.30wt%, 4.40wt%, 4.50wt%, 4.60wt%, 4.70wt%, 4.80wt%, 4.90wt% or 5.00wt%; or a range consisting of any of the foregoing values ​​as endpoints.

[0042] When the lubricant is a combination of magnesium stearate and micropowder silica gel, the mass ratio of magnesium stearate to micropowder silica gel may be 1:1 or more, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1 or 10:1.

[0043] The particle size D90 mentioned in this application refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%. Its physical meaning is that the particles with a particle size smaller than it account for 90%.

[0044] In some embodiments of the present application, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof having a particle size (D90) of 5-50 μm, preferably 8-12 μm.

[0045] In some embodiments, the dosage form of the pharmaceutical composition can be selected from tablets, capsules, powders, pills, pellets, pastes, dispersions or inhalable powders, preferably tablets.

[0046] In some embodiments, the pharmaceutical composition is formulated into a pharmaceutical composition in unit dose form. In some embodiments, the pharmaceutical composition in unit dose form contains 0.5 mg-4 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dose form contains 0.5 mg-4.0 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dose form contains 0.5 mg-3.0 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dose form contains 0.5 mg, 1.0 mg, 1.48 mg, 1.65 mg, 1.7 mg, 2 mg, 2.1 mg, 2.3 mg, 3.0 mg or 4.0 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the pharmaceutical composition in unit dose form is a tablet containing 1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dose form is a tablet containing 2 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dose form is a tablet containing 3 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dose form is a tablet containing 4 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] It should also be understood by those skilled in the art that, in addition to the active ingredient formula (I) compound and filler, disintegrant, or lubricant described above, the pharmaceutical composition of the present application may also include other pharmaceutically acceptable excipients or adjuvants as needed, such as but not limited to diluents, antioxidants, preservatives, colorants, flavorings, coating agents, etc., the selection and amount of which can be adjusted by those skilled in the art according to actual needs. In a preferred embodiment, the coating agent can be selected from a gastric coating agent or an enteric coating agent.

[0049] The function of pharmaceutical excipients is not single, and many excipients have different uses. The stability of the compound of formula (I) is poor and the dosage is small, so the choice of diluent is different. Generally, in the pharmaceutical field, diluents are also fillers. The diluents used in this application are different from common fillers. Considering the improvement of the flowability of the drug and the content uniformity of the finished preparation, the diluents of this application are not preferably lactose and mannitol, because their hygroscopicity and hydrophilicity lead to relatively poor use effect.

[0050] Previously, research on the compound of formula (I) has only been conducted on animal experiments, and the composition used therein cannot meet the requirements of pharmaceutical production and clinical trials, and the stability of the composition of the compound of formula (I) has not been studied in depth. The compound of formula (I) is unstable under hot and humid conditions. According to the pharmaceutical composition of the present application, the quality indicators such as the content uniformity, related substances, and dissolution of the finished product (e.g., tablet) are greatly improved, and the quality of the drug is effectively guaranteed. Moreover, through standardized clinical trials, it has been determined that the pharmaceutical composition of the present application can meet the requirements for large-scale tissue production and clinical research at different stages and industrial preparation processes, and the quality reliability and stability of the pharmaceutical composition of the present application have been confirmed by pharmaceutical studies standardized in all aspects.

[0051] Embodiments of the pharmaceutical composition

[0052] In some embodiments of the present application, the pharmaceutical composition described in the present application comprises, relative to the total amount of the pharmaceutical composition: 0.50wt%-20.00wt%, preferably 0.50wt%-5.00wt% of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; 55.00wt%-97.00wt%, preferably 90.00wt%-96.00wt% of a filler, wherein the filler is selected from pharmaceutical excipients with good compressibility; 0.50wt%-7.00wt%, preferably 2.00wt%-5.50wt% of a disintegrant, wherein the disintegrant is selected from one or more of starch and its derivatives (e.g., dry starch, sodium carboxymethyl starch), low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinyl pyrrolidone; 0.10wt%-5.00wt%, preferably 0.20wt%-2.00wt% of a lubricant, wherein the lubricant is selected from one or more of micropowdered silica gel, sodium stearyl fumarate and magnesium stearate.

[0053] In some embodiments of the present application, the pharmaceutical composition described herein comprises: 0.50wt%-4.00wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65wt%-97.00wt% of a filler, wherein the filler is microcrystalline cellulose; 0.50wt%-7.00wt% of a disintegrant, wherein the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose; and 0.10wt%-5.00wt% of a lubricant, wherein the lubricant is selected from one or more of micropowdered silica gel, sodium stearyl fumarate, and magnesium stearate. In some embodiments of the present application, the pharmaceutical composition described herein comprises: a compound of formula (I) or a pharmaceutically acceptable salt thereof; microcrystalline cellulose; one or more of low-substituted hydroxypropyl cellulose and / or cross-linked sodium carboxymethyl cellulose; and one or more of micropowdered silica gel, sodium stearyl fumarate, and magnesium stearate.

[0054] In some embodiments of the present application, the pharmaceutical composition described herein comprises, relative to the total amount of the pharmaceutical composition: 0.50 wt%-4.00 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65 wt%-97 wt% of a filler, which is a combination of microcrystalline cellulose and pregelatinized starch; 0.50 wt%-7.00 wt% of a disintegrant, which is low-substituted hydroxypropyl cellulose; and 0.10 wt%-5.00 wt% of a lubricant, which is sodium stearyl fumarate or magnesium stearate.

[0055] In some embodiments of the present application, the pharmaceutical composition described in the present application comprises, relative to the total amount of the pharmaceutical composition: 0.50 wt%-4.00 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65 wt%-97 wt% of a filler, which is a combination of microcrystalline cellulose and pregelatinized starch; 0.50 wt%-7.00 wt% of a disintegrant, which is low-substituted hydroxypropyl cellulose; and 0.10 wt%-5.00 wt% of a lubricant, which is a combination of micropowdered silica gel and magnesium stearate.

[0056] In some embodiments of the present application, the pharmaceutical composition described herein comprises, relative to the total amount of the pharmaceutical composition: 0.50 wt%-4.00 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65 wt%-97 wt% of a filler, which is a combination of microcrystalline cellulose and pregelatinized starch; 0.50 wt%-7.00 wt% of a disintegrant, which is low-substituted hydroxypropyl cellulose; and 0.10 wt%-5.00 wt% of a lubricant, which is magnesium stearate.

[0057] In some embodiments of the present application, relative to the total amount of the pharmaceutical composition, the pharmaceutical composition described in the present application comprises:

[0058] 0.50 wt%-2.50 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 92.00 wt%-96.00 wt% of a filler, which is a combination of microcrystalline cellulose and pregelatinized starch; 2.00 wt%-4.50 wt% of a disintegrant, which is cross-linked sodium carboxymethyl cellulose; and 0.20 wt%-2.00 wt% of a lubricant, which is magnesium stearate.

[0059] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof having a particle size (D90) of 5-50 μm, preferably 8-12 μm.

[0060] In some embodiments of the present application, the pharmaceutical composition described herein is in the form of a tablet, wherein the thickness of the tablet is 1-10 mm, preferably 3 mm-5 mm.

[0061] Preparation method

[0062] In another aspect, the present application provides a method for preparing the pharmaceutical composition according to the present application.

[0063] In one embodiment, the present application provides a method for preparing a pharmaceutical composition in tablet form.

[0064] In some embodiments, the pharmaceutical composition of the present application is prepared by dry mixing and then powder tableting.

[0065] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is mixed with a filler, a disintegrant, and a lubricant simultaneously. Alternatively, in some embodiments, the compound of formula (I) is mixed with a filler, a disintegrant, and a lubricant sequentially. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be mixed with a filler first, then with a disintegrant, and then with a lubricant.

[0066] In some embodiments, the API used in this application (the compound of formula (I) or a pharmaceutically acceptable salt thereof) is micronized to obtain a particle size (D90) of 5-50 μm, preferably 8-12 μm. In some embodiments, the API used in this application is micronized by airflow milling and then sieved, preferably using 80-120 mesh.

[0067] In some embodiments, the API used in the present application (the compound of formula (I) or a pharmaceutically acceptable salt thereof) is micronized and then mixed with excipients (except lubricants) in equal amounts, which can greatly improve the dissolution rate of the drug. In some embodiments, the API used in the present application is micronized and then mixed with a filler and a disintegrant in equal amounts, and then the resulting mixture is mixed with a lubricant; or, the API used in the present application is micronized and then mixed with a filler in equal amounts, and then the resulting mixture is mixed with a disintegrant and a lubricant simultaneously, or sequentially; or, the API used in the present application is micronized and then mixed with a portion of the filler in equal amounts, and then the resulting mixture is mixed with the remaining filler, disintegrant, and lubricant simultaneously, or sequentially.

[0068] In the present application, "equal amount addition" refers to mixing the raw material drug with an equal amount or multiple amount (preferably 2, 3 or 4 times) of filler, and then adding a filler equal to the total amount obtained by mixing in the previous step to further mix, and so on, until all the fillers are added. Preferably, the raw material drug and the filler are mixed in equal amounts or 2 times, such as the raw material drug + 2 times the amount of filler. For example, in some embodiments, the mixing is performed by sieving during the equal amount addition process, or by mixing by a mixer. For example, the filler is first mixed with the raw material drug in double the amount of the raw material drug, and then the same multiple is used twice. For example, 2 weight parts of the raw material drug + twice the amount of filler (e.g., microcrystalline cellulose + pregelatinized starch) 4 weight parts are mixed and sieved for the first time, 6 weight parts of filler are taken for the second time and added to the first mixture to continue mixing and sieving, and so on until the components are completely added.

[0069] In some embodiments, when mixing with a mixer, the following parameters can be used for mixing with the filler and disintegrant: a mixing speed of 20 rpm to 40 rpm, preferably 25 rpm to 35 rpm, preferably 30 rpm, and a mixing time of 20 min to 25 min. The above mixing parameters can also be used for mixing in a process of adding equal amounts incrementally.

[0070] In some embodiments, when a mixer is used for mixing, the mixing with the lubricant may adopt the following parameters: a mixing speed of 20 rpm to 40 rpm, preferably 25 rpm to 35 rpm, preferably 30 rpm; and a mixing time of 5 min to 10 min.

[0071] In the mixing operation of the method, the equipment used is a three-dimensional motion mixer.

[0072] In the method of the present application, tableting is performed using a rotary tablet press in a conventional tableting manner.

[0073] In a preferred embodiment, the thickness of the obtained tablet is 1-10 mm, preferably 3-5 mm.

[0074] In some embodiments, the method comprises:

[0075] Micronization treatment: The API is micronized to obtain a particle size (D90) of 5-50 μm, preferably 8-12 μm.

[0076] Equal amounts are added incrementally: the micronized API is mixed with at least a portion of the filler in equal amounts;

[0077] Total mixing: the mixture obtained by mixing equal amounts in successive amounts is mixed with the remaining portion of the filler, disintegrant and lubricant simultaneously or sequentially;

[0078] Compacting: The total blended mixture is compacted.

[0079] In some embodiments, the method of preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application comprises:

[0080] Micronize the raw material to obtain a material with a suitable particle size①;

[0081] Mixing material ① with at least a portion of the filler in equal amounts to obtain a mixture ①, wherein each mixing is performed at 20 rpm to 40 rpm for 20 min to 25 min;

[0082] Mix mixture ①, the remaining portion of the filler, and the disintegrant at 20 rpm to 40 rpm for 20 min to 25 min to obtain mixture ②;

[0083] Add lubricant to mixture ② and mix at 20-40 rpm for 5-10 minutes to obtain a total mixed mixture;

[0084] The total blended mixture is compressed through a die to form tablets with a thickness of 1-10 mm, preferably 3-5 mm.

[0085] In some embodiments, the method of preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application comprises:

[0086] 1) Micronizing the API to obtain a material with a D90 of 8-12 μm (①);

[0087] 2) adding material ① and one of the fillers in equal amounts to obtain a mixture ①, wherein each mixing is performed at 20-40 rpm for 20-25 minutes;

[0088] 3) Mixing mixture ①, the remaining portion of the filler, and the disintegrant at 20-40 rpm for 20-25 min to obtain mixture ②;

[0089] 4) Add lubricant to mixture ② and mix at 20-40 rpm for 5-10 minutes to obtain a total mixed mixture;

[0090] 5) The total blended mixture is pressed into tablets with a thickness of 3-5 mm through a die.

[0091] In a specific embodiment, the method of preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application comprises:

[0092] 1) Micronizing the API to obtain a material with a D90 of 8-12 μm (①);

[0093] 2) Material ① and pregelatinized starch are added in equal amounts to obtain a mixture ①, wherein material ① and pregelatinized starch are first mixed in a ratio of 1:2, and then added in equal amounts to mix, wherein each mixing is performed at 20 rpm-40 rpm for 20 min-25 min;

[0094] 3) mixing mixture ① with microcrystalline cellulose and low-substituted hydroxypropyl cellulose at 20 rpm to 40 rpm for 20 min to 25 min to obtain mixture ②;

[0095] 4) adding magnesium stearate to the mixture ② and mixing at 20-40 rpm for 5-10 minutes to obtain a total mixed mixture;

[0096] 5) The total blended mixture is pressed into tablets with a thickness of 3-5 mm through a die.

[0097] The selection and dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, as well as the filler, disintegrant, and lubricant used in the method are as described above.

[0098] In some embodiments, the pharmaceutical composition is a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition may further include a coating agent. In some embodiments, the coating agent is formed from an aqueous film coating composition, wherein the aqueous film coating composition comprises a film-forming polymer, water and / or alcohol as a carrier, and optionally one or more adjuvants, such as adjuvants known in the film coating art. In some embodiments, the coating agent is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, talc, polyethylene glycol, propylene glycol, castor oil, diethyl phthalate, glyceryl monostearate, and the like.

[0099] In the present application, the compound of formula (I) is micronized (for example, by airflow milling) and combined with a specific excipient composition and powder pressing, so that the quality indicators such as content uniformity, related substances, and dissolution of the intermediates and finished products obtained by dry mixing are greatly improved, thereby effectively ensuring the quality of the drug and meeting the on-site production process requirements for large-scale production and clinical sample preparation to the greatest extent.

[0100] Treatment or prevention methods and uses

[0101] The present application provides the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating nervous system diseases associated with acetylcholinesterase, such as Alzheimer's disease, Parkinson's syndrome, epilepsy, schizophrenia and the like.

[0102] Another aspect of the present application provides a method for treating acetylcholinesterase-related nervous system diseases, such as Alzheimer's disease, Parkinson's syndrome, epilepsy, schizophrenia, etc., which comprises administering a therapeutically effective amount of the above-mentioned pharmaceutical composition according to the present application to a subject in need.

[0103] The present application provides a pharmaceutical composition for treating a neurological disease associated with acetylcholinesterase. In some embodiments, the neurological disease associated with acetylcholinesterase is, for example, Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia, and the like. Beneficial effects

[0104] Compared with the existing technology, the present application has the following advantages and excellent technical effects: The present application adopts a unique equal amount incremental method combined with dry mixing and powder tableting process based on the physical and chemical properties of the drug and the results of the stability investigation, which effectively improves the dispersion uniformity of the drug, protects the chemical composition and structural integrity of the drug, improves the steady-state absorption and distribution of the drug in the body, and confirms the effectiveness of the drug through standardized clinical efficacy and pharmacokinetic studies, so that the drug has a broad clinical application prospect in the oral absorption route of the human body. The preparation method of the pharmaceutical composition of the present application is simple and easy to operate, and can be applied to batch preparation of clinical samples and large-scale production; the solubility of the prepared tablets is significantly improved under the same conditions, and the problem of unqualified content uniformity in the batch production process is solved, and the relevant substances are stable, and the quality is effectively guaranteed.

[0105] For the purposes of this application, unless otherwise stated, the following terms used in the specification and claims shall have the following meanings.

[0106] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0107] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0108] Unless specifically defined otherwise, ratios (including percentages) or parts used herein are by weight.

[0109] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0110] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to a subject.

[0111] In this document, when referring to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the amount is calculated based on the compound represented by formula (I).

[0112] The compound of formula (I) can be administered in its free base form, or in the form of its salts, solvates, and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo. For example, pharmaceutically acceptable salts of the compound of formula (I) are within the scope of this application, and the salts can be produced from various organic and inorganic acids according to methods known in the art.

[0113] In some embodiments, the pharmaceutically acceptable salt of the compound shown in formula (I) of the present application refers to a salt formed by the compound shown in formula (I) and a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is selected from sulfuric acid, carbonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, trifluoroacetic acid, lactic acid, mandelic acid, glycolic acid, p-toluenesulfonic acid, o-toluenesulfonic acid, citric acid, methanesulfonic acid, formic acid, acetic acid, benzoic acid, phenylacetic acid, malonic acid, cinnamic acid, malic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, acrylic acid, crotonic acid, oleic acid and linoleic acid. In some embodiments, the pharmaceutically acceptable acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, malic acid, maleic acid, tartaric acid and fumaric acid. In some embodiments, the molar ratio of the compound of formula (I) to the pharmaceutically acceptable acid in the salt is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0114] The term "administering" or "dosing" or "giving" means physically introducing a composition comprising an active compound into a host or patient or subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral.

[0115] "Unit dosage" or "unit dose" refers to a pharmaceutical composition packaged in a single package for ease of administration. For example, "a pharmaceutical composition in unit dosage form" means each tablet. "A pharmaceutical composition in unit dosage form containing 2 mg of the compound of Formula (I)" means that each final tablet contains 2 mg of the compound of Formula (I).

[0116] "Patient," "subject," or "subject" refers to a mammal, preferably a human.

[0117] "Therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to effect such treatment.

[0118] "Treatment" means any administration of a therapeutically effective amount of a compound, and includes:

[0119] (1) inhibiting the disease in a human being who is experiencing or exhibiting the pathology or symptomology of the disease (i.e., arresting further development of the pathology and / or symptomology), or

[0120] (2) Ameliorating a disease in a human who is experiencing or exhibiting the pathology or symptomology of the disease (i.e., reversing the pathology and / or symptomology).

[0121] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of such publications herein does not constitute an admission that the publication becomes part of the common general knowledge in the art.

[0122] Example

[0123] The following is a further illustrative description of the present invention with reference to specific examples, which do not limit the scope of this application. The auxiliary materials and reagents used are all commercially available products. The instruments and equipment used are commonly used in the art.

[0124] Detection of active compounds:

[0125] Solvent: acetonitrile-water = 50:50; Mobile phase: Mobile phase A: phosphate solution (take 2.72 g of potassium dihydrogen phosphate and 3 mL of triethylamine, dissolve and dilute to 1000 mL with water, and adjust the pH to 6.0 with phosphoric acid)-acetonitrile (90:10); Mobile phase B: acetonitrile; A:B = 61:39 (%).

[0126] Reference solution: Weigh 10 mg of the reference compound of formula (I), accurately weigh it, place it in a 100 mL volumetric flask, and add solvent to dissolve it to the volume to obtain a reference solution with a concentration of 100 μg / mL of the compound of formula (I).

[0127] Test solution: Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 10 mg of the compound of formula (I)) and place it in a 100 mL volumetric flask, add an appropriate amount of solvent, sonicate to dissolve the compound of formula (I), add solvent to the fixed volume, shake well, filter, and accurately measure the filtrate as the test solution.

[0128] Chromatographic conditions

[0129] Detection wavelength: UV270nm; chromatographic column: 4.6mm×15cm; 3.5μm, C18 column, model: Waters Xbridge C18; column temperature: 35℃; flow rate: 1.0ml / min; injection volume: 10μL; run time: 20min.

[0130] Total impurities measurement: HPLC method (Chinese Pharmacopoeia 2015 edition Part IV General Chapter 0512).

[0131] The solvent was acetonitrile-water = 50:50; the mobile phase was: mobile phase A: phosphate solution (2.72 g of potassium dihydrogen phosphate and 3 mL of triethylamine, dissolved in water and diluted to 1000 mL, and the pH was adjusted to 6.0 with phosphoric acid)-acetonitrile (80:20); mobile phase B: acetonitrile;

[0132] Mobile phase gradient table

[0133] Test solution: Take 20 tablets of this product, accurately weigh, grind finely, accurately weigh an appropriate amount (equivalent to 10 mg of the compound of formula (I)) and place it in a 20 mL volumetric flask, add an appropriate amount of solvent, sonicate to dissolve the compound of formula (I), dilute to the scale with solvent, shake well, filter, and use as the test solution.

[0134] Reference solution: Accurately weigh 10 mg of the reference compound of formula (I) and dissolve it in a 20 mL volumetric flask with solvent to make up the volume. Accurately measure 1 mL and place it in a 100 mL volumetric flask, dilute to the mark with solvent, and shake well to prepare the reference solution.

[0135] Chromatographic conditions

[0136] Detection wavelength: UV270nm; chromatographic column: 4.6mm×15cm; 3.5μm, C18 column, model: Waters Xbridge C18; column temperature: 35℃; flow rate: 1.0mL / min; injection volume: 10μL; run time: 50min.

[0137] Dissolution measurement: The tablets were tested using the paddle method according to the second method of dissolution determination in the appendix of Part II of the Chinese Pharmacopoeia (2015 edition). The dissolution medium was 500 mL of pH 4.5 acetate buffer (dissolve 2.99 g of sodium acetate and 14.0 mL of 2 mol / L acetic acid solution in water, dilute to 1000 mL, and shake well).

[0138] Hardness measurement: The tablets were tested using a YPD-300D intelligent tablet hardness tester from Shanghai Huanghai Pharmaceutical Testing Instrument Co., Ltd. Tablets with a hardness range of 2-12 kg are considered ideal.

[0139] Friability measurement: The friability tester was used at Tianjin University Radio Factory, FT-2000A, according to the tablet friability test method (Chinese Pharmacopoeia 2015 edition, Part IV, General Rules 0923).

[0140] Microbial limit measurement: Determine with reference to the microbial limit determination method (General Rules 1105 and 1106 of Part IV of the Chinese Pharmacopoeia 2015 Edition).

[0141] Content uniformity measurement: Chinese Pharmacopoeia 2015 edition Part IV General Chapter 0941, HPLC method (Chinese Pharmacopoeia 2015 edition Part IV General Chapter 0512).

[0142] Preparation Example 1 Preparation of the compound of formula (I)

[0143] The compound of formula (I) was prepared according to the method disclosed in CN 103787954 A.

[0144] Preparation Example 2 Study on the dosage form of the compound of formula (I)

[0145] 2.1 Selection of filler types and proportions

[0146] Commonly used fillers for tablets, such as mannitol, microcrystalline cellulose, pregelatinized starch, etc., were selected. The appearance, hardness, friability, and dissolution of the finished tablets were then used as screening indicators to investigate the effects of the type and proportion of fillers in tablets of the compound of formula (I).

[0147] Table 1 Filler type and ratio selection and its results

[0148] The compound of formula (I) and the excipients listed in Table 1 in the prescribed proportion were mixed evenly, pressed into tablets, and then the relevant indicators of the tablets were measured.

[0149] Among them, Formulation 2 and Formulation 3 were discontinued due to defects in appearance, poor hardness, and unsatisfactory friability. Formulations 1, 4, and 5 were selected for dissolution evaluation. The tablets were incubated at 37°C and 50 rpm in 500 mL of pH 4.5 acetate buffer as the dissolution medium. Samples were taken at 5, 10, 15, 30, 45, and 60 minutes to measure the drug dissolution rate.

[0150] Table 2 Dissolution test results of prescription 1, prescription 4 and prescription 5

[0151] From the dissolution results in Table 2 above, it can be seen that the compound of formula (I) in formulation 1 cannot be completely dissolved in a pH 4.5 medium, while formulations 4 and 5 have better solubility.

[0152] The above screening revealed that when mannitol and pregelatinized starch were used alone as fillers, the tablets produced exhibited sticking or flakes, had poor hardness, and substandard friability. Furthermore, when microcrystalline cellulose was used alone as a filler, tablet dissolution was incomplete. Considering the high cost of directly compressible mannitol and its compatibility issues under high humidity conditions, the combination of pregelatinized starch and microcrystalline cellulose was preferred. While the addition of pregelatinized starch accelerated tablet disintegration and dissolution, it also reduced tablet hardness and affected drug friability. Therefore, further research was conducted based on the filler ratio in Formulation 4.

[0153] 2.2 Selection of disintegrant type and ratio

[0154] Commonly used disintegrants for tablets, such as low-substituted hydroxypropyl cellulose and croscarmellose sodium, were selected. The effects of the type and proportion of disintegrant in tablets containing the compound of formula (I) were examined using the appearance, disintegration time, hardness, friability, and dissolution of the finished tablets as screening criteria. Microcrystalline cellulose and pregelatinized starch were used as fillers, and the specific formulation is shown in Table 3 below.

[0155] Table 3 Disintegrant type and dosage selection and its results

[0156] The compound of formula (I) in the prescribed proportions and the remaining excipients in the prescribed proportions listed in Table 3 were uniformly mixed and compressed into tablets. The tablets were then tested for relevant indices. Comparison of disintegration times revealed that different disintegrants exhibited essentially equivalent disintegration performance during use, and that increasing the amount of disintegrant accelerated tablet disintegration. The hardness of the compressed tablets was also tested. Comparison of hardness and flowability revealed that low-substituted hydroxypropyl cellulose was more likely to achieve higher hardness. The prepared tablets were incubated at 37°C and 50 rpm in 500 mL of pH 4.5 acetate buffer as the dissolution medium. Samples were taken at 5, 10, 15, 30, 45, and 60 minutes to determine drug dissolution.

[0157] Table 4 Dissolution test results of prescription 4, prescription 7 and prescription 8

[0158] From the above results, it can be seen that the three dosages of low-substituted hydroxypropyl cellulose can make the drug dissolution rate reach more than 80% in 30 minutes; as the dosage of disintegrant increases, the drug dissolution becomes faster. In order to ensure rapid disintegration of tablets and considering cost issues, the dosage of disintegrant needs to be controlled.

[0159] 2.3 Lubricant type and ratio selection

[0160] Commonly used lubricants for tablets, such as magnesium stearate, sodium stearyl fumarate, talc, and micropowdered silica gel, were selected. The appearance, hardness, friability, and dissolution of the finished tablets were used as screening criteria to investigate the effects of lubricant type and ratio in tablets containing the compound of formula (I). Microcrystalline cellulose and pregelatinized starch were used as fillers, and low-substituted hydroxypropyl cellulose was used as a disintegrant. The specific formulation is shown in Table 5 below.

[0161] Table 5 Lubricant type and ratio selection and its results

[0162] The compound of formula (I) and the excipients listed in the table were mixed uniformly in the prescribed proportions and compressed into tablets. The tablets were then tested for relevant indices. Formulations 11 and 13 were discontinued due to flake breakage and sticking, respectively. Formulations 9, 10, and 12 were selected for dissolution evaluation. The tablets were incubated at 37°C, 50 rpm, and 500 mL of pH 4.5 acetate buffer was used as the dissolution medium. Samples were taken at 5, 10, 15, 30, 45, and 60 minutes to determine drug dissolution.

[0163] Table 6 Dissolution test results of prescription 9, prescription 10 and prescription 12

[0164] From the comparison of the dissolution results of the above prescriptions, it can be seen that the dissolution data of prescriptions 9 and 12 are better.

[0165] Through the above screening, it was found that the tablets of the compound of formula (I) prepared using magnesium stearate as a lubricant had a hardness that met the requirements and had good dissolution behavior.

[0166] In summary, the intermediate powders of Prescriptions 4 and 12 have good fluidity, good mixing uniformity, and the hardness after tableting meets the requirements. In addition, the dosage of disintegrant is moderate, which can ensure the rapid disintegration of tablets. Therefore, Prescriptions 4 and 12 are the preferred prescriptions.

[0167] Conclusion: The research results of the above different formulations show that in terms of excipient selection, magnesium stearate can significantly increase the solubility of the drug and improve the dissolution of tablets compared with talc.

[0168] 2.4 Composition ratio in the preparation formula

[0169] Dissolution analysis

[0170] According to the second method of dissolution determination in the appendix of Part II of the 2015 edition of the Chinese Pharmacopoeia, 500 mL of pH 4.5 acetate buffer was used as the dissolution medium. The dissolution profile of the drug was measured at 5, 10, 15, 30, 45, and 60 min. The results are shown in Table 8.

[0171] Table 8 Dissolution test results of prescriptions 14 to 22 (%)

[0172] From the comparison of the above prescription dissolution results, it can be seen that the dissolution data of the pharmaceutical composition with the ratio screened according to the present invention is better.

[0173] Through the above screening, it was found that the hardness of the compound of formula (I) tablets obtained according to the ratio of the present invention met the requirements and had good dissolution behavior.

[0174] 2.5 Particle size screening

[0175] The particle size of the raw material of the compound of formula (I) may have a certain impact on the disintegration and dissolution of the preparation. At the same time, the product specification is small (2 mg / tablet), and the large difference in particle size can easily cause uneven mixing and unqualified content uniformity. Therefore, the raw material of the compound of formula (I) was screened, and the raw material of different particle sizes was mixed with the excipients in the prescribed amount, pressed into tablets, and the hardness and dissolution were used as indicators to evaluate.

[0176] Table 9 Prescription composition:

[0177] The dissolution profiles of the compound of formula (I) tablets prepared in process 1, process 2, process 3, and process 4 were measured at 37°C, 50 rpm, and 500 mL of pH 4.5 acetate buffer as the dissolution medium at 5, 10, 15, 30, 45, and 60 minutes. The results are shown in Table 10.

[0178] Table 10 Dissolution test results of tablets obtained by process 1, process 2, process 3 and process 4

[0179] f2* is the value of process 2 or process 3 compared with process 1 or process 2; RSD is the relative standard deviation, where RSD less than 5% meets the requirements

[0180] The results show that the dissolution of the compound of formula (I) tablets prepared with different particle size ranges of raw materials in pH 4.5 acetate buffer can be compared. It can be found that the dissolution endpoint test results at the same time under the four process conditions are similar, and all can meet the dissolution quality test standards. However, from the dissolution curve, it can be observed that as the particle size decreases, such as in process 2 and process 3, the initial dissolution rate of the tablets becomes faster and faster, while the initial dissolution rate of the tablets with larger particle size, such as in process 4, is significantly slower. In addition, the RSD values ​​of process 3 and process 4 are significantly larger, indicating that the dissolution difference is large and uneven. Taking into account that the particle size control range between process 1 and process 2 can better meet the requirements of clinical research on related indicators such as Cmax and AUC, and also show certain advantages in terms of quality uniformity and stability, the preferred particle size range D90 of the raw material of formula (I) for micro-differentiation treatment is 8-12 μm, and the mesh size should be sieved to 80 mesh before production to prevent agglomeration.

[0181] 2.6 Screening of mixing time

[0182] Taking Prescription 14 as an example, this product has a dosage of 2 mg and a tablet weight of 130 mg, with the active ingredient comprising 1.5%. Mixing uniformity directly affects the content uniformity of the compound of formula (I) tablets. Directly mixing the drug with the prescribed proportion of excipients is difficult to achieve uniform mixing. A stepwise mixing method was proposed for this product, with a mixer and a selected mixing time. The specific process is shown in Table 11.

[0183] Table 11 Process screening of mixing time

[0184] Samples were taken from the three corners and the upper and lower middle parts of the container, and the content was determined using the assay method. The mixing uniformity was calculated to assess the mixing time. The results are summarized in Table 12.

[0185] Table 12 Measurement results of intermediate powders obtained from process 5 to process 9

[0186] It can be seen from the results that the angle of repose of the intermediate powder meets the requirements at different mixing times, and the angle of repose tends to decrease with increasing mixing time; the content of different parts of the intermediate powder is low when the mixing time is 5min-10min after each excipient is added; when mixed for 15min, the RSD value is greater than 5%, which does not meet the requirements; when the mixing time is 20min and 25min, that is, the RSD value of process 8 and process 9 is less than 5%, and the mixing uniformity meets the requirements, so the mixing time range for adding excipients except magnesium stearate is selected to be 20min-25min.

[0187] Since magnesium stearate has strong hydrophobicity, the mixing time of magnesium stearate was screened. The specific process is shown in Table 13 below.

[0188] Table 13 Lubricant mixing time optimization

[0189] Samples were taken from the three corners and the upper and lower middle parts of the container, and the content was determined using the assay method. The mixing uniformity was calculated to assess the mixing time. The results are summarized in Table 14.

[0190] Table 14 Measurement results of mixed powders of process 10-process 11

[0191] The results show that the RSD value is less than 5% when the mixing time is 5-10 minutes after the addition of magnesium stearate, and the mixing uniformity and repose angle meet the requirements. Therefore, the mixing time range of magnesium stearate addition is selected to be 5-10 minutes.

[0192] After further research, regarding the equal amount increment method, the pharmaceutical composition of the compound of formula (I) can be prepared by the following method:

[0193] 1) Micronizing the API to obtain a material with a D90 of 8-12 μm (①);

[0194] 2) adding material ① and pregelatinized starch in equal amounts to obtain a mixture ①, wherein material ① and pregelatinized starch are first mixed in a ratio of 1:2, and then added in equal amounts to mix;

[0195] 3) thoroughly mixing the mixture ① with microcrystalline cellulose and low-substituted hydroxypropyl cellulose to obtain a mixture ②;

[0196] 4) adding magnesium stearate to the mixture ② and continuing to mix for 5-10 minutes to obtain a total mixed mixture;

[0197] 5) The total blended mixture is pressed into tablets with a thickness of 3-5 mm through a die.

[0198] Example 1

[0199] Table 15 The composition of pharmaceutical composition 1 is as follows:

[0200] Conduct scale-up studies on three batches of product, with scales of 3,000 tablets / batch, 3,000 tablets / batch, and 10,000 tablets / batch, respectively, to achieve the following objectives:

[0201] Investigate the main links of the production process and further optimize the process conditions;

[0202] Determine the equipment and production methods suitable for process production to ensure product quality and reproducibility after process expansion.

[0203] Table 16-1 Summary of production process changes

[0204] Table 16-2 Analysis results of quality control of three batches of samples

[0205] Yield refers to the ratio of actual output to theoretical batch; yield examines the continuity and stability of the process production. A high yield means good process control and relatively more guaranteed quality.

[0206] Comparative Example

[0207] Table 17 The composition of pharmaceutical composition 2 is as follows:

[0208] The raw materials were sieved through 80 mesh and the auxiliary materials were sieved through 60 mesh to remove lumps and obtain uniform powder.

[0209] Weigh the prescribed amount of the compound of formula (I) and add the prescribed amount of croscarmellose sodium, lactose, and microcrystalline cellulose in a progressively increasing manner. Sieve and mix thoroughly. Then add magnesium stearate and micro-powdered silica gel (1:1), sieve and mix thoroughly. Capsule-shaped tablets are punched. Samples are taken and tested for hardness and weight variation, and the results meet the requirements. Package in polyvinyl chloride bags.

[0210] Effect Example 1

[0211] High humidity test

[0212] Tablet samples from different examples were taken and subjected to impurity determination and dissolution tests at 0 days, 5 days, 10 days, and 30 days under high humidity conditions of 25°C and 90% RH. The test results are as follows:

[0213] Table 18 Tablet high humidity test results

[0214] Conclusion: The research results of the above examples of different prescriptions and processes show that in Example 1, due to the selection of a prescription based on insoluble excipients, the properties and impurities of the product under high relative humidity conditions are less changed than those of other examples, and the quality of the finished product is more stable.

[0215] Light test

[0216] A 30 mg sample of the tablet of Example 1 was taken and subjected to impurity determination and dissolution tests under light conditions at 0 days, 5 days, 10 days, and 30 days. The test results are as follows:

[0217] Table 19 Results of the light stability test of the tablets of Example 1

[0218] High temperature test

[0219] Tablet samples of Example 1 were taken and subjected to impurity determination and dissolution tests at a high temperature of 60° C. for 0 days, 5 days, 10 days, and 30 days. The test results are as follows:

[0220] Table 20 Study results of high temperature stability test of tablets in Example 1

[0221] Accelerated experiments

[0222] Three batches of tablet samples from Example 1 were subjected to impurity determination and dissolution tests at 0 day and accelerated temperatures of 1 month, 2 months, 3 months, and 6 months (40°C ± 2°C, 75% ± 5% RH);

[0223] The results are as follows:

[0224] Table 21 Results of accelerated test on tablets of Example 1

[0225] Long-term experiments

[0226] Tablet samples of Example 1 were taken and subjected to impurity determination and dissolution tests at 0 day and long-term for 3 months and 6 months (25±2°C / 60±5%RH). The test results are as follows:

[0227] Table 22 Results of long-term study on tablets of Example 1

[0228] Conclusion: From the research results in Tables 18 to 22 above, it can be seen that the pharmaceutical composition of the present application (represented by Example 1) can meet high-standard quality requirements and has excellent stability.

[0229] Effect Example 2 Pharmacokinetics of a single dose in healthy Chinese subjects

[0230] Trial Design: Single-center, randomized, double-blind, placebo-controlled, dose-escalation, single-dose.

[0231] Number of subjects: Planned inclusion: 52, final analysis: 51.

[0232] Subject inclusion criteria:

[0233] 18 years old ≤ ≤ 40 years old, healthy subjects, regardless of gender;

[0234] Weight: Men ≥50 kg, Women ≥45 kg; and Body Mass Index (BMI) ≤ 19 ≤ 26 kg / m 2 ;

[0235] No history of heart, liver, kidney, digestive tract, nervous system, mental or metabolic disorders, or severe infection or injury;

[0236] No plans to have children during the trial and within 3 months after the last medication and able to take reliable contraceptive measures;

[0237] Fully understand the purpose and requirements of this trial, voluntarily participate in the clinical trial and sign the written informed consent, and be able to complete the entire trial process according to the trial requirements.

[0238] Subject exclusion criteria:

[0239] Patients with a known history of allergy to the test drug ingredients or similar drugs, a history of allergic diseases or allergic constitution;

[0240] Patients with a history of diseases affecting the central nervous system, cardiovascular system, digestive system, respiratory system, urinary system, blood system, metabolic disorders, malignant tumors, or other diseases that are not suitable for clinical trials (such as a history of mental illness);

[0241] Any surgical condition or illness that may significantly affect drug absorption, distribution, metabolism, and excretion, or any surgical condition or illness that may pose a hazard to the subjects participating in the trial; such as a history of gastrointestinal surgery (gastrectomy, gastrointestinal anastomosis, intestinal resection, etc.), urinary tract obstruction or dysuria, gastroenteritis, peptic ulcer, gastrointestinal bleeding, etc.;

[0242] History of clinically significant electrocardiogram (ECG) abnormalities, or the following ECG abnormalities at screening or baseline: PR interval > 220ms, QRS complex duration > 120ms, QTcB > 450ms;

[0243] Laboratory tests show clinically significant abnormalities [a. Liver function laboratory tests such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or bilirubin show clinically significant abnormalities, suggesting liver disease or liver damage, or are defined as exceeding 1.5 times the upper limit of normal; b. Creatinine or urea nitrogen exceeds the upper limit of normal and shows clinical significance, or urine component abnormalities show clinical significance (such as proteinuria, occult blood in urine, white blood cells in urine, etc.); c. Clinically significant abnormalities in routine blood tests, such as anemia, leukopenia, and significantly decreased platelets];

[0244] Those who donated blood or lost blood ≥400 mL within 3 months before enrollment;

[0245] Those who had taken any medication within 2 weeks before enrollment;

[0246] Pregnant or breastfeeding women;

[0247] Participated in other drug clinical trials within 1 month before enrollment;

[0248] Those with a history of drug use or a positive urine test for drug abuse;

[0249] Current or past alcoholics (drinking more than 196g of alcohol per week, such as 360ml of beer, 45ml of 40% alcohol liquor, or 150mL of wine), or those with a positive breath alcohol test;

[0250] Smoking ≥10 cigarettes per day;

[0251] Those who are positive for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), syphilis antibody and HIV antibody (HIV-Ab);

[0252] Those who are deemed by the researchers to be unsuitable for the trial due to other factors.

[0253] Trial drug:

[0254] Specifications: 0.5 mg / tablet, 1 mg / tablet, 2 mg / tablet, prepared according to the method of Example 1;

[0255] Dosage: 0.5mg, 1mg, 2mg, 4mg, 8mg, 12mg.

[0256] Dosage: Single dose, take with appropriate amount of water (240ml).

[0257] Control drug (placebo):

[0258] Specifications: 1mg / tablet, 2mg / tablet;

[0259] Dose:NA.

[0260] Dosage: Single dose, take with appropriate amount of water (240ml).

[0261] Pharmacokinetic parameter evaluation indicators: peak time (Tmax), peak concentration (Cmax), area under the plasma concentration-time curve from time 0 to t (AUC0 －t ), the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞ ), elimination rate constant (λz), half-life (t 1 / 2 ), total clearance / bioavailability (CL / F), apparent volume of distribution / bioavailability (Vd / F).

[0262] Pharmacokinetic Analysis: Pharmacokinetic parameters were calculated using the non-compartmental model (NCA) method and Phoenix WinNonlin 7.0 data analysis software. Descriptive statistical analysis of pharmacokinetic parameters was performed, providing the number of cases, arithmetic mean, standard deviation, minimum, median, maximum, and coefficient of variation (CV). Tmax was expressed as the median (minimum - maximum). AUC and Cmax were log-normally distributed, and the geometric mean was also provided. The relationship between dose and plasma drug exposure was evaluated by plotting scatter plots of log-transformed pharmacokinetic parameters (AUC and Cmax) against log dose. In addition, a power model was used to further explore the linear relationship between dose and plasma drug exposure.

[0263] Pharmacokinetic results:

[0264] When healthy volunteers were orally administered a single fasting dose of the compound of formula (I) tablet, the compound of formula (I) in plasma reached its peak concentration (median) at 0.75 to 1.5 hours, and the average plasma drug elimination half-life was 14.2 to 32.1 hours. When the dosage was 1 mg, 2 mg, 4 mg, 8 mg, and 12 mg, the peak drug concentrations were 1.19 ng / ml, 2.43 ng / ml, 8.61 ng / ml, 16.4 ng / ml, and 23.5 ng / ml, respectively. The AUC 0-∞ The correlation and linear analysis of the drug's plasma exposure and the dose showed that within the range of 1 mg to 12 mg, the Cmax and AUC of the compound of formula (I) were 14.7 h*ng / ml, 29.8 h*ng / ml, 69.4 h*ng / ml, 135 h*ng / ml and 220 h*ng / ml, respectively. 0-∞ The β values ​​of β-catenin and β-catenin were 1.22 and 1.08, respectively. In the dose range of 1 to 12 mg, Cmax and AUC 0-∞ As the dosage increases, AUC 0-∞ The increase in the proportion of the drug exposure was basically consistent with the increase in the dose. The inter-individual variation in plasma drug exposure was about 30%.

[0265] The plasma metabolite M4 reaches its peak (median) in 1.5-1.75 hours, and the average plasma elimination half-life is 2.88-7.19 hours. At a dose of 1-12 mg, the metabolic ratio (MR_Cmax) of M4 is 0.238-0.377 ng / ml, and the MR_AUC is 0.153-0.220 h*ng / ml.

[0266] in conclusion

[0267] Following a single oral dose of the compound of formula (I) tablet on an empty stomach in healthy volunteers, the compound of formula (I) reached peak plasma concentrations (median) between 0.75 and 1.5 hours, with an average plasma elimination half-life of 14.2 to 32.1 hours. Within the 1-12 mg dose range, Cmax and AUC0-∞ increased with increasing dose, with the AUC0-∞ increasing in proportion to the dose increase.

[0268] No SAEs occurred within the dose range of 1-12 mg, and no grade 3 or higher treatment-emergent adverse events (TEAEs) occurred. Overall, the safety and tolerability of a single dose of the compound of formula (I) tablets in healthy Chinese subjects were good, which is consistent with the safety risks suggested by preclinical studies of the compound of formula (I) tablets and the similar drug donepezil.

[0269] In summary, the tablets of the compound of formula (I) prepared by the present invention have good in vivo effects, and the exposure in vivo is proportional to the dosage. The prepared tablets have stable quality, good mixing uniformity, and meet the hardness requirements after tableting. The dosage of disintegrant is moderate, which can ensure rapid disintegration of the tablets. The direct powder tableting process adopted by the present invention is relatively simple, does not require granulation and drying, simplifies the process flow, can improve production efficiency, and save energy.

Claims

1. A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein: The pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant and a lubricant.

2. The pharmaceutical composition according to claim 1, characterized in that In terms of weight percentage, the pharmaceutical composition comprises 0.50 wt % to 20.00 wt % of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, characterized in that In terms of weight percentage, the pharmaceutical composition comprises 0.50wt%-5.00wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof with a D90 particle size of 5-50 μm.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof with a D90 particle size of 8-12 μm.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The filler is selected from pregelatinized starch and microcrystalline cellulose, and the filler accounts for 55.00wt%-97.00wt% of the weight of the pharmaceutical composition; The disintegrant is selected from one or more of starch and its derivatives, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinyl pyrrolidone, and the disintegrant accounts for 0.50wt%-7.00wt% of the weight of the pharmaceutical composition; or The lubricant is selected from one or more of micro powder silica gel, sodium stearyl fumarate and magnesium stearate, and the lubricant accounts for 0.10wt%-5.00wt% of the weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The filler is selected from pregelatinized starch and microcrystalline cellulose, and the filler accounts for 90.00wt%-96.00wt% of the weight of the pharmaceutical composition; The disintegrant is selected from one or more of starch and its derivatives, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinyl pyrrolidone, and the disintegrant accounts for 2.00wt%-5.50wt% of the weight of the pharmaceutical composition; or The lubricant is selected from one or more of micro powder silica gel, sodium stearyl fumarate and magnesium stearate, and the lubricant accounts for 0.20wt%-2.00wt% of the weight of the pharmaceutical composition.

8. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The filler is a combination of microcrystalline cellulose and pregelatinized starch; The disintegrant is selected from low-substituted hydroxypropyl cellulose and / or cross-linked sodium carboxymethyl cellulose; or The lubricant is selected from micro powder silica gel and / or magnesium stearate.

9. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The pharmaceutical composition comprises: 0.50wt%-4.00wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65wt%-97.00wt% of a filler, wherein the filler is microcrystalline cellulose; 0.50wt%-7.00wt% of a disintegrant, wherein the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose; and 0.10wt%-5.00wt% of a lubricant, wherein the lubricant is selected from one or more of micropowdered silica gel, sodium stearyl fumarate and magnesium stearate; Alternatively, the pharmaceutical composition comprises: 0.50wt%-4.00wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65wt%-97wt% of a filler, wherein the filler is a combination of microcrystalline cellulose and pregelatinized starch; 0.50wt%-7.00wt% of a disintegrant, wherein the disintegrant is low-substituted hydroxypropyl cellulose; and 0.10wt%-5.00wt% of a lubricant, wherein the lubricant is sodium stearyl fumarate or magnesium stearate; Alternatively, the pharmaceutical composition comprises: 0.50wt%-4.00wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65wt%-97wt% of a filler, wherein the filler is a combination of microcrystalline cellulose and pregelatinized starch; 0.50wt%-7.00wt% of a disintegrant, wherein the disintegrant is low-substituted hydroxypropyl cellulose; and 0.10wt%-5.00wt% of a lubricant, wherein the lubricant is a combination of micro powder silica gel and magnesium stearate; Alternatively, the pharmaceutical composition comprises: 0.50wt%-4.00wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65wt%-97wt% of a filler, wherein the filler is a combination of microcrystalline cellulose and pregelatinized starch; 0.50wt%-7.00wt% of a disintegrant, wherein the disintegrant is low-substituted hydroxypropyl cellulose; and 0.10wt%-5.00wt% of a lubricant, wherein the lubricant is magnesium stearate.

10. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The pharmaceutical composition comprises: 0.50wt%-2.50wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 92.00wt%-96.00wt% of a filler, wherein the filler is a combination of microcrystalline cellulose and pregelatinized starch; 2.00wt%-4.50wt% of a disintegrant, wherein the disintegrant is low-substituted hydroxypropyl cellulose; and 0.20wt%-2.00wt% of a lubricant, wherein the lubricant is magnesium stearate.

11. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The pharmaceutical composition is in the form of a tablet.

12. The pharmaceutical composition according to claim 11, characterized in that The thickness of the tablet is 1 mm-10 mm.

13. The pharmaceutical composition according to claim 12, characterized in that The thickness of the tablet is 3mm-5mm.

14. A method for preparing the pharmaceutical composition according to any one of claims 1 to 13, the method comprising: Micronization: Micronization of APIs; Equal amount incremental mixing: the micronized API and at least a portion of the filler are incrementally mixed in equal amounts; Total mixing: the mixture obtained by mixing equal amounts in successive additions is mixed with the remaining portion of the filler, the disintegrant and the lubricant simultaneously, or mixed in sequence, to obtain a total mixed mixture; Compacting: The total blended mixture is compacted.

15. The method according to claim 14, comprising: 1) Micronizing the raw material to obtain material ①; 2) mixing material ① with at least a portion of the filler in equal amounts to obtain a mixture ①; 3) Mixing the mixture ①, the remaining portion of the filler and the disintegrant at 20 rpm-40 rpm for 20 min-25 min to obtain a uniform mixture ②; 4) Add lubricant to mixture ② and mix at 20 rpm-40 rpm for 5 min-10 min to obtain a total mixed mixture; 5) The total blended mixture is pressed into tablets with a thickness of 1-10 mm using a die.

16. The method according to claim 14 or 15, characterized in that The raw material is micronized to a D90 particle size of 5-50 μm.

17. The method according to claim 16, characterized in that The raw material drug is micronized to a D90 particle size of 8-12 μm.

18. The method according to any one of claims 14 to 17, characterized in that: In equal increments, mix at 20 rpm to 40 rpm for 20 min to 25 min each time.

19. The method according to any one of claims 14 to 18, characterized in that Made into tablets with a thickness of 1-10mm.

20. The method according to any one of claims 14 to 19, wherein: The method comprises: 1) Micronizing the API to obtain a material with a D90 of 8-12 μm①; 2) Material ① and one of the fillers are added in equal amounts to obtain a mixture ①, wherein each mixing is performed at 20 rpm to 40 rpm for 20 min to 25 min; 3) Mixing mixture ①, the remaining portion of the filler, and the disintegrant at 20 rpm to 40 rpm for 20 min to 25 min to obtain mixture ②; 4) Add lubricant to mixture ② and mix at 20 rpm-40 rpm for 5 min-10 min to obtain a total mixed mixture; 5) The total blended mixture is pressed into tablets with a thickness of 3-5 mm through a die.

21. The method according to any one of claims 14 to 20, wherein: The method comprises: 1) Micronizing the API to obtain a material with a D90 of 8-12 μm①; 2) adding material ① and pregelatinized starch in equal amounts to obtain a mixture ①, wherein material ① and pregelatinized starch are first mixed in a ratio of 1:2, and then mixed in equal amounts, wherein each mixing is performed at 20 rpm to 40 rpm for 20 min to 25 min; 3) mixing mixture ① with microcrystalline cellulose and low-substituted hydroxypropyl cellulose at 20 rpm to 40 rpm for 20 min to 25 min to obtain mixture ②; 4) adding magnesium stearate to the mixture ② and mixing at 20 rpm to 40 rpm for 5 min to 10 min to obtain a total mixed mixture; 5) The total blended mixture is pressed into tablets with a thickness of 3-5 mm through a die.

22. Use of the pharmaceutical composition according to any one of claims 1 to 13 or the pharmaceutical composition prepared according to the method according to any one of claims 14 to 21 in the preparation of a medicament for treating a nervous system disease associated with acetylcholinesterase.

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