Brexpiprazole sustained-release microspheres with high drug loading capacity and preparation method of brexpiprazole sustained-release microspheres

Abstract

The invention discloses brexpiprazole sustained-release microspheres with high drug loading capacity and a preparation method thereof, and the preparation method comprises the following steps: dissolving brexpiprazole and PLGA (poly (lactic-co-glycolic acid)) in an organic solvent to prepare a dispersion phase, and then mixing with a PVA (polyvinyl alcohol) aqueous solution through a microfluidic technology to prepare micro-droplets; and curing the micro-droplets in a curing solution which is a PVA-NaCl solution, and carrying out centrifugal freeze-drying to obtain the brexpiprazole sustained-release microspheres. The brexpiprazole sustained-release microsphere prepared efficiently and stably has the advantages of good roundness, uniform particle size, high drug loading capacity, high encapsulation efficiency, long-acting release and the like.

Description

Technical Field

[0001] This invention belongs to the field of sustained-release drug formulation technology, specifically relating to a high-drug-loaded ipilapiazole sustained-release microsphere and its preparation method. Background Technology

[0002] Bripiprazole (trade name: Rexulti) is a novel atypical antipsychotic drug, approved by the U.S. Food and Drug Administration (FDA) on July 10, 2015. It is clinically used as adjunctive therapy for schizophrenia and depressive disorders; clinical studies have shown that bripiprazole is effective and has good safety and tolerability in adjunctive treatment of these disorders. Due to the specific nature of psychiatric patients, many cannot adhere to regular medication regimens. Therefore, during treatment, adherence to conventional dosage forms is low, with frequent missed doses or even refusal to take medication, leading to treatment interruption, worsening of the patient's condition, or readmission, increasing the psychological and financial burden on patients and their families. Therefore, there is a need to develop dosage forms and long-acting formulations that improve adherence. Long-acting injectable sustained-release microspheres offer advantages such as reduced dosing frequency, convenient administration, good bioavailability, stable blood drug concentrations, no first-pass effect in the liver, and high patient compliance. Therefore, controlled-release bripiprazole microspheres have high clinical value.

[0003] Chinese patent CN116531379A discloses an epilapiazole sustained-release composition and its preparation method. Microspheres are prepared by mechanical stirring using polylactic acid, polylactic acid-glycolic acid copolymer, and polycaprolactone in a specific ratio as excipients, dissolved together with epilapiazole in dichloromethane as the oil phase. The resulting microspheres have a particle size of approximately 10-30 μm. However, the microspheres exhibit insufficient particle size uniformity, inconsistent sizes, and a wide particle size distribution. This not only leads to poor batch-to-batch repeatability and particle size inhomogeneity but also restricts the study of the structure-activity relationship of the microspheres, affecting application effects and potentially causing unpredictable adverse reactions. Furthermore, the complex excipient formulation makes it difficult to understand and analyze the in vitro and in vivo release of the microspheres.

[0004] International patent WO2023 / 036003A1 discloses an injectable long-acting epipiperazole formulation and its preparation method, which uses a solvent precipitation method to prepare an epipiperazole suspension. However, the particle size distribution of the drug in the suspension is uneven, with most particles ranging from 0 to 30 μm. This results in poor batch-to-batch reproducibility, leading to inconsistent actual doses for each administration. Furthermore, compared to microsphere formulations, suspensions are less stable and more prone to chemical degradation, losing their activity and thus reducing therapeutic efficacy.

[0005] Furthermore, current PLGA microsphere preparation processes all require curing. Conventional curing methods involve stirring to evaporate organic solvents, or curing through heating or vacuuming. However, excessively high stirring speeds can cause the microsphere structure to collapse, ultimately failing to produce microspheres, and also result in low curing efficiency. Heating and vacuuming place high demands on curing equipment, making them unsuitable for large-scale production. Therefore, there is an urgent need for a stable and efficient method to prepare epilapiazole sustained-release microspheres to improve their encapsulation efficiency, drug loading, and release stability. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a high-drug-loaded ipilapiazole sustained-release microsphere and its preparation method. The ipilapiazole sustained-release microsphere prepared efficiently and stably has advantages such as good sphericity, uniform particle size, high drug loading, high encapsulation efficiency, and long-term release.

[0007] To achieve the above objectives, the present invention provides a method for preparing high-drug-loaded ipilapiazole sustained-release microspheres, comprising the following steps: (1) Add epilapiazole and polylactide-glycolic acid copolymer to an organic solvent and mix to obtain a clear dispersed phase; (2) Mix PVA with water to obtain a continuous phase; (3) Microdroplets are prepared by mixing the dispersed phase and the continuous phase through microfluidics; (4) Place the microdroplets in an open container containing the curing liquid, shake to complete the curing, and obtain cured slow-release microspheres; (5) The solidified sustained-release microspheres were centrifuged and freeze-dried to obtain epilapiazole sustained-release microspheres.

[0008] Preferably, in the dispersed phase described in step (1), the mass ratio of epipiperazole to polylactide-glycolic acid copolymer is 1:1-10, wherein the concentration of epipiperazole is 10-40 mg / mL and the concentration of polylactide-glycolic acid copolymer is 25-250 mg / mL.

[0009] More preferably, the mass ratio of the epipiperazole to the polylactide-glycolic acid copolymer is 1:3.

[0010] Preferably, the organic solvent in step (1) is any one of dichloromethane, dichloromethane-acetone solution, and dichloromethane-acetonitrile solution.

[0011] More preferably, the mass ratio of dichloromethane to acetone in the chloromethane-acetone solution is 1-4:1; and the mass ratio of dichloromethane to acetonitrile in the dichloromethane-acetonitrile solution is 1-8:1.

[0012] Preferably, the dispersed phase described in step (1) needs to be treated with a tetrafluoroethylene filter membrane (0.22 μm).

[0013] Preferably, the concentration of the continuous phase in step (2) is 0.5-2%.

[0014] More preferably, the preparation conditions of the continuous phase are: magnetic stirring for 30 min followed by constant temperature dissolution at 90°C for 30-50 min; the continuous phase is then filtered through a 0.22 μm filter membrane.

[0015] Preferably, the microfluidic in step (3) uses a multi-channel microfluidic pressure controller / pressure pump, wherein the glass chip GL-FF-250A is used and the material is B270 glass; the dispersed phase flow rate of the microfluidic is 20-40 μL / min and the pressure is 130-150 mbar; the continuous phase flow rate is 80-90 μL / min and the pressure is 210-230 mbar.

[0016] More preferably, the dispersed phase has a flow rate of 30 μL / min and a pressure of 140 mbar; the continuous phase has a flow rate of 85 μL / min and a pressure of 220 mbar.

[0017] Preferably, the volume ratio of microdroplets to curing liquid in step (4) is 1:40-60, and the shaking speed is 40-60 rpm.

[0018] More preferably, the curing solution is a PVA-NaCl solution.

[0019] Preferably, the open container in step (4) is made of glass, and the ratio of the diameter (mm) of the open container to the volume (mL) of the microdroplets is 50-150:1-5; the height of the solidified liquid in the open container is 0.4-1cm.

[0020] More preferably, the concentration of PVA in the PVA-NaCl solution is 1-2.5%, and the concentration of NaCl is 0.1-0.5%.

[0021] Preferably, the centrifugation conditions are 1000-3000 r / min for 5 min, and the number of centrifugations is 3-8.

[0022] The present invention also provides a high-drug-loaded ipilapiazole sustained-release microsphere, wherein the ipilapiazole sustained-release microsphere is prepared by the above-described preparation method.

[0023] Preferably, the molar ratio of lactic acid to glycolic acid in the PLGA sustained-release microspheres of the epipipezazole is (50-75):(25-50), M w The weight-average molecular weight is 15.0-85.0 kDa.

[0024] Further preferred, PLGA's Mw The range is 17.0-76.0 kDa.

[0025] Preferably, the particle size of the epipiperazole-PLGA sustained-release microspheres is 30-100 μm, and epipiperazole accounts for 10-50% of the total mass of the microspheres.

[0026] The beneficial effects of this invention are as follows: 1. Biodegradable, long-acting sustained-release microspheres were prepared by encapsulating epipiperazole using polylactic-co-glycolic acid copolymer (PLCA), a biodegradable polymer, as a carrier material. These microspheres exhibit good sphericity, uniform particle size, and high drug loading. The epipiperazole encapsulated within the microspheres is slowly released through internal aqueous channels. It is expected to provide stable, sustained release in vitro for 30 days, with a cumulative release exceeding 90%, and the release is uniform and stable. A single dose can maintain treatment for one month, improving patient compliance, enhancing efficacy, and importantly, ensuring safety and controllability.

[0027] 2. Uniformly sized microdroplets containing epilapiazole were prepared using microfluidic control. These microdroplets were then solidified in a PVA-NaCl solution, improving solidification efficiency. Before complete solidification, the microdroplets act as a semi-permeable membrane separating the inner and outer aqueous phases. The drug within the microdroplets causes its osmotic pressure to be higher than that of the outer aqueous phase. This osmotic pressure difference promotes drug diffusion from the inner to the outer aqueous phase, while the osmotic pressure also causes water in the outer phase to migrate inwards. The resulting "channels" further exacerbate drug loss, leading to a decrease in the encapsulation efficiency of the microspheres. Adding an appropriate concentration of NaCl solution to the solidification solution during the microsphere solidification process can reduce or balance the osmotic pressure difference between the inner and outer aqueous phases, thereby increasing the encapsulation efficiency and improving solidification efficiency.

[0028] 3. PLGA with a molar ratio of lactic acid to glycolic acid between (50-75):(25-50) is selected to ensure that the degradation rate of the epipiperazole sustained-release microspheres is maintained at an appropriate level, thereby ensuring a stable release time of 30 days. Furthermore, the epipiperazole sustained-release microspheres prepared by this invention have uniform particle size, good repeatability, and good sustained-release effect, which can effectively reduce the frequency of medication administration for patients. Attached Figure Description

[0029] Figure 1 This is an optical microscope image of the ipiliprazole sustained-release microspheres prepared in Example 1.

[0030] Figure 2 The particle size distribution diagram is shown for the ipilipazole sustained-release microspheres prepared in Example 1.

[0031] Figure 3 This is an optical microscope image of the ipiliprazole sustained-release microspheres prepared in Example 3.

[0032] Figure 4This is an optical microscope image of the PLGA unloaded microspheres prepared in Example 10 after curing.

[0033] Figure 5 This is a detection wavelength scan of the 60 μg / mL PLGA empty microsphere solution in Example 10.

[0034] Figure 6 This is a detection wavelength scan of the 10 μg / mL epilapiazole solution in Example 10.

[0035] Figure 7 This is a detection wavelength scan of the microsphere solution containing 10 μg / mL epilapiazole + 60 μg / mL PLGA in Example 10. Figure 8 This is the standard curve of the epipiperazole solution in Example 11.

[0036] Figure 9 The images show the in vitro release curves of different microspheres in Example 11. Detailed Implementation

[0037] The technical solution of the present invention will be further explained and described below with reference to the accompanying drawings and specific embodiments. It is worth noting that the following embodiments are only preferred embodiments of the present invention and should not be construed as limiting the present invention. The scope of protection of the present invention should be determined by the contents of the claims. Modifications and substitutions made by those skilled in the art to the technical solution of the present invention without creative effort all fall within the scope of protection of the present invention.

[0038] In the following examples, PLGA is selected from 5002A, 5002E, 5005E and 5007A, wherein the weight-average molecular weight (M) of 5002A is... W The value is 22.1 kDa, and the molar ratio of lactic acid to glycolic acid is 50:50; The weight-average molecular weight (M) of 5002E W The energy content is 17.3 kDa, and the molar ratio of lactic acid to glycolic acid is 50:50. The weight-average molecular weight (M) of 5005E W The energy content is 76.7 kDa, and the molar ratio of lactic acid to glycolic acid is 50:50. The weight-average molecular weight (M) of 5007A W The content is 83.5 kDa, and the molar ratio of lactic acid to glycolic acid is 50:50.

[0039] Example 1 (1) Weigh 150mg PLGA (5002A, M) w 75 mg of ipilipazole (22.1 kDa) was added to 3 mL of organic solvent, vortexed and sonicated for 5 min to prepare the dispersed phase; (2) Add 2g PVA to 100mL of double-distilled water, stir magnetically for 30 min, then place in a water bath and keep at 90℃ for 30 min until PVA is completely dissolved to obtain a continuous phase; (3) The pressure of the dispersed phase and the continuous phase are controlled by a pressure controller and connected to a microfluidic instrument to prepare microdroplets, wherein the flow rate of the dispersed phase is 30 μL / min and the pressure is 140 mbar, and the flow rate of the continuous phase is 85 μL / min and the pressure is 220 mbar. (4) Collect the microdroplets obtained in step (3), place them in 50 times their volume of curing solution, transfer the curing solution to a glass culture dish, and slowly shake on a shaker at 40 r / min to remove organic solvent, and then cure to obtain cured microspheres; the curing solution is a PVA-NaCl solution, wherein the concentration of PVA is 2% and the concentration of NaCl is 0.1 M; wherein the diameter of the glass culture dish is 116 mm, the height is 27 mm, the volume of the microdroplets is 5 mL, and the height of the curing solution is 10 mm; (5) Collect the solidified microspheres into centrifuge tubes, centrifuge at 1000 r / min at room temperature for 5 min, centrifuge 5 times, collect the microspheres, freeze them at -80℃, and then freeze-dry them in a freeze dryer for 48 h to obtain epilapiazole sustained-release microspheres.

[0040] Example 2 The method and steps are the same as in Example 1, except that the curing liquid in step (4) is changed to PVA-NaCl solution, wherein the concentration of PVA is 2% and the concentration of NaCl is 0.5 M, and ipilexazole sustained-release microspheres are prepared.

[0041] Example 3 The method and steps are the same as in Example 1, except that PLGA in step (1) is replaced with an index of 5002E, M. w For PLGA with a strength of 17.3 kDa, the curing solution in step (4) was changed to PVA-NaCl solution, where the concentration of PVA was 2% and the concentration of NaCl was 0.1 M, and ipilexazole sustained-release microspheres were prepared.

[0042] Example 4 The method and steps are the same as in Example 1, except that PLGA in step (1) is replaced with an index of 5002E, M. w For PLGA with a strength of 17.3 kDa, the curing solution in step (4) was changed to PVA-NaCl solution, wherein the concentration of PVA was 2% and the concentration of NaCl was 0.5 M, and ipilexazole sustained-release microspheres were prepared.

[0043] Example 5 The method and steps are the same as in Example 1, except that the mass of PLGA in step (1) is changed to 750mg and the model is changed to 5005E. WWith a strength of 76.7 kDa, epilapiazole sustained-release microspheres were prepared.

[0044] Example 6 The method and steps are the same as in Example 1, except that the mass of PLGA in step (1) is changed to 75mg and the model is changed to 5007A. W With a strength of 83.5 kDa, epilapiazole sustained-release microspheres were prepared.

[0045] Example 7 The method and steps are the same as in Example 1, except that the concentration of the continuous phase in step (2) is changed to 0.5%, and the curing solution is a PVA-NaCl solution, wherein the concentration of PVA is 0.5% and the concentration of NaCl is 0.1M; thus, ipilexazole sustained-release microspheres are prepared.

[0046] Example 8 The method and steps are the same as in Example 1, except that the volume of the curing liquid in step (4) is changed to 40 times the volume of the microdroplets, and the shaking speed is changed to 50 r / min, so as to prepare the ipiperazole sustained-release microspheres.

[0047] Example 9 The method and steps are the same as in Example 1, except that the volume of the curing liquid in step (4) is changed to 60 times the volume of the microdroplets, and the shaking speed is changed to 60 r / min, so as to prepare the ipiperazole sustained-release microspheres.

[0048] Comparative Example 1 The method and steps are the same as in Example 1, except that the curing liquid in step (4) is replaced with a 2% PVA aqueous solution to prepare ipilexazole sustained-release microspheres.

[0049] Comparative Example 2 The method and steps are the same as those in Comparative Example 1, except that PLGA in step (1) is replaced with an index of 5002E, M. w Epilipazole sustained-release microspheres were prepared using PLGA with a strength of 17.3 kDa.

[0050] Comparative Example 3 The method and steps are the same as in Example 1, except that the microdroplets prepared in step (3) are directly transferred to a culture dish, and the organic solvent is removed by slowly shaking at 40 r / min on a shaker. The solidified microspheres are then obtained by solidification, and finally obtained by centrifugation and freeze-drying.

[0051] Comparative Example 4 The method and steps are the same as in Example 1, except that the volume of the curing liquid in step (4) is changed to 30 times to prepare ipilexazole sustained-release microspheres.

[0052] Comparative Example 5 The method and steps are the same as in Example 1, except that the volume of the curing liquid in step (4) is changed to 70 times to prepare ipilexazole sustained-release microspheres.

[0053] Comparative Example 6 The method and steps are the same as in Example 1, except that the curing liquid in step (4) is changed to PVA-NaCl solution, wherein the concentration of PVA is 2% and the concentration of NaCl is 0.6M, and ipilexazole sustained-release microspheres are prepared.

[0054] Comparative Example 7 The method and steps are the same as in Example 1, except that the shaking speed in step (4) is changed to 70 r / min to prepare ipilexazole sustained-release microspheres.

[0055] Comparative Example 8 (1) Weigh 150mg PLGA (5002A, M) w 75 mg of ipilipazole (22.1 kDa) was added to 3 mL of organic solvent, vortexed and sonicated for 5 min to prepare the dispersed phase; (2) Add 2g PVA and 0.58g NaCl to 100mL of double-distilled water, stir magnetically for 30 min, and then place it in a water bath. Keep it at 90℃ for 30 min until PVA is completely dissolved to obtain a continuous phase, wherein the concentration of PVA is 2% and the concentration of NaCl is 0.1M. (3) The pressure of the dispersed phase and the continuous phase are controlled by a pressure controller and connected to a microfluidic instrument to prepare microdroplets, wherein the flow rate of the dispersed phase is 30 μL / min and the pressure is 140 mbar, and the flow rate of the continuous phase is 85 μL / min and the pressure is 220 mbar. (4) Transfer the microdroplets to a petri dish and shake slowly at 40 r / min on a shaker to remove the organic solvent and solidify to obtain solidified microspheres; (5) Collect the solidified microspheres into centrifuge tubes, centrifuge at 1000 r / min at room temperature for 5 min, centrifuge 5 times, collect the microspheres, freeze them at -80℃, and then freeze-dry them in a freeze dryer for 48 h to obtain epilapiazole sustained-release microspheres.

[0056] Example 10 (1) 5 mg of precise ipiperazole was placed in a 10 mL volumetric flask, and an appropriate amount of dichloromethane was added. After dissolving, dichloromethane was added to make up to 10 mL to obtain a mixed liquid. (2) Accurately measure 0.3 mL of the mixed liquid described in step (1), dilute it with dichloromethane to a final volume of 10 mL, and obtain a solution containing 15 μg / mL of epilapiazole; (3) Accurately weigh 5 mg of PLGA and place it in a 10 mL volumetric flask. Add an appropriate amount of dichloromethane. After dissolving, add dichloromethane to make up to 10 mL to obtain a PLGA solution. Then accurately measure 1.2 mL of the PLGA solution and dilute it with dichloromethane to make up to 10 mL to obtain an empty microsphere solution containing 60 μg / mL of PLGA. (4) Take the solution containing epipipeazole in step (2) and the empty microsphere solution containing PLGA in step (3), mix them in equal volumes to obtain a microsphere solution containing 60 μg / ml PLGA + 15 μg / ml epipipeazole. (5) Take the three solutions from steps (2)-(4) and test them under a UV absorption spectrum of 190-500 nm. It was found that ipiperazole has absorption peaks at 227 nm, 276 nm and 327 nm, and PLGA microspheres also have an absorption peak at 227 nm. The final detection wavelength was determined to be 327 nm.

[0057] Example 11 (1) Prepare solutions containing 5 μg / mL, 7.5 μg / mL, 10 μg / mL, 12.5 μg / mL and 15 μg / mL of ipiperazole, and measure their absorbance at 327 nm to obtain a standard curve; (2) Weigh 6 mg of the epilapiazole sustained-release microspheres prepared in the above examples and comparative examples, place them in a 10 mL volumetric flask, add an appropriate amount of dichloromethane, and after dissolving, add dichloromethane to make up to 10 mL to obtain a mixed solution. (3) Accurately measure 0.5 mL of the mixed solution obtained in step (2), dilute it with dichloromethane to a final volume of 10 mL, and prepare 3 parallel portions; (4) The absorbance of the solution obtained in step (3) was measured three times in parallel using a UV spectrophotometer at 327 nm. The average value was then taken. The average absorbance was then substituted into the standard curve to obtain the actual concentration of epipiperazole. The drug loading and encapsulation efficiency were then calculated using the following formula: Encapsulation efficiency (%) = Drug content in microspheres / Theoretical drug loading * 100%; Drug loading (%) = Drug content in microspheres / Weight of microspheres * 100%, results are shown in Table 1; (5) Weigh the ipilipazole sustained-release microspheres prepared in the above examples and comparative examples and use a laser particle size analyzer to determine the particle size (including D50, particle size distribution map and SPAN value). Clean the sample cell with double-distilled water and use double-distilled water as the dispersion medium. Add appropriate amounts of the samples in Examples 1-6 to make their shading rate meet the requirements. Measure and record the results (three parallel measurements are taken and the average value is taken). The results are shown in Table 1.

[0058] Table 1 Performance of ipilipazole sustained-release microspheres

[0059] Note: The drug-lipid ratio is the mass ratio of epipiperol to PLGA.

[0060] The results, as shown in Table 1, indicate that the performance of the sustained-release microspheres is related to various factors, primarily including the type of excipient PLGA, the drug-to-lipid ratio, the type and volume of the curing solution, and the oscillation speed of the shaker during curing. This patent mainly investigated the influence of the type of curing solution on the microsphere performance. Adding an appropriate concentration of NaCl salt solution to the curing solution of the microspheres to adjust the osmotic pressure difference between the internal and external aqueous phases of the microspheres can effectively reduce drug leakage from the microspheres, thereby improving the encapsulation efficiency. Furthermore, adding an appropriate volume of curing solution during the microsphere curing process can effectively prevent the microspheres from sticking together, improving the collection efficiency. Placing the glass container containing the microspheres on a shaker and slowly oscillating it at a certain speed during curing can accelerate the curing speed, prevent the microspheres from sticking together, and also improve the encapsulation efficiency.

[0061] Example 12 (1) Accurately weigh 20 mg of the ipiperazole sustained-release microspheres prepared in Example 1 and Example 2 and place them in a stoppered glass bottle. Add 200 ml of release medium (pH 7.4 PBS buffer solution + 0.2% CTAB), mix well, and then stopper and shake well. (2) Place it in a constant temperature shaking water bath at 37℃ and shake it. At the set time, take 4 mL of dialysate and replenish it with an equal amount of fresh release medium in time. (3) The dialysate was filtered, and the drug release was detected by high performance liquid chromatography (HPLC) to obtain the cumulative release curve. The cumulative release percentage and burst release rate were calculated. The chromatographic conditions were as follows: column: XB-C18 column; mobile phase: gradient elution acetonitrile:water = 50:50~80:20; elution time: 20 min; column temperature: 30℃; detection wavelength: 327 nm; injection volume: 20 μL. The calculation formula is as follows: Cumulative release percentage = Final drug concentration released by microspheres * Volume of release medium / Mass of microspheres * Drug loading * 100%; Burst release rate = drug concentration released from microspheres over 0.5 hours * volume of release medium / mass of microspheres * drug loading * 100%.

[0062] The results are as follows Figure 9 As shown, the burst release rate of Example 1 was 4.25%, and the cumulative release percentage was 96.65%; the burst release rate of Example 3 was 7.25%, and the cumulative release percentage was 48.00%.

[0063] Comparative Example 9 The method and steps are the same as in Example 1, except that the diameter of the glass culture dish is changed to 56 mm and the height is changed to 18 mm to prepare ipilipazole sustained-release microspheres.

[0064] Comparative Example 10 The method and steps are the same as in Example 1, except that the glass culture dish is replaced with an Erlenmeyer flask with the same bottom diameter to prepare ipilexazole sustained-release microspheres.

[0065] Results Detection: The ipilipazole sustained-release microspheres prepared in Example 1 and Comparative Examples 9-10 were analyzed for curing after 4 hours. The results are shown in Table 2. Table 2. The Influence of Containers on Curing Process

[0066] As shown in Table 1, the diameter of the container during curing has a significant impact on the curing process. The larger the diameter of the container during curing, the more microspheres are cured in the same amount of time, indicating a higher curing efficiency.

Claims

1. A method for preparing high-drug-loaded epiriprazole sustained-release microspheres, characterized in that: The steps include: (1) adding ipriprazole and poly(lactide-co-glycolide) copolymer to an organic solvent and mixing to obtain a clear dispersed phase; (2) Mix PVA and water to obtain a continuous phase; (3) Mixing the dispersed phase and the continuous phase through microfluidics to prepare microdroplets; (4) placing the microdroplets in a solidifying liquid and shaking to complete solidification to obtain solidified slow-release microspheres; (5) The solidified sustained-release microspheres are centrifuged and freeze-dried to obtain epiriprazole sustained-release microspheres.

2. The method for preparing a high-drug-loading epiriprazole sustained-release microsphere according to claim 1, characterized in that: In the dispersed phase of step (1), the mass ratio of epiriprazole to polylactide-glycolide copolymer is 1:1-10.

3. The method for preparing a high-drug-loading epiriprazole sustained-release microsphere according to claim 1, characterized in that: The concentration of the continuous phase in step (2) is 0.5-2%.

4. The method for preparing a high-drug-loading epiriprazole sustained-release microsphere according to claim 1, characterized in that: The microfluidic parameters of step (3) are: dispersed phase flow rate of 20-40 μL / min, pressure of 130-150 mbar; continuous phase flow rate of 80-90 μL / min, pressure of 210-230 mbar.

5. The method for preparing a high-drug-loading epiriprazole sustained-release microsphere according to claim 1, characterized in that: The volume ratio of the micro-droplets to the solidifying liquid in step (4) is 1:40-60, and the shaking speed is 40-60 r / min.

6. The method for preparing the high drug loading epiriprazole sustained-release microspheres according to claim 5, characterized in that: The solidifying liquid is a PVA-NaCl solution.

7. The method for preparing the high drug loading epiriprazole sustained-release microspheres according to claim 6, characterized in that: The concentration of PVA in the PVA-NaCl solution is 1-2.5%, and the concentration of NaCl is 0.1-0.5%.

8. A high-drug-loaded epiriprazole sustained-release microsphere, characterized in that: The epiriprazole sustained-release microspheres are epiriprazole PLGA sustained-release microspheres prepared according to the preparation method according to any one of claims 1 to 7.

9. The high drug loading epiriprazole sustained-release microspheres according to claim 8, characterized in that: The molar ratio of lactic acid and glycolic acid in PLGA in the described epiridol PLGA sustained-release microspheres is (50-75): (25-50), M w 15.0-85.0kDa.

10. The sustained-release microspheres of epiriprazole with high drug loading according to claim 8, characterized in that: The particle size of the epiriprazole PLGA sustained-release microspheres is 30-100 μm, and the epiriprazole accounts for 10-50% of the total mass of the microspheres.

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