A kind of breprazol sustained-release microspheres and preparation method thereof

Abstract

The present invention belongs to the field of new drugs, and provides a brepirazole sustained-release microsphere with no lag period and stable release and a preparation method thereof, wherein the microsphere comprises brepirazole, additives and lactide-co-glycolide copolymer, and has good microsphere morphology, high drug loading and encapsulation efficiency. The present invention obtains brepirazole microspheres with good morphology by adding oil phase additives and adjusting the composition of the aqueous phase; the more critical advantage is that the obtained brepirazole microspheres have excellent release characteristics: no lag period, stable release. In addition, the preparation method of brepirazole microspheres provided by the present invention has the technical advantages of simple process, high yield, and easy large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of new drugs and provides a brepazine sustained-release microsphere with no lag period and stable release and a preparation method thereof. Background Art

[0002] Brexpiprazole is a second-generation antipsychotic drug used as an adjuvant treatment for schizophrenia and major depressive disorder in adults. Its structural formula is as follows:

[0003]

[0004] It is the serotonin receptor 5-HT 1A and dopamine receptor D 2 , D 3 It is also a partial agonist of the serotonin receptor 5-HT 2A and 5-HT 2B , and a partial antagonist of adrenergic receptors alpha-1 and alpha-2. Brepirapazole exhibits high affinity for these receptors.

[0005] In July 2015, the FDA approved brexpiprazole tablets (trade name: ) is on the market and is taken orally once a day. Schizophrenia requires long-term medication, with a high relapse rate. Patients often hide medication, refuse to take medication, and have poor compliance. Compared with oral antipsychotics, reservoir antipsychotics such as long-acting microsphere injections can reduce the number of medications used by patients, improve compliance, and improve treatment effects. Currently, the long-acting antipsychotic injections on the market can be injected once every 6 months at most, and are widely favored by patients and doctors in clinical practice. There is currently no long-acting injection of brepazole on the market, and the development of brepazole long-acting sustained-release microspheres has high clinical value.

[0006] Patent CN 116531379 A discloses a sustained-release composition of brepirazole and its preparation method and application. It uses polylactic acid, lactide-co-glycolide copolymer and polycaprolactone as carriers, and adopts emulsified solvent volatilization method to prepare microspheres with a drug release cycle of 3 weeks. The 3-week administration cycle does not conform to the conventional long-acting sustained-release preparation medication cycle. CDE clearly points out that the administration frequency or interval of sustained-release preparations should conform to clinical medication habits, such as once a week, once every two weeks or once every four weeks. Secondly, due to the limited solubility of brepirazole in dichloromethane, the oil phase cannot achieve the preparation of high-drug-loaded microspheres with dichloromethane as solvent, and the three materials are mixed as carriers. The material quality is difficult to control, resulting in poor reproducibility and large batch-to-batch variability of the prepared microspheres. Among them, polycaprolactone has not been used in the development of commercial microsphere products and has no registration number. Its legality is worth considering. Moreover, its preparation scale is small, the volume of the external water phase is only 50ml, the concentration of PLGA in the prescription is low, the preparation efficiency is low, and it is difficult to achieve industrialization.

[0007] Sun Jinmei, Yu Fei and others from Yantai University conducted a study on the in vitro release of injectable irinotecan sustained-release microspheres. The prepared microsphere samples had a hysteresis period of about 14 days after administration to rats, and only the in vitro test methods and in vitro release performance of the microspheres were disclosed. The key quality attributes of the microspheres, such as the prescription composition, preparation process, drug loading, encapsulation rate, and polymer material model, were not disclosed, so they have no practical application value.

[0008] Patent WO 2023036003 A1 discloses a long-acting preparation of brepazine for injection and a preparation method thereof, specifically a microcrystalline injection. Since the microcrystalline injection does not contain a polymer controlled release material, it has a high drug loading and is suitable for a long-acting preparation with a high dose. However, the microcrystalline injection also has obvious technical defects: (1) The burst release is large, which poses a safety hazard. The drug crystals are dispersed in the form of a micron-level suspension and have a certain particle size distribution range. After intramuscular injection, the crystalline drug with a small particle size has a high drug solubility, rapid release and absorption, and the blood drug concentration quickly reaches a peak, which is several times or even hundreds of times the trough concentration (such as olanzapine pamoate); (2) There are large species and individual differences. The drug crystals are insoluble, and the in vitro release experiment is the basis for determining its data. However, the composition of animal muscle tissue is complex, containing lipoproteins, lymph, plasma and other components, which results in large species and individual differences in pharmacokinetic experiments; (3) The preparation process is complex, and the aseptic control requirements are high, making it difficult to achieve industrial scale-up production. At present, the common preparation method of microcrystalline suspension is media grinding, that is, using a grinder to reduce the particle size through media grinding, which has the disadvantages of small preparation scale, obvious scale-up effect, and difficulty in aseptic control. Therefore, there are only four varieties of microcrystalline injections on the market: aripiprazole microcrystalline injection, aripiprazole laurate injection, paliperidone palmitate injection, and olanzapine pamoate injection.

[0009] Patent WO2021233402 A1 discloses a pharmaceutical composition containing ipriprazole and a preparation method thereof, which is a microcrystalline suspension injection, using a sterile wet grinding process, requiring complex equipment such as a ball mill and a high-pressure homogenizer, with a complex process, a low degree of sterility assurance, and difficulty in scaled-up production. The data provided in Test Example 1 show that the peak time after administration to rats is on the 5th day, the peak concentration is high, much higher than the average blood drug concentration; the blood drug concentration on the first day is above 15ng / ml, and the burst release is large; the drug release cycle is set to 1 month, the in vivo drug release cycle is short, and it is completely released in about 26 days. This technology has the same technical defects as the technology of the above-mentioned patent WO 2023036003 A1, with high burst release, large species and individual differences, and complex preparation process.

[0010] Patent CN111603439A discloses a long-acting in-situ phase-change gel injection of brepazol and its preparation method, which uses phospholipid as a matrix to dissolve the drug in NMP to prepare an injectable sustained-release preparation. In-situ gel injection requires a certain amount of time to form a gel after intramuscular injection. During this period of time, the drug diffuses quickly, which easily causes rapid release of the drug, i.e., a "burst release effect", which poses a safety hazard; Patent CN115998694A discloses an orally disintegrating tablet containing brepazol and its preparation method, which is still administered orally, and has the defect of high administration frequency and lack of sustained-release function.

[0011] It can be seen that the long-acting preparations developed for brepazole at home and abroad include microcrystals, in situ gel implants, etc. Both have high burst release. The increase in blood drug concentration in a short time may cause local or systemic toxic reactions. Therefore, it is urgent to develop a suitable long-acting preparation of brepazole. Summary of the invention

[0012] In view of the shortcomings of the above-mentioned technologies, the inventors provide a brepirazole microsphere with no lag period and stable release and a preparation method thereof, wherein the microsphere comprises brepirazole, additives and lactide-glycolide copolymer, and has good microsphere morphology, high drug loading and encapsulation efficiency. The brepirazole microspheres obtained by the present invention have good morphology by adding oil phase additives and adjusting the composition of the water phase; the more critical advantage is that the brepirazole microspheres obtained have excellent release characteristics: no lag period and stable release. In addition, the preparation method of brepirazole microspheres provided by the present invention has the technical advantages of simple process, high yield and easy large-scale production.

[0013] The specific technical solutions of the present invention are as follows:

[0014] A brepaxole sustained-release microsphere, the raw materials of which include brepaxole and a lactide-glycolide copolymer; wherein the content of the brepaxole is 10%-50% of the total weight of the brepaxazole and the lactide-glycolide copolymer, preferably 30-40%; the content of the lactide-glycolide copolymer is 50%-90% of the total weight of the lactide-glycolide copolymer, more preferably 60-70%.

[0015] In addition, the microspheres also contain additives, the amount of which is 0.5%-5% by weight of the lactide-glycolide copolymer, more preferably 1%-3%.

[0016] The additive is selected from one or more of an organic base, a basic amino acid, or an insoluble alkaline carbonate in any proportion; wherein the organic base is selected from one of N-methyl-D-glucamine, tromethamine, ethylenediamine, and triethanolamine; the basic amino acid is selected from one of lysine, arginine, and histidine; and the insoluble alkaline carbonate is selected from micronized magnesium carbonate or micronized zinc carbonate;

[0017] The additive is preferably N-methyl-D-glucamine.

[0018] The lactide-glycolide copolymer structural formula is as follows:

[0019]

[0020] For the convenience of description, it is abbreviated as PLGA. The terminal group of the above-mentioned lactide-glycolide copolymer is carboxyl; the weight average molecular weight of the lactide-glycolide copolymer is 5000-90000 Dalton; the intrinsic viscosity is 0.14-0.75 dL / g; the molecular weight distribution coefficient is 1.0-3.0; and the molar ratio of lactide to glycolide is 95:05-50:50.

[0021] In addition, the inventors also provide a method for preparing the brepazine sustained-release microspheres, comprising the following steps:

[0022] (1) Oil phase preparation

[0023] dissolving brepazole, additives and lactide-glycolide copolymer in an organic solvent and mixing them well to form an oil phase;

[0024] (2) Water phase preparation

[0025] Polyvinyl alcohol is dissolved in water, a certain amount of buffer salt or electrolyte and surfactant solution and / or thickener are added, and mixed to form the aqueous phase;

[0026] (3) Shear emulsification

[0027] At a certain temperature, the oil phase of step (1) and the aqueous phase solution of step (2) are emulsified at a certain ratio by high-speed shearing to prepare an O / W emulsion;

[0028] (4) Curing

[0029] Stirring the emulsion from step (3) at a certain temperature and / or pressure to volatilize and remove the organic solvent;

[0030] (5) Collection and freeze-drying

[0031] The solidified suspension is collected through a sieve, washed, and freeze-dried to obtain the product.

[0032] The organic solvent in step (1) is a mixed solvent consisting of dichloromethane and a second solvent; the second solvent is selected from one of methanol, benzyl alcohol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone; the volume ratio of dichloromethane to the second solvent in the mixed solvent is 15:1-1:1, preferably 9:1-2:1; the weight ratio of the mixed solvent to brexpiprazole is 15:1-5:1; the weight ratio of the mixed solvent to the lactide-glycolide copolymer and the additive is 9:1-2:1; the temperature of the organic phase in step (1) is 5-30°C.

[0033] The concentration of the polyvinyl alcohol solution in step (2) is 0.5%-2.5% w / v; the temperature of the water phase is 5-30°C, preferably 10-25°C; the buffer salt or electrolyte is selected from one of disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, etc., or a combination of any two in any proportion, and the final salt concentration in the water phase is 0.02mol / L-0.5mol / L; the surfactant is selected from one of polysorbate 80, polysorbate 20 or poloxamer 188, and the final surfactant concentration in the water phase is 0.01%-2% w / v; the thickener is selected from one of hydroxypropyl methylcellulose, hydroxyethyl starch, sodium carboxymethyl cellulose, or a combination of any proportion, and the final thickener concentration in the water phase is 0.01%-2% w / v.

[0034] The above-mentioned buffer salt and surfactant can be directly added to the aqueous phase in step (2) or added after shear emulsification in step (3).

[0035] In step (3), the volume ratio of the oil phase solvent to the water phase solution is 1:50-1:300; the rotation speed of the high-speed shearing is 1500rpm-3000rpm, and more preferably 1600-2500rpm.

[0036] The solvent volatilization temperature in step (4) is 20°C-40°C; the pressure during the solvent volatilization can be normal pressure or negative pressure; and the solvent volatilization time is 4h-6h.

[0037] In step (5), the solidified suspension is collected by a sieve, and washing and freeze-drying are conventional steps in the art, which will not be described in detail by the inventors.

[0038] The particle size range of the microspheres prepared by the above preparation method is 15-200 μm.

[0039] The microspheres prepared above can be suspended in a pharmaceutically acceptable special solvent to obtain a sustained-release microsphere composition;

[0040] The special solvent is selected from one or more of a suspending agent, a pH adjusting agent, an isotonic adjusting agent, a surfactant, and water for injection; the suspending agent is selected from sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium alginate or glycerol; the isotonic adjusting agent is selected from sodium chloride, glucose, mannitol or sorbitol; the surfactant is a non-ionic surfactant, specifically selected from a polysorbate series and a poloxamer series. The pH adjusting agent is a commonly used adjusting agent in pharmacy, and the inventor will not repeat it.

[0041] The sustained-release microsphere composition obtained by the above scheme can be used to prepare therapeutic drugs for schizophrenia and auxiliary therapeutic drugs for major depression.

[0042] Compared with the prior art, the core innovation of the present invention is:

[0043] 1. The inventiveness of the present invention lies first in the innovativeness of the formulation design: the inventor creatively adds additives to the oil phase, and the additives include organic bases or basic amino acids or insoluble basic carbonates or any combination of the three. Brapiprazol is a free base drug with a pKa value of 13.56 and contains amino groups in its structure. During the preparation process, it combines with the carboxyl end groups in the lactide-glycolide copolymer, resulting in a slow release of the drug from the microspheres and a time lag. Subsequently, the lactide-glycolide copolymer degrades and presents a pulsed release. Insoluble alkaline carbonates have a certain alkalinity and can combine with the carboxyl end groups of the lactide-glycolide copolymer. Organic bases such as N-methyl-D-glucosamine, triethanolamine, ethylenediamine, etc. and basic amino acids also have a certain alkalinity. The amino groups in their structures are highly active. By competing with Brapiprazol to combine with the carboxyl end groups of the lactide-glycolide copolymer, the interaction between the drug and the lactide-glycolide copolymer can be reduced, the release can be improved, the time lag period can be eliminated, and the stable release of the drug can be achieved.

[0044] The above-mentioned organic bases, amino acids and insoluble alkaline carbonates all have a certain improvement effect on the release of microspheres. Among them, the most preferred N-methyl-D-glucamine has a pKa value of 9.6 and is a mild alkalizing agent. It is widely used in various pharmaceutical preparations such as injections and oral preparations, such as calcitonin, omeprazole, lipoic acid, ramipril, telmisartan, etc.; in addition, N-methyl-D-glucamine has good solubility in the solvent system of the present invention, which is conducive to process implementation and scale-up production.

[0045] 2. Another inventiveness of the present invention is to add surfactants, electrolytes or buffer salts and thickeners to the water phase. Adding surfactants to the water phase plays an auxiliary emulsification role, which can significantly improve the spherical shape, making it round and uniform. Simply increasing the PVA concentration cannot play the same role; adding buffer salts or electrolytes not only plays a role in adjusting the pH value of the water phase, but also can adjust the osmotic pressure of the water phase, reduce the solubility of the drug in water, and reduce the rate and degree of drug diffusion from the microspheres to the water phase, so as to achieve the purpose of increasing the drug loading and encapsulation rate; adding thickeners can increase the viscosity of the water phase, reduce the collision between microspheres, improve the morphological changes caused by the amplification effect, and inhibit the generation of crystals, reduce burst release, and facilitate the realization of amplified production.

[0046] 3. The preparation method of brepazine sustained-release microspheres provided by the present invention adopts stator-rotor shear emulsification and online shearing to prepare microspheres. Compared with the traditional mechanical stirring method, the process is simple, the particle size of the prepared microspheres is concentrated, the results are stable, the reproducibility is good, continuous production can be achieved, and industrial scale-up is easy to achieve.

[0047] 4. According to animal experiments, the brepazine sustained-release microspheres provided by the present invention have low burst release after administration, no lag period, and can be released smoothly, achieving a sustained-release effect of 1 month or longer. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Optical microscope image of microspheres prepared in Example 1;

[0049] Figure 2 This is a scanning electron microscope image of the microspheres prepared in Example 1;

[0050] Figure 3 Optical microscope image of microspheres prepared in Example 11;

[0051] Figure 4 Optical microscope image of microspheres prepared for Example 14;

[0052] Figure 5 Optical microscope image of microspheres prepared in Example 10;

[0053] Figure 6 Optical microscope image of microspheres prepared for Example 15;

[0054] Figure 7 The in vitro release curve of microspheres prepared in Example 1;

[0055] Figure 8 In vitro release curve of microspheres prepared for Example 3;

[0056] Fig. 9 In vitro release profile of microspheres prepared for Example 13;

[0057] Fig.10The in vitro release profile of microspheres prepared for Example 14;

[0058] Fig.11 The in vitro release curve of microspheres prepared for Comparative Example 1;

[0059] Fig.12 The in vitro release curve of microspheres prepared for Comparative Example 2;

[0060] Fig.13 The blood drug concentration-time curve of the microspheres prepared in Example 1 in rats;

[0061] Fig.14 The blood drug concentration-time curve of the microspheres prepared in rats in Example 13;

[0062] Fig.15 The blood drug concentration-time curve of the microspheres prepared in Example 14 in rats;

[0063] Fig.16 is the liquid chromatogram of the reference solution in Experimental Example 1;

[0064] Fig.17 This is the liquid chromatogram of the test solution in Example 1 in Experimental Example 1. DETAILED DESCRIPTION

[0065] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention, and unless otherwise specified, the following embodiments are all completed using conventional existing technologies.

[0066] The lactide-glycolide copolymers (PLGA) used were from Evonik Specialty Chemicals Co., Ltd.;

[0067] The dichloromethane and methanol used were from Nanjing Chemical Reagent Co., Ltd.;

[0068] The benzyl alcohol (injection grade) used was sourced from Jiangsu Baoyi Pharmaceutical Co., Ltd.;

[0069] The PVA used was from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd.;

[0070] The hypromellose used was sourced from Taian Ruitai Cellulose Co., Ltd.;

[0071] The tromethamine, triethanolamine, N -methyl-D-glucamine, ethylenediamine, and L -lysine used were from Merck;

[0072] The polysorbate 80 used was from Nanjing Well Pharmaceutical Group Co., Ltd.;

[0073] The anhydrous disodium hydrogen phosphate and anhydrous potassium hydrogen phosphate used were from Sinopharm Chemical Reagent Co., Ltd.;

[0074] The sodium chloride used was from Jiangsu Qinfen Pharmaceutical Co., Ltd.;

[0075] The shearing equipment used was a high shear emulsifier of the Silverson manufacturer, model L5M-A (stalar-rotor shearing) and model Verso (online shearing).

[0076] Example 1

[0077] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0078] (1) Weigh 0.30 g of brepazole, 0.44 g of lactide-co-glycolide copolymer (RG 504H 0.58 dL / g), and 10 mg of N-methyl-D-glucamine, add 3 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0079] (2) Prepare 250 ml of 1.5% polyvinyl alcohol solution, add 3.549 g of anhydrous disodium hydrogen phosphate, add 2.5 g of polysorbate 80, dissolve completely, degas by ultrasonication, and keep warm at 25°C as the aqueous phase;

[0080] (3) the speed of the high-speed emulsifier was set to 1600 rpm to disperse the oil phase into the water phase to obtain an O / W emulsion;

[0081] (4) The O / W emulsion obtained in step (3) is stirred at a low speed at 25° C. for 4 h, and then stirred at 40° C. for 1 h to evaporate and remove the organic solvent. After solidification, the emulsion is sieved, collected, washed, and freeze-dried to obtain the product.

[0082] Example 2

[0083] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0084] (1) Weigh 0.54 g of brepazole and 0.66 g of lactide-glycolide copolymer (RG 504H 0.58 dL / g), add 20 μl of ethylenediamine and 3 ml of a mixed solvent (dichloromethane:methanol=3:1) and dissolve completely to obtain the oil phase;

[0085] (2) Prepare 250 ml of 1.0% polyvinyl alcohol solution, add 1.78 g of anhydrous disodium hydrogen phosphate, add 0.25 g of polysorbate 80, dissolve completely, degas by ultrasonication, and keep warm at 5°C as the aqueous phase;

[0086] The other operation steps are the same as those in Example 1.

[0087] Example 3

[0088] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0089] (1) Weigh 0.30 g of brepazole, 0.396 g of lactide-glycolide copolymer (RG504H 0.58 dL / g), 0.044 g of lactide-glycolide copolymer (RG503H 0.36 dL / g), 5 mg of N-methyl-D-glucosamine, and 5 mg of lysine, add 3 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0090] (2) Prepare 250 ml of 1.75% polyvinyl alcohol solution, add 2.5 g of polysorbate 80, dissolve completely, degas by ultrasonication, and keep warm at 25° C. as the aqueous phase; weigh 1.78 g of anhydrous dipotassium hydrogen phosphate and 1.10 g of sodium chloride, add 20 ml of water and dissolve completely, record as solution 1.

[0091] (3) The speed of the high-speed emulsifier is set to 1600 rpm to disperse the oil phase into the water phase to obtain an O / W emulsion; after the shearing is completed, solution 1 is added at a uniform speed.

[0092] The other operation steps are the same as those in Example 1.

[0093] Example 4

[0094] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0095] (1) Weigh 0.40 g of brepazole, 0.411 g of lactide-co-glycolide (RG 753H 0.38 dL / g), 0.176 g of lactide-co-glycolide (RG 752H 0.20 dL / g), and 13 mg of N-methyl-D-glucamine, add 3 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0096] (2) Prepare 250 ml of 1% polyvinyl alcohol solution, add 3.549 g of anhydrous disodium hydrogen phosphate, add 1.25 g of polysorbate 80, dissolve completely, degas by ultrasonication, and keep warm at 25°C as the aqueous phase;

[0097] (3) the speed of the high-speed emulsifier was set to 2300 rpm to disperse the oil phase into the water phase to obtain an O / W emulsion;

[0098] (4) The O / W emulsion obtained in step (3) was stirred at a low speed of 25° C. for 4 h and at 40° C. for 1 h to evaporate and remove the organic solvent. After solidification, the emulsion was sieved, collected, washed, and freeze-dried to obtain microspheres.

[0099] Example 5

[0100] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0101] (1) Weigh 0.24 g of brepazole and 0.44 g of lactide-glycolide copolymer (RG 753H 0.38 dL / g), add 10 mg of meglumine and 2.5 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0102] (2) Prepare 250 ml of 2.0% polyvinyl alcohol solution, add 3.549 g of anhydrous disodium hydrogen phosphate, add 1.25 g of polysorbate 80, dissolve completely, degas by ultrasonication, and keep warm at 25° C. as the aqueous phase; weigh 1.25 g of poloxamer 188, add 20 ml of water and dissolve completely, record as solution 1.

[0103] (3) The speed of the high-speed emulsifier is set to 1600 rpm to disperse the oil phase into the water phase to obtain an O / W emulsion; after shearing is complete, solution 1 is added.

[0104] (4) The O / W emulsion obtained in step (3) was stirred at a low speed of 5° C. for 1 h and at 25° C. for 4 h to evaporate and remove the organic solvent. After solidification, the emulsion was sieved, collected, washed, and freeze-dried to obtain microspheres.

[0105] Example 6

[0106] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0107] (1) Weigh 0.36 g of brepazole, 0.53 g of lactide-co-glycolide copolymer (RG 504H 0.58 dL / g), and 20 μl of ethylenediamine, add 3 ml of a mixed solvent (dichloromethane:methanol=5:1), and dissolve completely to obtain the oil phase;

[0108] The other operation steps are the same as those in Example 1.

[0109] Example 7

[0110] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0111] (1) Weigh 0.45 g of brepazole, 0.44 g of lactide-glycolide copolymer (RG 504H 0.58 dL / g), and 10 mg of N-methyl-D-glucamine, add 5 ml of a mixed solvent (dichloromethane: N-methylpyrrolidone (NMP) = 3:2) and dissolve completely to obtain the oil phase;

[0112] The other operation steps are the same as those in Example 1.

[0113] Example 8

[0114] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0115] (1) Weigh 0.30 g of brepazole, 0.445 g of lactide-glycolide copolymer (RG 504H 0.58 dL / g), and 5 mg of tromethamine, add 3 ml of a mixed solvent (dichloromethane:benzyl alcohol=5:1), and dissolve completely to obtain the oil phase;

[0116] Other operations are the same as in Example 1.

[0117] Example 9

[0118] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0119] (1) Weigh 1.20 g of brepazole, 1.76 g of lactide-glycolide copolymer (RG 504H 0.58 dL / g), and 40 mg of N-methyl-D-glucamine, add 9 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0120] (2) Prepare 420 ml of 5% polyvinyl alcohol solution, add 8.518 g of anhydrous disodium hydrogen phosphate, 6 g of polysorbate 80, and 240 ml of 1% hydroxypropyl methylcellulose solution, dissolve completely, add water to make up to 1200 ml, degas by ultrasonication, and keep warm at 25°C as the aqueous phase;

[0121] (3) the speed of the high-speed emulsifier was set to 1700 rpm to disperse the oil phase into the water phase to obtain an O / W emulsion;

[0122] (4) The O / W emulsion obtained in step (3) was purged with compressed air (flow rate was 2.68 m 3 / h), stirred at a low speed at 25°C for 4h, stirred at 40°C for 1h, and the organic solvent was evaporated to remove. After solidification, the microspheres were collected by sieving, washed, and freeze-dried.

[0123] Example 10

[0124] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0125] (1) Weigh 1.44 g of brepazole, 2.11 g of lactide-glycolide copolymer (RG 504H 0.58 dL / g), and 48 mg of N-methyl-D-glucamine, add 9 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0126] (2) Prepare 360 ​​ml of 5% polyvinyl alcohol solution, add 1.2 g of polysorbate 80 and 120 ml of 1% hydroxypropyl methylcellulose solution, dissolve completely, add water to make up to 1200 ml, degas by ultrasonication, and keep warm at 25°C as the aqueous phase;

[0127] (3) Weigh 17.035 g of anhydrous disodium hydrogen phosphate and dissolve it in 50 ml of water for later use, which is referred to as solution 1. Set the speed of the high-speed emulsifier to 1500 rpm, disperse the oil phase into the water phase to obtain an O / W emulsion, and slowly add solution 1.

[0128] (4) The O / W emulsion obtained in step (3) was purged with compressed air (flow rate was 2.72 m 3 / h), stirred at a low speed at 25°C for 5h, the organic solvent was evaporated and removed, and after solidification, the microspheres were collected by sieving, washed, and freeze-dried.

[0129] Examples 11-15

[0130] The preparation method of brepazine sustained-release microspheres, the compositions and some preparation parameters of Examples 11-15 are as follows:

[0131]

[0132] The other operating steps of Examples 11-13 and 15 are the same as those of Example 1; the other operating steps of Example 14 are the same as those of Example 9.

[0133] Example 16

[0134] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0135] (1) Weigh 1.3208 g of brepazole, 1.9360 g of lactide-glycolide copolymer (RG 504H 0.58 dL / g), and 45 mg of triethanolamine, add 9 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0136] (2) Measure 1000 ml of 2% polyvinyl alcohol solution, add 17.035 g of anhydrous disodium hydrogen phosphate, add 1.2 g of polysorbate 80 and 120 ml of 1% hydroxypropyl methylcellulose, and after complete dissolution, add purified water to 1200 ml, degas by ultrasonication, and keep warm at 25° C. as the aqueous phase;

[0137] (3) the speed of the high-speed emulsifier was set to 1500 rpm to disperse the oil phase into the water phase to obtain an O / W emulsion;

[0138] (4) The O / W emulsion obtained in step (3) is stirred at a low speed of 25° C. for 4 h, then the temperature is adjusted to 40° C. and stirring is continued for 1 h to evaporate and remove the organic solvent. After solidification, the emulsion is sieved, collected, washed, and freeze-dried to obtain the product.

[0139] Embodiment 17

[0140] A method for preparing brepazine sustained-release microspheres, the specific steps are as follows:

[0141] (1) Weigh 1.2016 g of brepazole, 1.8005 g of lactide-glycolide copolymer (RG 504H 0.58 dL / g), and 40 mg of micronized magnesium carbonate, add 9 ml of a mixed solvent (dichloromethane:methanol=3:1), and dissolve completely to obtain the oil phase;

[0142] (2) Measure 1000 ml of 2% polyvinyl alcohol solution, add 17.035 g of anhydrous disodium hydrogen phosphate, add 1.2 g of polysorbate 80 and 24 ml of 1% hydroxypropyl methylcellulose, and after complete dissolution, add purified water to 1200 ml, degas by ultrasonication, and keep warm at 25° C. as the aqueous phase;

[0143] (3) the speed of the high-speed emulsifier was set to 1500 rpm to disperse the oil phase into the water phase to obtain an O / W emulsion;

[0144] (4) The O / W emulsion obtained in step (3) is stirred at a low speed of 25° C. for 4 h, then the temperature is adjusted to 40° C. and stirring is continued for 1 h to evaporate and remove the organic solvent. After solidification, the emulsion is sieved, collected, washed, and freeze-dried to obtain the product.

[0145] The shearing equipment used in the above Examples 1-8, 11-13, and 15 is the L5M-A model (stator-rotor shearing); the equipment used in the remaining Examples is the Verso model (online shearing) high shear emulsifier.

[0146] Experimental Example 1: Microsphere drug loading and encapsulation efficiency detection

[0147] Reference substance solution: accurately weigh 10 mg of brexpiprazole reference substance, dissolve it in methanol and quantitatively dilute it to make a solution with a concentration of 0.02 mg / ml.

[0148] Test solution: Take about 10 mg of the product, accurately weigh it, put it in a 100 ml volumetric flask, add 2 ml of dimethyl sulfoxide, dissolve it by ultrasonication, dilute it to the scale with 0.01 mol / L hydrochloric acid solution, shake well, filter, and take the filtrate.

[0149] Chromatographic conditions: octadecylsilane bonded silica gel as filler (YMC-Triart C18, 4.6mm×150mm, 3μm or chromatographic columns of equivalent performance are recommended); 10mmol / L potassium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid)-acetonitrile (60:40) as mobile phase; flow rate of 1.2ml / min; column temperature of 40℃; detection wavelength of 274nm; injection volume of 20μl.

[0150] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0151] The drug loading and encapsulation efficiency of microspheres were calculated according to the following formula:

[0152]

[0153] Where: A 样 is the peak area of ​​the main peak of breprazol in the chromatogram of the test solution;

[0154] A 对 is the peak area of ​​the main peak of breprazol in the chromatogram of the reference solution;

[0155] W 对 is the sample weight of brexpiprazole reference substance, mg;

[0156] W 样 is the sample weight of the test product, mg;

[0157] P is the content of breprazol reference substance;

[0158] V 对 is the dilution volume of the reference solution, ml;

[0159] V 样 is the dilution volume of the test solution, ml.

[0160] Encapsulation efficiency = actual drug loading / theoretical drug loading × 100%

[0161] The liquid chromatograms of the reference solution and the test solution in Example 1 are shown in the attached Fig.16 , 17 .

[0162] Experimental Example 2 Microsphere Release Test

[0163] Preparation of reference solution: Weigh 10 mg of brepazine reference substance, place in a 25 ml volumetric flask, add methanol, shake and ultrasonically dissolve and dilute to scale, shake well as reference stock solution. Take 1 ml of reference stock solution, place in a 10 ml volumetric flask, dilute to scale with methanol, shake well, and the release rate is obtained. The release rate determination method is shown in the following table:

[0164]

[0165]

[0166] C1 is the concentration of the filtrate measured for the first time (mg / ml);

[0167] Cn-1 is the concentration of the filtrate measured for the n-1th time (mg / ml);

[0168] Cn is the concentration of the filtrate measured for the nth time (mg / ml);

[0169] W 样 is the weight of brexpiprazole microsphere sample, mg.

[0170] Experimental Example 3 Microsphere Particle Size Detection

[0171] The particle size of the samples was measured using a Mastersizer 3000 laser particle size analyzer.

[0172] Sample preparation: Add the sample to a glass bottle with a diameter of 2 cm, spread it on the bottom of the glass bottle, add 5 ml of water, and ultrasonicate in a water bath for 1-2 seconds, repeat 3 times. Ultrasonicate and degas the purified water, measure 400 ml of water, put it in a 500 ml beaker, put it into the HydroEV dispersion system, rotate at 2100 rpm, and add the sample to the beaker after deducting the background (if there is any sample residue, rinse it into the beaker with an appropriate amount of purified water).

[0173] Experimental Example 4: Residual Solvent Detection

[0174] Reference solution: Take 35 mg of methanol and 65 mg of dichloromethane, place them in a 20 ml volumetric flask, dilute to the mark with dimethyl sulfoxide, and shake well. Accurately measure 1 ml, place it in a 20 ml volumetric flask, dilute to the mark with dimethyl sulfoxide, and shake well.

[0175] Test solution: Accurately weigh 50 mg of the product, place it in a 20 ml headspace bottle, add 1 ml of dimethyl sulfoxide to dissolve it, and shake well.

[0176] Chromatographic conditions: a capillary column (0.53 mm × 30 m, 3.00 μm) with 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as the stationary phase; the starting temperature is 40°C, maintained for 15 min, then heated to 240°C at a rate of 100°C / min, and maintained for 27 min; the injection port temperature is 250°C; the detector is a hydrogen flame ionization detector (FID), and the detector temperature is 280°C; the column flow rate is 2.0 ml / min; and the split ratio is 10:1.

[0177] Experimental Example 5 Pharmacokinetics of Brepirapazole Microspheres in Rats

[0178] Single parallel administration was adopted, 12 male rats were divided into 3 groups, and the brepazole microspheres prepared in Example 1, Example 13, and Example 14 were taken, suspended in a special solvent, and then intramuscularly injected into rats, and the dosage was 8.4 mg / Kg. Blood samples were collected before administration (0h), 0.5h, 1h, 2h, 6h, 1d, 3d, 5d, 7d, 10d, 14d, 17d, 21d, 24d, 28d, 31d, and 35d after administration, about 0.5ml / time point, and the brepazole concentration in the blood was determined by the established LC-MS / MS analysis method, and the drug-time curve was drawn to evaluate the blood drug concentration-time relationship.

[0179] Experimental Examples 1-5 Results and Discussion

[0180] 1. Observation of microsphere morphology during curing process

[0181] After emulsification, samples were taken at different curing times to observe the morphology under a microscope. Electron microscope, model AX-300, manufacturer Jinan Qiangsheng Optoelectronic Instrument Co., Ltd.

[0182] Example 11 The PVA concentration in the aqueous phase was selected to be 1.50%, and no surfactant such as polysorbate 80 was added to prepare microspheres with the morphology as shown in Figure 3 As shown in A and 3B (3A indicates that the surface of the obtained microspheres is granular; 3B indicates that the roundness of the microspheres is poor), the microspheres are uneven in shape, have poor roundness, and the surface of the spheres is granular and uneven; Example 15 prepares microspheres by simply increasing the concentration of the aqueous phase PVA solution to 2.50% without adding a surfactant such as polysorbate 80. The microspheres prepared are partially rounded, but there are spheres of varying depths and a small number of spheres with pimples on the surface under a microscope, such as Figure 6 As shown; Example 1 The concentration of PVA in the aqueous phase was selected to be 1.50%, and 1% polysorbate 80 was added to prepare the microspheres, which were round and uniform in shape. Figure 1 As shown in the electron microscope image Figure 2 As shown. In summary, the addition of surfactants can assist emulsification and significantly improve the spherical shape, making it round and uniform. It can be seen that simply increasing the PVA concentration cannot play the same role.

[0183] Example 14 Online shear amplification preparation of microspheres, no hydroxypropyl methylcellulose solution was added to the aqueous phase, and sampling was observed after emulsification. There was a little adhesion between the microspheres, and a small number of goose egg-shaped spheres appeared. The morphology is shown in the figure Figure 4 As shown in A, drug crystals (mostly rhombus and rod-shaped) appear in the aqueous phase after about 3 hours of solidification. Figure 4 As shown in B, in the subsequent microsphere collection and washing process, only pure water washing cannot remove the crystals, and 1‰ hydrochloric acid solution or an acidic solution with a certain pH value is required to remove the crystals, but it will also corrode the polymer and affect the subsequent release of the microspheres. In Example 10, the microspheres prepared by online shearing are round, uniform, and evenly dispersed. Figure 5 As shown, it is preferred that a thickener be added to the water phase when online shearing is selected.

[0184] 2. Drug loading, encapsulation efficiency, and residual solvent test results

[0185] According to the detection method in the above experimental example, the drug loading, encapsulation efficiency and residual solvent of the microspheres prepared in Examples 1-17 were detected, and the results were calculated according to the above calculation formula. The results are shown in the following table.

[0186] Summary table of encapsulation efficiency, drug loading, and residual solvent results

[0187]

[0188] Note: “ / ” means not detected; ND means not detected.

[0189] As can be seen from the above table, the microspheres prepared in Examples 1-10 have high drug loading and the drug is well encapsulated. No buffer salt was added to the aqueous phase in Example 12, and the encapsulation rate was significantly reduced compared with Example 1, indicating that adding buffer salts or electrolytes to the aqueous phase can adjust the pH value and osmotic pressure of the aqueous phase, reduce the solubility of the drug in water, and significantly increase the drug loading and encapsulation rate.

[0190] 3. In vitro release test results

[0191] Example 1 Release curve see Figure 7 , the release curve of Example 3 is shown in Figure 8 , the release curve of Example 13 is shown in Fig. 9 , Example 14 Release curve see Fig.10 .

[0192] The microspheres prepared in Examples 1 and 3 released the drug smoothly. There was no hysteresis period in the early stage after the addition of the additives. The drug was released almost linearly, and the release period reached 30 days, which was in line with expectations.

[0193] The microspheres prepared in Example 13 had almost no drug release in 4-15 days, and there was a "lag period" of about 10 days. However, when organic bases and basic amino acids were added to the oil phase (Examples 1 and 3), there was no lag period, and the drug was released almost linearly, with a more stable release.

[0194] Example 14 In the online shear-amplification batch preparation of microspheres, no hypromellose was added to the aqueous phase. During the preparation process, drug crystals appeared in the external aqueous phase, and the early burst release was relatively high.

[0195] 4. Particle size test results

[0196]

[0197]

[0198] The particle size of the microspheres prepared in Examples 1-17 is 40-70 μm, which meets the particle size requirements for intramuscular injection of microsphere preparations, and the particle size can be controlled by adjusting the shear speed.

[0199] 5. Pharmacokinetic results

[0200] Experimental results: The blood drug concentration-time curves of rats in Example 1, Example 13 and Example 14 are shown in Fig.13 (0-35 days), Fig.14 , Fig.15 .

[0201] The results show that the microspheres prepared in Example 1 release a small amount of drug in rats initially, and then release the drug steadily for 30 days. The sudden release and blood drug concentration fluctuation are small, and the drug can be administered once every 4 weeks.

[0202] After the initial release of the drug from the microspheres prepared in Example 13 in rats, there was almost no drug release from days 1 to 7, and there was a lag period of about 1 week.

[0203] Example 14 Preparation of microspheres Initial large-scale drug release in rats, then maintained at a lower concentration for 30 days. The burst release was high and the drug release period was difficult to guarantee.

[0204] Comparative Example 1

[0205] According to Example 1 in patent CN116531379, the breprazol sustained-release composition is prepared, and the steps are as follows:

[0206] 24 mg of polylactic acid, 120 mg of lactide-co-glycolide (RG753H 0.38 dL / g), 48 mg of polycaprolactone and 96 mg of brepazole were ultrasonically dissolved in 3 ml of dichloromethane to form an oil phase, and the oil phase was added to 300 ml of 0.5% (w / v) polyvinyl alcohol aqueous solution, and sheared at 3000 rpm for 60 seconds with a high-speed emulsifier to form an oil-in-water emulsion, and stirred at 400 rpm for 4 hours with a magnetic stirrer to volatilize the organic solvent. The solidified composition was collected by centrifugation, washed and freeze-dried to obtain the product.

[0207] According to the detection method of Experimental Examples 1-4, the drug loading, encapsulation efficiency and residual solvent were tested. The results are shown in the following table:

[0208] Theoretical drug loading (%) Actual drug loading (%) Encapsulation rate (%) Residual solvent (%) Comparative Example 1 33.33 28.74 86.23 0.32

[0209] The drug loading of the composition prepared in Comparative Example 1 is 28.74% and the encapsulation efficiency is 86.23%. It uses three polymer materials, has a complex prescription, has a lower drug loading than the present invention, and has a small preparation batch and low preparation efficiency, making it difficult to scale up.

[0210] The release rate was determined according to the method of Experimental Example 2. The release curve is as follows Fig.11 As shown, after the initial large amount of drug (about 20%) is released, it enters a hysteresis period of about 10 days, and then the drug is continuously released for about 20 days. The overall release shows a release behavior with a large burst release and a long initial hysteresis period.

[0211] Comparative Example 2

[0212] According to Example 1 of the patent WO 2023036003 A1 brepirazole long-acting preparation for injection and its preparation method, brepirazole suspension is prepared in the following steps:

[0213] (1) Preparation of brepazole solution: weigh 10 g of brepazole, add 100 ml of dimethyl sulfoxide, and stir at 60° C. to dissolve;

[0214] (2) Preparation of precipitation solution: Measure 200 ml of purified water and 0.1 g of Tween 80 in a 500 ml beaker;

[0215] (3) Sample preparation: Place the shear head into the precipitation solution and set the shear rate to 3.14 m / s. Pump the brepazole solution into the precipitation solution at a rate of 100 ml / min (36 s), filter and remove the filtrate. Wash the filter cake with 1000 ml of pure water, and transfer the obtained solid to a 40°C drying oven for drying to obtain a dry powder.

[0216] (4) Preparation of suspension:

[0217] Dispersant preparation: weigh 2.5g sodium carboxymethyl cellulose, 0.2g sodium dihydrogen phosphate, and 12.5g mannitol into a 500ml beaker, add 249ml purified water, and stir until completely dissolved.

[0218] Sample dispersion: weigh 5.7 g of the above dry powder, add 44.3 g of dispersant, shake manually for 5 min to mix, and then a suspension can be obtained.

[0219] According to the determination method in Experimental Examples 2 and 3, the particle size and release rate in the suspension were detected. The particle size was Dv10 = 2.1 μm, Dv50 = 4.3 μm, Dv90 = 10.4 μm, the span was 1.93, and the particle size distribution range was wide; the release curve was as follows Fig.12 As shown in the figure, the drug reaches a plateau phase after a large amount of initial release, and is basically completely released in 4 hours, without a sustained-release effect.

[0220] Experimental Example 6 Screening of PLGA concentration in oil phase

[0221] The properties of microspheres prepared with PLGA concentrations of 150 mg / ml, 200 mg / ml, and 250 mg / ml were investigated respectively. The prescription parameters are shown in the table below.

[0222]

[0223]

[0224] Note: To facilitate the study of solvent volume usage, PLGA concentration is calculated by dividing PLGA weight by oil phase solvent volume.

[0225] PLGA concentration test results

[0226]

[0227] The results showed that the encapsulation efficiency of the prepared microspheres was similar when the PLGA concentration was in the range of 150mg / ml-250mg / ml; the in vitro release slightly accelerated with the increase of PLGA concentration, but the difference was not significant.

[0228] Experimental Example 7 Investigation of Theoretical Drug Loading

[0229] The theoretical drug loading will affect the release rate and dosage of microspheres. The properties of microspheres prepared at theoretical drug loadings of 35%, 40%, and 45% were investigated respectively. The theoretical drug loading screening prescription design table is as follows:

[0230]

[0231]

[0232] Theoretical drug loading test results

[0233]

[0234] From the above results, it can be seen that there is no significant difference in the encapsulation efficiency of microspheres prepared with different theoretical drug loadings; the release of microspheres increases slightly with the increase of theoretical drug loading, but the overall difference is not large, and the drug loading can be selected from 30% to 50%.

[0235] Experimental Example 8 Investigation of Oil-Water Ratio

[0236] The oil-water ratio is a key factor affecting the drug loading, encapsulation efficiency and release rate of microspheres. The oil-water ratio will also affect the batch output during production. The effects of oil-water ratios of 1:50, 1:100 and 1:150 on the properties of microspheres were investigated respectively.

[0237] Oil-water ratio investigation prescription design table

[0238]

[0239]

[0240] Oil-water ratio test results

[0241]

[0242] The results showed that there was no significant difference in drug loading, encapsulation efficiency and release rate of microspheres prepared in the oil-water ratio range of 1:50-1:150.

[0243] For ordinary technicians in this field, the specific embodiments are only illustrative descriptions of the present invention. It is obvious that the specific implementation of the present invention is not limited to the above-mentioned methods. As long as various non-substantial improvements are made using the method concepts and technical solutions of the present invention, or the concepts and technical solutions of the present invention are directly applied to other occasions without improvement, they are all within the protection scope of the present invention.

Claims

1. A brepazine sustained-release microsphere, characterized in that: The raw materials include brepazole and lactide-glycolide copolymer; wherein the content of brepazole is 10%-50% of the total weight of brepazole and lactide-glycolide copolymer; the content of lactide-glycolide copolymer is 50%-90% of the total weight of brepazole and lactide-glycolide copolymer; the above microspheres also contain additives, the amount of which is 0.5%-5% of the weight of lactide-glycolide copolymer; wherein the additive is N-methyl-D-glucamine; The method for preparing the above-mentioned brepazine sustained-release microspheres comprises the following steps: (1) Oil phase preparation dissolving brepazole, additives and lactide-glycolide copolymer in an organic solvent and mixing them well to form an oil phase; (2) Water phase preparation Polyvinyl alcohol is dissolved in water, a certain amount of buffer salt or electrolyte and surfactant solution and / or thickener are added, and mixed to form the aqueous phase; (3) Shear emulsification At a certain temperature, the oil phase of step (1) and the water phase solution of step (2) are subjected to high-speed shear emulsification in a certain ratio to prepare an O / W emulsion; (4) Curing Stirring the emulsion from step (3) at a certain temperature and / or pressure to volatilize and remove the organic solvent; (5) Collection and freeze-drying The solidified suspension is collected through a sieve, washed, and freeze-dried to obtain; The concentration of the polyvinyl alcohol solution in step (2) is w / v 0.5%-2.5%; the temperature of the water phase is 5-30°C; the buffer salt or electrolyte is selected from one of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and sodium chloride, or a combination of any two of them in any ratio, and the final salt concentration in the water phase is 0.02 mol / L-0.5 mol / L; the surfactant is selected from one of polysorbate 80, polysorbate 20, or poloxamer 188, and the final surfactant concentration in the water phase is w / v 0.01%-2%; the thickener is selected from one of hydroxypropyl methylcellulose, hydroxyethyl starch, and sodium carboxymethyl cellulose, or a combination of any two of them in any ratio, and the final thickener concentration in the water phase is w / v 0.01%-2%.

2. The brepazine sustained-release microspheres according to claim 1, characterized in that: The content of brepazole is 30-40% of the total weight of brepazole and lactide-glycolide copolymer; the content of lactide-glycolide copolymer is 60-70% of the total weight of brepazole and lactide-glycolide copolymer; the amount of additives is 1%-3% of the weight of lactide-glycolide copolymer.

3. The breprazol sustained-release microspheres according to claim 1 or 2, characterized in that: The lactide-glycolide copolymer structural formula is as follows: The terminal groups of the lactide-glycolide copolymer are carboxyl groups; the weight average molecular weight of the lactide-glycolide copolymer is 5000-90000 Daltons; the intrinsic viscosity is 0.14-0.75 dL / g; the molecular weight distribution coefficient is 1.0-3.0; and the molar ratio of lactide to glycolide is 95:05-50:

50.

4. The method for preparing the brepazine sustained-release microspheres according to claim 1, characterized in that: The steps include: (1) Oil phase preparation dissolving brepazole, additives and lactide-glycolide copolymer in an organic solvent and mixing them well to form an oil phase; (2) Water phase preparation Polyvinyl alcohol is dissolved in water, a certain amount of buffer salt or electrolyte and surfactant solution and / or thickener are added, and mixed to form the aqueous phase; (3) Shear emulsification At a certain temperature, the oil phase of step (1) and the water phase solution of step (2) are subjected to high-speed shear emulsification in a certain ratio to prepare an O / W emulsion; (4) Curing Stirring the emulsion from step (3) at a certain temperature and / or pressure to volatilize and remove the organic solvent; (5) Collection and freeze-drying The solidified suspension is collected through a sieve, washed, and freeze-dried to obtain; The concentration of the polyvinyl alcohol solution in step (2) is w / v 0.5%-2.5%; the temperature of the water phase is 5-30°C; the buffer salt or electrolyte is selected from one of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and sodium chloride, or a combination of any two of them in any ratio, and the final salt concentration in the water phase is 0.02 mol / L-0.5 mol / L; the surfactant is selected from one of polysorbate 80, polysorbate 20, or poloxamer 188, and the final surfactant concentration in the water phase is w / v 0.01%-2%; the thickener is selected from one of hydroxypropyl methylcellulose, hydroxyethyl starch, and sodium carboxymethyl cellulose, or a combination of any two of them in any ratio, and the final thickener concentration in the water phase is w / v 0.01%-2%.

5. The method for preparing brepazine sustained-release microspheres according to claim 4, characterized in that: The organic solvent in step (1) is a mixed solvent consisting of dichloromethane and a second solvent; the second solvent is selected from one of methanol, benzyl alcohol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone; the volume ratio of dichloromethane to the second solvent in the mixed solvent is 15:1-1:1; the weight ratio of the mixed solvent to brexpiprazole is 15:1-5:1; the temperature of the organic phase in step (1) is 5-30°C.

6. The method for preparing brepazine sustained-release microspheres according to claim 4, characterized in that: In step (3), the volume ratio of the oil phase solvent to the water phase solution is 1:50-1:300; the rotation speed of the high-speed shear is 1500rpm-3000rpm.

7. The method for preparing brepazine sustained-release microspheres according to claim 4, characterized in that: The solvent volatilization temperature in step (4) is 20°C-40°C; the pressure during the solvent volatilization is normal pressure or negative pressure; and the solvent volatilization time is 4h-6h.

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