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

Abstract

The invention relates to a pharmaceutical composition of a compound shown in a formula (I) or a salt thereof, a preparation and a preparation method thereof. Specifically, the invention discloses a pharmaceutical composition taking a compound as shown in a formula (I) or pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition contains a compound as shown in a formula (I) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials. The pharmaceutical composition provided by the invention has good pharmaceutical stability and safety, and the preparation method is simple and convenient and is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular, relates to a pharmaceutical composition and preparation of indanone compounds and a preparation method thereof. Background Art

[0002] Alzheimer's disease (AD) is a fatal neurodegenerative disease of the central nervous system and the most common type of Alzheimer's disease. Acetylcholinesterase inhibitors (AChEI) are currently the main drugs for the treatment of AD. AChE inhibitors can increase acetylcholine neurotransmitters in the cerebral cortex and hippocampus by inhibiting cholinesterase activity, 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 ability. Currently, the AChE inhibitors on the market are mainly donepezil, huperzine A and galantamine. According to the survey, among the main varieties of anti-dementia drugs in sample hospitals in 22 cities in China, Japan's Eisai Company's AChE inhibitor donepezil accounted for nearly 57%; my country's independently developed natural product drug huperzine A only accounted for 25% of the market share.

[0003] CN103787954A discloses 2-(4-fluoro-(1-(2-fluorobenzyl))piperidin-4-methyl)-5,6-dimethoxy-2,3-dihydro-1-indanone (hereinafter referred to as formula (I) compound), the specific structure of which is as follows. It is a novel and highly efficient acetylcholinesterase inhibitor with high affinity / slow dissociation and high selectivity, and has strong in vivo and in vitro selective inhibitory activity of 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 vivo and in vitro selective inhibitory activity of AChE, good safety performance, and no hERG and genetic toxicity.

[0004]

[0005] However, the compound of formula (I) or its pharmaceutically acceptable salt is unstable under hot and humid conditions, and therefore there is still a need to develop a formulation that can provide a stable compound of formula (I) and can be mass-produced. Summary of the invention

[0006] In order to solve the above technical problems, the present invention adopts a process combining dry mixing and powder tableting to prepare a preparation of the compound of formula (I) which has stable drug quality and can be mass-produced.

[0007] The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition has the advantages of high solubility, good stability, low total impurity content, excellent content uniformity, simple operation and easy industrial production. The present invention also provides a method for preparing the pharmaceutical composition.

[0008]

[0009] 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.

[0010] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, further comprising one or more of a filler, a disintegrant and a lubricant.

[0011] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 0.50wt%-20.00wt%, preferably 0.50wt%-5.00wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof having a particle size (D90) of 5-50μm, preferably 8-12μm.

[0012] In some embodiments, the filler is selected from pharmaceutical excipients with good compressibility. In some embodiments, the filler is selected from fillers containing microcrystalline cellulose. In terms of weight percentage, the filler accounts for 55.00wt%-97.00wt% of the weight of the pharmaceutical composition, preferably 90.00wt%-96.00wt%.

[0013] In some embodiments, the disintegrant accounts for 0.50 wt%-7.00 wt%, preferably 2.00 wt%-5.50 wt%, of the weight of the pharmaceutical composition.

[0014] 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%.

[0015] 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: 0.50wt%-4.00wt% of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; 92.00wt%-96.00wt% of a filler; 2.00wt%-5.50wt% of a disintegrant; 0.20wt%-2.00wt% of a lubricant. Most preferably, the pharmaceutical composition comprises, by weight percentage: 0.50wt%-2.50wt% of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; 92.00wt%-96.00wt% of a filler; 2.00wt%-5.50wt% of a disintegrant; 0.20wt%-2.00wt% of a lubricant.

[0016] In a preferred embodiment, the pharmaceutical composition is in a dosage form for oral administration, for example, a tablet.

[0017] In another aspect, the present invention provides a method for preparing the pharmaceutical composition according to the present invention, said method comprising dry mixing followed by powder tableting.

[0018] In another aspect, the present application provides the use of the above-mentioned pharmaceutical composition in the preparation of drugs for treating nervous system diseases associated with acetylcholinesterase, such as Alzheimer's disease, Parkinson's syndrome, epilepsy, schizophrenia and the like.

[0019] Compared with the prior art, the present invention has the following advantages and excellent technical effects: the present invention combines dry mixing with 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 invention has good stability, excellent content uniformity, and slow growth of total impurities, which is beneficial to the production and storage of the product. DETAILED DESCRIPTION

[0020] Hereinafter, exemplary embodiments of the present invention are described, but the protection scope of the present invention is not limited thereto.

[0021] Pharmaceutical composition of the present invention

[0022] The present invention provides a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0023] In some embodiments, the pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant and a lubricant.

[0024] 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 for the treatment of acetylcholinesterase-related neurological diseases, such as Alzheimer's disease.

[0025] 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 of the 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.

[0026] In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition according to the present invention 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 invention, the amount of the compound of formula (I) or its pharmaceutically acceptable salt 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 the range consisting of endpoints. In some embodiments, in the pharmaceutical composition of the present invention, 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 invention, 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%.

[0027] 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, by weight percentage, the filler accounts for 55.00wt%-97.00wt% of the weight of the pharmaceutical composition, preferably 90.00wt%-96.00wt%.

[0028] 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.

[0029] 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.

[0030] In some embodiments, the filler is a filler comprising microcrystalline cellulose, preferably 55.00 wt%-80.00 wt% of microcrystalline cellulose, preferably 60.00 wt%-80.00 wt% of microcrystalline cellulose based on the amount of the pharmaceutical composition.

[0031] In some embodiments, the filler comprises pregelatinized starch, preferably 15.00 wt%-20.00 wt% of pregelatinized starch, preferably 16.00 wt%-17.00 wt% of pregelatinized starch based on the amount of the pharmaceutical composition.

[0032] 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.

[0033] 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.

[0034] In some embodiments, by weight percentage, in the pharmaceutical composition of the present invention, the amount of the disintegrant is selected from 0.50wt%-7.00wt%, preferably 2.00wt%-5.50wt%. In some embodiments, in the pharmaceutical composition of the present invention, 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 ... %, 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 of the foregoing values ​​as the range consisting of endpoints. In some embodiments, in the pharmaceutical composition of the present invention, the amount of the disintegrant is selected from 2.00wt%-4.50wt%.

[0035] 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.

[0036] When the disintegrant is low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose, the two can be combined in any ratio. For example, the mass ratio of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose can be 10:1 to 1:10, for example, 10:1, 5:1, 1:1, 1:2, 1:3, 1:5 or 1:10.

[0037] In some embodiments, the lubricant is selected from one or more of micro powder silica gel, sodium stearyl fumarate and magnesium stearate. In some embodiments, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, magnesium stearate and micro powder silica gel.

[0038] In some embodiments, the amount of the lubricant in the pharmaceutical composition according to the present invention is selected from 0.10wt%-5.00wt%, preferably 0.20wt%-2.00wt%. In some embodiments, in the pharmaceutical composition of the present invention, 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.

[0039] When the lubricant is a combination of magnesium stearate and micro powder silica gel, the mass ratio of magnesium stearate to micro powder 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.

[0040] The particle size D90 mentioned in the present invention refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%, and its physical meaning is that particles with a particle size smaller than it account for 90%.

[0041] In some embodiments of the present invention, 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.

[0042] 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.

[0043] 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 0.5mg-4mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dose form contains 0.5mg-4.0mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dose form contains 0.5mg-3.0mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dose form contains 0.5mg, 1.0mg, 1.48mg, 1.65mg, 1.7mg, 2mg, 2.1mg, 2.3mg, 3.0mg or 4.0mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0044] In some specific 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 specific 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 specific 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 specific 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.

[0045] It should also be understood by those skilled in the art that, in addition to the active ingredient formula (I) compound described above and fillers, disintegrants, or lubricants, the pharmaceutical composition of the present application may also include other pharmaceutically acceptable adjuvants or auxiliary agents as needed, such as but not limited to diluents, antioxidants, preservatives, colorants, flavoring agents, 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.

[0046] The function of pharmaceutical excipients is not single, and many excipients have different uses. The compound of formula (I) has poor stability and small dosage, so the selection of diluents is different. Generally, in the pharmaceutical field, diluents are also fillers. The diluent used in the present invention is different from the usual filler. Considering the improvement of the fluidity of the drug and the uniformity of the content of the finished preparation, the diluent of the present invention is not preferably lactose and mannitol, because their own hygroscopicity and hydrophilicity lead to relatively poor use effect.

[0047] Previous studies on the compound of formula (I) have only been conducted on animal experiments, and the composition used therein cannot meet the requirements of drug 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, and the pharmaceutical composition of the present invention greatly improves the quality indicators of the finished product (e.g., tablets), such as content uniformity, related substances, and dissolution, so that the quality of the drug is effectively guaranteed, and through standardized clinical trials, it is determined that the pharmaceutical composition of the present invention 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 invention are confirmed by standardized pharmaceutical studies in various aspects.

[0048] Embodiments of the pharmaceutical composition

[0049] 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.

[0050] In some embodiments of the present application, the pharmaceutical composition described in the present application comprises: 0.50wt%-4.00wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 65wt%-97.00wt% of a filler, the filler being microcrystalline cellulose; 0.50wt%-7.00wt% of a disintegrant, the disintegrant being selected from one or more of low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose; and 0.10wt%-5.00wt% of a lubricant, the lubricant being 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 in the present application 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.

[0051] 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%-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.

[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%-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 micropowdered silica gel and magnesium stearate.

[0053] 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%-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.

[0054] 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:

[0055] 0.50wt%-2.50wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof; 92.00wt%-96.00wt% of a filler, which is a combination of microcrystalline cellulose and pregelatinized starch; 2.00wt%-4.50wt% of a disintegrant, which is cross-linked sodium carboxymethyl cellulose; and 0.20wt%-2.00wt% of a lubricant, which is magnesium stearate.

[0056] 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.

[0057] In some embodiments of the present application, the pharmaceutical composition described in the present application is in the form of a tablet, wherein the thickness of the tablet is 1-10 mm, preferably 3 mm-5 mm.

[0058] Preparation method

[0059] In another aspect, the present invention provides a process for preparing a pharmaceutical composition according to the present invention.

[0060] In one embodiment, the present invention provides a method for preparing a pharmaceutical composition in the form of a tablet.

[0061] In some embodiments, the pharmaceutical composition of the present invention is prepared by dry mixing and then powder tableting.

[0062] 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 in sequence. 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.

[0063] In some embodiments, the API used in the present invention (the compound represented by formula (I) or a pharmaceutically acceptable salt thereof) is micronized to obtain a API having a particle size (D90) of 5-50 μm, preferably 8-12 μm. In some embodiments, the API used in the present invention is micronized by air flow milling and then sieved, preferably using 80-120 mesh for sieving.

[0064] In some embodiments, the bulk drug used in the present invention (compound of formula (I) or a pharmaceutically acceptable salt thereof) is micronized and mixed with excipients (except lubricants) in equal amounts, which can greatly improve the dissolution rate of the drug. In some embodiments, the bulk drug used in the present invention is micronized and mixed with fillers and disintegrants in equal amounts, and then the resulting mixture is mixed with lubricants; or, the bulk drug used in the present invention is micronized and mixed with fillers in equal amounts, and then the resulting mixture is mixed with disintegrants and lubricants at the same time, or sequentially; or, the bulk drug used in the present invention is micronized and mixed with a portion of the fillers in equal amounts, and then the resulting mixture is mixed with the remaining fillers, disintegrants and lubricants at the same time, or sequentially.

[0065] In the present application, "equal amount addition" refers to mixing the bulk 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 bulk drug is mixed with the filler in equal amounts or twice, such as the bulk drug + 2 times the amount of filler. For example, in some embodiments, the bulk drug is mixed by sieving during the equal amount addition process, or mixed by a mixer. For example, the filler is first mixed with the bulk drug in double the amount of the bulk drug, and then the same multiple twice. For example, 2 parts by weight of the bulk drug + twice the amount of filler (e.g., microcrystalline cellulose + pregelatinized starch) 4 parts by weight are mixed and sieved for the first time, and 6 parts by weight of the 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.

[0066] In some embodiments, when a mixer is used for mixing, the following parameters can be used for mixing with fillers and disintegrants: mixing speed is 20 rpm-40 rpm, preferably 25 rpm-35 rpm, preferably 30 rpm; time is 20 min-25 min. The above mixing parameters can also be used for mixing in the process of equal amount addition.

[0067] 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-40 rpm, preferably 25 rpm-35 rpm, preferably 30 rpm; and a mixing time of 5 min-10 min.

[0068] In the mixing operation of the method, the equipment used is a three-dimensional motion mixer.

[0069] In the method of the present invention, tableting is performed using a rotary tablet press in a conventional tableting manner.

[0070] In a preferred embodiment, the thickness of the obtained tablet is 1-10 mm, preferably 3-5 mm.

[0071] In some embodiments, the method comprises:

[0072] Micronization treatment: The API is micronized to obtain an API with a particle size (D90) of 5-50 μm, preferably 8-12 μm;

[0073] Equal amount incremental mixing: the micronized API and at least a portion of the filler are incrementally mixed in equal amounts;

[0074] Total mixing: the mixture obtained by mixing equal amounts in successive additions is mixed with the remaining portion of the filler, disintegrant and lubricant simultaneously, or sequentially;

[0075] Compacting: The total blended mixture is compacted.

[0076] In some embodiments, the method of preparing a pharmaceutical composition of a compound of formula (I) of the present invention comprises:

[0077] Micronize the raw material to obtain a material with a suitable particle size①;

[0078] The material ① is mixed 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;

[0079] Mix the 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 a mixture ②;

[0080] Add lubricant to mixture ② and mix at 20 rpm to 40 rpm for 5 min to 10 min to obtain a total mixed mixture;

[0081] The total blended mixture is compressed through a die into tablets having a thickness of 1-10 mm, preferably 3-5 mm.

[0082] In some embodiments, the method of preparing a pharmaceutical composition of a compound of formula (I) of the present invention comprises:

[0083] 1) Micronizing the API to obtain a material with a D90 of 8-12 μm①;

[0084] 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;

[0085] 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;

[0086] 4) Add lubricant to mixture ② and mix at 20 rpm-40 rpm for 5 min-10 min to obtain a total mixed mixture;

[0087] 5) The total blended mixture is pressed through a die to form tablets with a thickness of 3-5 mm.

[0088] In a specific embodiment, the method of preparing a pharmaceutical composition of a compound of formula (I) of the present invention comprises:

[0089] 1) Micronizing the API to obtain a material with a D90 of 8-12 μm①;

[0090] 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 to 40 rpm for 20 min to 25 min;

[0091] 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;

[0092] 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;

[0093] 5) The total blended mixture is pressed through a die to form tablets with a thickness of 3-5 mm.

[0094] 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.

[0095] 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 optional one or more auxiliary agents, such as auxiliary agents known in the film coating field. 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, etc.

[0096] In the present invention, the compound of formula (I) is micronized (for example, by air flow pulverization), and combined with a specific auxiliary material composition and powder pressing, 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.

[0097] Treatment or prevention methods and uses

[0098] 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.

[0099] Another aspect of the present invention provides a method for treating acetylcholinesterase-related nervous system diseases, such as Alzheimer's disease, Parkinson's syndrome, epilepsy, schizophrenia and the like, comprising administering a therapeutically effective amount of the above-mentioned pharmaceutical composition according to the present invention to a subject in need.

[0100] Beneficial Effects

[0101] Compared with the prior art, the present invention has the following advantages and excellent technical effects: the present invention 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 stability investigation results, 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 pathway of the human body. The preparation method of the pharmaceutical composition of the present invention is simple and easy to operate, and can be applied to batch preparation of clinical samples and large-scale production; the dissolution 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 related substances are stable, and the quality is effectively guaranteed.

[0102] For the purposes of this application, unless otherwise stated, the following terms used in the specification and claims shall have the following meanings.

[0103] 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.

[0104] Unless specifically defined otherwise, ratios (including percentages) or parts used herein are by weight.

[0105] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, 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.

[0106] 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).

[0107] The compound of formula (I) can be administered in the form of its free base, or in the form of its salt, solvate, and prodrug, which is 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 different organic acids and inorganic acids according to methods known in the art.

[0108] In some embodiments, the pharmaceutically acceptable salt of the compound shown in formula (I) of the present application refers to the 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 represented by 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.

[0109] "Unit dosage" or "unit dose" refers to a pharmaceutical composition packaged in a single package for the convenience of taking. For example, "a pharmaceutical composition in unit dosage form" means each tablet. "A pharmaceutical composition in unit dosage form contains 2 mg of the compound of formula (I)" means that each tablet finally prepared contains 2 mg of the compound of formula (I).

[0110] "Patient," "subject," or "subject" refers to a mammal, preferably a human.

[0111] "Therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to effect treatment for the disease.

[0112] "Treatment" means any administration of a therapeutically effective amount of a compound, and includes:

[0113] (1) inhibiting a disease in a human being who is experiencing or displaying the pathology or symptomology of the disease (i.e., arresting further development of the pathology and / or symptomology), or

[0114] (2) Ameliorating a disease in a human being experiencing or displaying the pathology or symptomology of the disease (i.e., reversing the pathology and / or symptomology).

[0115] Example

[0116] The following is a further exemplary description of the content of the present invention in conjunction with specific embodiments, but it does not constitute any limitation to the scope of the present invention. The auxiliary materials and reagents used are all commercially available products. The instruments and equipment used are commonly used in the art.

[0117] Detection of active compounds:

[0118] 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 in water and dilute to 1000 mL, adjust the pH to 6.0 with phosphoric acid)-acetonitrile (90:10); mobile phase B: acetonitrile; A:B = 61:39 (%).

[0119] Reference solution: Weigh 10 mg of the reference compound of formula (I), accurately weigh it, place it in a 100 mL volumetric flask, add solvent to dissolve it to volume, and obtain a reference solution with a concentration of 100 μg / mL of the compound of formula (I).

[0120] 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.

[0121] Chromatographic conditions

[0122] Detection wavelength: UV270nm; chromatographic column: 4.6mm×15cm; 3.5μm, C18 column, model: Waters XbridgeC18; column temperature: 35℃; flow rate: 1.0ml / min; injection volume: 10μL; running time: 20min.

[0123] Total impurities measurement: HPLC method (Chinese Pharmacopoeia 2015 edition, Part IV, General Rules 0512).

[0124] Wherein, solvent: acetonitrile-water = 50:50; mobile phase: mobile phase A: phosphate solution (take 2.72g of potassium dihydrogen phosphate and 3mL of triethylamine, add water to dissolve and dilute to 1000mL, adjust the pH value to 6.0 with phosphoric acid)-acetonitrile (80:20); mobile phase B: acetonitrile;

[0125] Mobile phase gradient table

[0126] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 20 75 25 40 63 37 45 38 62 50 38 62

[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 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.

[0128] Reference solution: Accurately weigh 10 mg of the reference compound of formula (I), 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.

[0129] Chromatographic conditions

[0130] Detection wavelength: UV270nm; chromatographic column: 4.6mm×15cm; 3.5μm, C18 column, model: Waters XbridgeC18; column temperature: 35℃; flow rate: 1.0mL / min; injection volume: 10μL; running time: 50min.

[0131] Dissolution measurement: Paddle method, according to the second method of dissolution determination in Appendix II of the 2015 edition of the Chinese Pharmacopoeia, the dissolution of the tablets was measured. The dissolution medium was pH 4.5 acetate buffer (2.99 g of sodium acetate and 14.0 mL of 2 mol / L acetic acid solution, dissolved in water and diluted to 1000 mL, shaken well, and obtained), 500 mL.

[0132] Hardness measurement: measured by Shanghai Huanghai Drug Testing Instrument Co., Ltd. YPD-300D intelligent tablet hardness tester. Among them, the hardness range between 2-12kg is the ideal tablet.

[0133] Friability measurement: The friability tester was used at Tianjin University Radio Factory to test the friability of the tablets (Chinese Pharmacopoeia 2015 edition, Part IV, General Rules 0923).

[0134] Microbial limit measurement: Determine with reference to the method for determination of microbial limits (General Rules 1105 and 1106 of Part IV of the Chinese Pharmacopoeia 2015 Edition).

[0135] Content uniformity measurement: Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0941, HPLC method (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0512).

[0136] Preparation Example 1 Preparation of Compound of Formula (I)

[0137] The compound of formula I is prepared according to the method disclosed in CN 103787954 B.

[0138] Preparation Example 2 Study on the dosage form of the compound of formula (I)

[0139] 2.1 Selection of filler types and proportions

[0140] Fillers commonly used in tablets, such as mannitol, microcrystalline cellulose, pregelatinized starch, etc., were selected, and the appearance, hardness, friability and dissolution of the finished tablets were used as screening indicators to examine the effects of the type and proportion of the filler in the tablets of the compound of formula (I).

[0141] Table 1 Filler type and proportion selection and its results

[0142]

[0143] The compound of formula (I) and the auxiliary materials listed in Table 1 in the prescribed proportion are mixed uniformly, pressed into tablets, and then the relevant indicators of the tablets are measured.

[0144] Among them, prescription 2 and prescription 3 were no longer studied due to appearance defects, poor hardness, unqualified friability, etc. Prescription 1, prescription 4 and prescription 5 were selected to continue the dissolution evaluation. The tablets were placed at 37°C and 50 rpm in 500 mL of pH 4.5 acetate buffer as the dissolution medium, and samples were taken at 5, 10, 15, 30, 45, and 60 minutes to measure the dissolution of the drug.

[0145] Table 2 Dissolution test results of prescription 1, prescription 4 and prescription 5

[0146]

[0147]

[0148] It can be seen from the dissolution results in Table 2 above that the compound of formula (I) in formulation 1 cannot be completely dissolved in the pH 4.5 medium, while formulations 4 and 5 have better solubility.

[0149] Through the above screening, it was found that when mannitol and pregelatinized starch were used alone as fillers, the prepared tablets showed sticking or cracking, and the hardness was poor and the friability was unqualified; when microcrystalline cellulose was used alone as a filler, the tablets were not completely dissolved. Considering the high cost of using direct compression mannitol and the compatibility problem under high humidity conditions, pregelatinized starch and microcrystalline cellulose were used in combination. The addition of pregelatinized starch can accelerate the disintegration and dissolution of tablets, but the hardness of tablets will be reduced accordingly, and the friability of drugs will be affected. Therefore, the research was continued based on the filler ratio in prescription 4.

[0150] 2.2 Selection of disintegrant type and proportion

[0151] Select the commonly used disintegrants for tablets, such as low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc., and then use the appearance, disintegration time, hardness, friability, and dissolution of the finished tablets as screening indicators to investigate the effects of the type and proportion of disintegrants in the tablets of the compound of formula (I). Among them, microcrystalline cellulose and pregelatinized starch are used as fillers, and the specific prescription is shown in Table 3 below.

[0152] Table 3 Disintegrant type and dosage selection and its results

[0153]

[0154] The compound of formula (I) in the prescription ratio and the remaining excipients in the prescription ratio listed in Table 3 were mixed evenly, pressed into tablets, and then the relevant indicators of the tablets were measured. Among them, by comparing the disintegration time, it was found that the disintegration performance of different disintegrants during use was basically the same, and the increase in the amount of disintegrant can accelerate the disintegration of the tablets; and the hardness of the compressed tablets was tested. Comparison of the hardness and fluidity results showed that low-substituted hydroxypropyl cellulose is easier to achieve a higher hardness. The prepared tablets were placed at 37°C and 50rpm, with 500mL of pH 4.5 acetate buffer as the dissolution medium, and samples were taken at 5, 10, 15, 30, 45, and 60min to measure the dissolution rate of the drug.

[0155] Table 4 Dissolution test results of prescription 4, prescription 7 and prescription 8

[0156]

[0157] It can be seen from the above results that the three dosages of low-substituted hydroxypropyl cellulose can make the drug solubility reach more than 80% in 30 minutes; the drug dissolution becomes faster as the dosage of disintegrant increases. In order to ensure the rapid disintegration of tablets and consider the cost issue, the dosage of disintegrant needs to be controlled.

[0158] 2.3 Lubricant type and ratio selection

[0159] The commonly used lubricants for tablets, such as magnesium stearate, sodium stearyl fumarate, talc, and micro-powdered silica gel, were selected, and the appearance, hardness, friability, and dissolution of the finished tablets were used as screening indicators to investigate the effects of the type and proportion of lubricants in the tablets of the compound of formula (I). Among them, microcrystalline cellulose and pregelatinized starch were used as fillers, and low-substituted hydroxypropyl cellulose was used as a disintegrant. The specific prescription is shown in Table 5 below.

[0160] Table 5 Lubricant type and ratio selection and its results

[0161]

[0162]

[0163] The compound of formula (I) and the excipients listed in the table were mixed uniformly in the prescription ratio, pressed into tablets, and then the relevant indicators of the tablets were measured. Among them, prescription 11 and prescription 13 were no longer studied due to fragmentation and sticking. Prescription 9, prescription 10 and prescription 12 were selected to continue the dissolution evaluation. The tablets were placed at 37°C and 50 rpm, with 500 mL of pH 4.5 acetate buffer as the dissolution medium, and the dissolution of the drug was measured at 5, 10, 15, 30, 45, and 60 minutes.

[0164] Table 6 Dissolution test results of prescription 9, prescription 10 and prescription 12

[0165]

[0166] 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.

[0167] Through the above screening, it was found that the hardness of the compound of formula (I) tablets prepared using magnesium stearate as a lubricant met the requirements and had good dissolution behavior.

[0168] In summary, the intermediate powders of Prescription 4 and Prescription 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, Prescription 4 and Prescription 12 are the preferred prescriptions.

[0169] Conclusion: The research results of the above different prescriptions 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.

[0170] 2.4 Composition ratio in the preparation formula

[0171]

[0172] Dissolution analysis

[0173] 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 to determine the dissolution curve of the drug at 5, 10, 15, 30, 45, and 60 minutes. The results are shown in Table 8.

[0174] Table 8 Dissolution test results of prescription 14 to prescription 22 (%)

[0175]

[0176] From the comparison of the dissolution results of the above prescriptions, it can be seen that the dissolution data of the pharmaceutical composition with the ratio screened according to the present invention is better.

[0177] 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.

[0178] 2.5 Particle size screening

[0179] The particle size of the raw material of the compound of formula (I) may have a certain effect 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) is screened, and the raw materials of different particle sizes in the prescription amount are mixed with the excipients, pressed into tablets, and the hardness and dissolution are used as indicators for inspection.

[0180] Table 9 Prescription composition:

[0181] Element Process 1 Craft 2 Craft 3 Craft 4 API particle size D90 (μm) 11.58 8.22 5.14 48.73 Compound of formula (I) 2mg 2mg 2mg 2mg Microcrystalline Cellulose 100mg 100mg 100mg 100mg Pregelatinized starch 22mg 22mg 22mg 22mg Low substituted hydroxypropyl cellulose 5mg 5mg 5mg 5mg Magnesium Stearate 1mg 1mg 1mg 1mg hardness 7.38kg 7.26kg 8.28kg 8.14kg

[0182] The tablets of the compound of formula (I) prepared in process 1, process 2, process 3 and process 4 were subjected to dissolution curves of the drug at 5, 10, 15, 30, 45 and 60 min at 37°C and 50 rpm with 500 mL of pH 4.5 acetate buffer as the dissolution medium. The results are shown in Table 10.

[0183] Table 10 Dissolution test results of tablets obtained by process 1, process 2, process 3 and process 4

[0184]

[0185]

[0186] 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

[0187] 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 found that the dissolution endpoint test results under the four process conditions at the same time are similar, and all can meet the dissolution quality test standards, but from the dissolution curve, it can be observed that as the particle size decreases, such as process 2 and process 3, the initial dissolution rate of the tablets is getting faster and faster, while the initial dissolution rate of the tablets with larger particle size, such as process 4, is significantly slower, and the RSD value results of process 3 and process 4 are significantly larger, indicating that the dissolution difference is large and uneven. Comprehensively considering 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, stability, etc., it is selected to determine the preferred particle size range D90 of the compound of formula (I) for microdifferentiation treatment of raw materials as 8-12μm, and the mesh number should be sieved to prevent agglomeration before feeding.

[0188] 2.6 Screening of mixing time

[0189] Taking prescription 14 as an example, the specification of this product is 2 mg, the tablet weight is 130 mg, the main drug accounts for 1.5%, and the mixing uniformity directly affects the content uniformity of the compound of formula (I) tablet. It is difficult to mix the drug and the auxiliary materials of the prescription ratio directly. It is proposed to adopt the incremental method to mix this product with a mixer and screen the mixing time. The specific process is shown in Table 11.

[0190] Table 11 Process screening of mixing time

[0191]

[0192] Samples were taken from the three corners and the upper and lower parts of the middle of the container, and the content was measured according to the content determination method. The mixing uniformity was calculated to examine the mixing time. The results are summarized in Table 12.

[0193] Table 12 Determination results of intermediate powders obtained from process 5 to process 9

[0194]

[0195]

[0196] It can be seen from the results that the angle of repose of the intermediate powder at different mixing times meets the requirements, 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 values ​​of process 8 and process 9 are less than 5%, the mixing uniformity meets the requirements, so the mixing time range of 20min-25min is selected for the addition of excipients except magnesium stearate.

[0197] Since magnesium stearate has strong hydrophobicity, the mixing time of magnesium stearate is screened. The specific process is shown in Table 13 below.

[0198] Table 13 Lubricant mixing time optimization

[0199]

[0200] Samples were taken from the three corners and the upper and lower parts of the middle of the container, and the content was measured according to the content determination method. The mixing uniformity was calculated to examine the mixing time. The results are summarized in Table 14.

[0201] Table 14 Measurement results of mixed powders of process 10-process 11

[0202]

[0203] The results show that the RSD value is less than 5% when the mixing time is 5-10 minutes after adding magnesium stearate, and the mixing uniformity and repose angle meet the requirements. Therefore, the mixing time range of adding magnesium stearate is selected to be 5-10 minutes.

[0204] After further research, regarding the equal amount incremental method, the pharmaceutical composition of the compound of formula (I) can be prepared by the following method:

[0205] 1) Micronizing the API to obtain a material with a D90 of 8-12 μm①;

[0206] 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;

[0207] 3) fully mixing the mixture ① with microcrystalline cellulose and low-substituted hydroxypropyl cellulose to obtain a mixture ②;

[0208] 4) adding magnesium stearate to the mixture ② and continuing to mix for 5-10 minutes to obtain a total mixed mixture;

[0209] 5) The total blended mixture is pressed through a die to form tablets with a thickness of 3-5 mm.

[0210] Example 1

[0211] Table 15 The composition of pharmaceutical composition 1 is as follows:

[0212]

[0213] Conduct scale-up studies on three batches of products, with scales of 3,000 tablets / batch, 3,000 tablets / batch, and 10,000 tablets / batch, respectively, to achieve the following objectives:

[0214] Investigate the main links of the production process and further optimize the process conditions;

[0215] Determine the equipment and production methods suitable for process production to ensure product quality and reproducibility after process expansion.

[0216] Table 16 Summary of production process changes

[0217]

[0218]

[0219] Table 16 Analysis results of quality control of three batches of samples

[0220]

[0221] Yield refers to the ratio of actual output to theoretical batch; yield examines the continuity and stability of the process production process. The higher the yield, the better the process control and the relatively more guaranteed quality.

[0222] Comparative Example

[0223] Table 17 The composition of pharmaceutical composition 2 is as follows:

[0224]

[0225] The raw materials were sieved through 80 mesh and the auxiliary materials through 60 mesh to remove lumps and obtain uniform powder.

[0226] Weigh the compound of formula (I) in the prescribed amount, add the prescribed amount of cross-linked carboxymethyl cellulose sodium, lactose, and microcrystalline cellulose in a progressive addition method, sieve and mix evenly; then add magnesium stearate + micro-powder silica gel (1:1), sieve and mix evenly; capsule-shaped punching tablets. Samples are taken to test the hardness and weight difference of this product, and the results meet the requirements. Packaged in polyvinyl chloride bags.

[0227] Effect Example 1

[0228] High humidity test

[0229] Tablet samples from different embodiments 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 results are as follows:

[0230] Table 18 Tablet high humidity test results

[0231]

[0232] 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 have changed less than those of other examples under high relative humidity, and the quality of the finished product is more stable.

[0233] Light test

[0234] A 30 mg tablet sample of Example 1 was taken and subjected to impurity determination and dissolution tests at 0 days, 5 days, 10 days and 30 days under light conditions. The results are as follows:

[0235] Table 19 Results of the light stability test of the tablets in Example 1

[0236]

[0237] High temperature test

[0238] The 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 results are as follows:

[0239] Table 20 Results of high temperature stability test of tablets in Example 1

[0240]

[0241] Accelerated Experiment

[0242] Three batches of tablet samples of Example 1 were subjected to impurity determination and dissolution experiments at 0 day and accelerated temperatures of 1 month, 2 months, 3 months, and 6 months (40°C ± 2°C, 75% ± 5% RH);

[0243] The results are as follows:

[0244] Table 21 Results of accelerated test on tablets of Example 1

[0245]

[0246] Long-term experiments

[0247] Tablet samples of Example 1 were taken for impurity determination and dissolution test at 0 day and long-term 3 months and 6 months (25±2°C / 60±5%RH). The results are as follows:

[0248] Table 22 Results of long-term study on tablets of Example 1

[0249]

[0250] 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.

[0251] Effect Example 2 Pharmacokinetics of a single dose in healthy Chinese subjects

[0252] Trial design: Single-center, randomized, double-blind, placebo-controlled, dose-escalation, single-dose.

[0253] Number of subjects: Planned inclusion: 52, final analysis: 51.

[0254] Subject inclusion criteria:

[0255] 18 years old ≤ ≤ 40 years old, healthy subjects, regardless of gender;

[0256] Weight: Male ≥50kg, Female ≥45kg; and Body Mass Index (BMI) ≤26kg / m 2 ;

[0257] No history of heart, liver, kidney, digestive tract, nervous system, mental and metabolic disorders, severe infection or serious injury;

[0258] No plans to have children during the trial and within 3 months after the last medication and able to take reliable contraceptive measures;

[0259] 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.

[0260] Subject exclusion criteria:

[0261] Those who are known to have a history of allergy to the test drug ingredients or similar drugs, a history of allergic diseases or allergic constitution;

[0262] Have a history of central nervous system, cardiovascular system, digestive system, respiratory system, urinary system, blood system, etc., a history of metabolic disorders, a history of malignant tumors, or other diseases that are not suitable for clinical trials (such as a history of mental illness, etc.);

[0263] 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 history of gastrointestinal surgery (gastrectomy, gastrointestinal anastomosis, intestinal resection, etc.), urinary tract obstruction or dysuria, gastroenteritis, peptic ulcer, history of gastrointestinal bleeding, etc.;

[0264] 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;

[0265] 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, indicating liver disease or liver damage, or defined as exceeding 1.5 times the upper limit of normal; b. Creatinine and urea nitrogen exceed the upper limit of normal and show clinical significance or urine components are abnormal and show clinical significance (such as proteinuria, urine occult blood, white blood cells in urine, etc.); c. Clinically significant abnormalities in routine blood tests, such as anemia, decreased white blood cells, significantly decreased platelets, etc.];

[0266] Those who had donated blood or lost blood ≥400 ml within 3 months before enrollment;

[0267] Those who had taken any medication within 2 weeks before enrollment;

[0268] Pregnant or breastfeeding women;

[0269] Participated in other drug clinical trials within 1 month before enrollment;

[0270] Those with a history of drug use or a positive urine test for drug abuse;

[0271] Current or past alcoholics (drinking more than 196g of alcohol per week, such as 360ml of beer or 45ml of 40% alcohol liquor or 150ml of wine), or those with a positive breath alcohol test;

[0272] Those who smoke ≥10 cigarettes per day;

[0273] Those who are positive for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), syphilis antibody and HIV antibody (HIV-Ab);

[0274] Those who are deemed by the researchers to be unsuitable for the trial due to other factors.

[0275] Trial Drugs:

[0276] Specifications: 0.5 mg / tablet, 1 mg / tablet, 2 mg / tablet, prepared according to the method of Example 1;

[0277] Dosage: 0.5mg, 1mg, 2mg, 4mg, 8mg, 12mg.

[0278] Dosage: Single dose, take with appropriate amount of water (240ml).

[0279] Control drug (placebo):

[0280] Specifications: 1mg / tablet, 2mg / tablet;

[0281] Dose:NA.

[0282] Dosage: Single dose, take with appropriate amount of water (240ml).

[0283] Pharmacokinetic parameter evaluation indicators: peak time (Tmax), peak concentration (Cmax), area under the blood drug concentration time curve from 0 to t time (AUC 0－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).

[0284] Pharmacokinetic analysis: The pharmacokinetic parameters were calculated using the non-compartmental model method (NCA) and Phoenix WinNonlin 7.0 data analysis software. Descriptive statistical analysis was performed on the pharmacokinetic parameters, providing the number of cases, arithmetic mean, standard deviation, minimum value, median value, maximum value, and coefficient of variation (CV). Tmax was expressed as the median value (minimum value - maximum value). AUC and Cmax belonged to the log-normal distribution, and the geometric mean was also provided. The relationship between the dose and the drug plasma exposure was evaluated by drawing a scatter plot of the logarithmic transformed pharmacokinetic parameters (AUC and Cmax) related to the logarithmic dose. In addition, the Powermodel method was used to further explore the linear analysis of the dose and the drug plasma exposure.

[0285] Pharmacokinetic results:

[0286] Healthy volunteers took a single fasting oral tablet of the compound of formula (I), and the compound of formula (I) in plasma reached a peak value (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, and 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 1.22 and 1.08 were respectively. In the dose range of 1 to 12 mg, Cmax and AUC 0-∞ As the dosage increases, AUC 0-∞ The increase ratio of the drug exposure was basically consistent with the increase ratio of the dose. The inter-individual variation of plasma drug exposure was about 30%.

[0287] The metabolite M4 in plasma reaches its peak value (median) at 1.5-1.75h, and the average plasma drug elimination half-life is 2.88-7.19h. At a dose of 1-12mg, the metabolic ratio MR_Cmax of M4 is 0.238-0.377ng / ml, and MR_AUC is 0.153-0.220h*ng / ml.

[0288] in conclusion

[0289] Healthy volunteers took a single fasting oral administration of the compound of formula (I) tablets, and the compound of formula (I) in plasma reached a peak value (median) at 0.75 to 1.5 hours, and the average plasma drug elimination half-life was 14.2 to 32.1 hours. Within the dose range of 1 to 12 mg, Cmax and AUC0-∞ increased with increasing doses, and the increase ratio of AUC0-∞ was basically consistent with the increase ratio of doses.

[0290] No SAEs occurred within the dose range of 1 to 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 similar drugs such as donepezil.

[0291] In summary, the tablets of the compound of formula (I) prepared by the present invention have good in vivo effects, and the exposure amount in the body is proportional to the dosage; the prepared tablets have stable quality, good mixing uniformity, and the hardness after tableting meets the requirements, and the amount of disintegrant is moderate, which can ensure the rapid disintegration of the tablets; the powder direct 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, 2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant and a lubricant.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that By weight percentage, the pharmaceutical composition comprises 0.50wt%-20.00wt%, preferably 0.50wt%-5.00wt% of the compound of formula (I) or its pharmaceutically acceptable salt; preferably, the pharmaceutical composition comprises the compound of formula (I) or its pharmaceutically acceptable salt having a D90 particle size of 5-50μm, preferably 8-12μm.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The filler is selected from pregelatinized starch and microcrystalline cellulose, preferably a combination of microcrystalline cellulose and pregelatinized starch, and the filler accounts for 55.00wt%-97.00wt%, preferably 90.00wt%-96.00wt% of the weight of the pharmaceutical composition by weight percentage; 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, preferably selected from low-substituted hydroxypropyl cellulose and / or cross-linked sodium carboxymethyl cellulose, and in terms of weight percentage, the disintegrant accounts for 0.50wt%-7.00wt%, preferably 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, preferably selected from micro powder silica gel and / or magnesium stearate, and by weight percentage, the lubricant accounts for 0.10wt%-5.00wt%, preferably 0.20wt%-2.00wt% of the weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that In terms of weight percentage, 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, by weight percentage: 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, by weight percentage: 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, by weight percentage: 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.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that Relative to the total amount of the pharmaceutical composition, 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.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The pharmaceutical composition is in the form of a tablet; preferably, the thickness of the tablet is 1-10 mm, preferably 3 mm-5 mm.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 7, the method comprising: Micronization: micronizing the API to obtain an API with a D90 particle size of 5-50 μm, preferably 8-12 μm; 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.

9. The method according to claim 8, 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 compressed into tablets with a thickness of 1-10 mm, preferably 3-5 mm, using a die.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating a nervous system disease associated with acetylcholinesterase.

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