Bruxpiprazole long-acting sustained-release microsphere as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a brexpiprazole long-acting sustained-release microsphere as well as a preparation method and application thereof. According to the method for preparing the brexpiprazole long-acting sustained-release microspheres, provided by the invention, on the basis of micro-fluidic control, a step-by-step drying process method (namely, pre-drying and formal drying are carried out step by step) is innovatively provided, and meanwhile, the step-by-step drying process conditions are optimized; furthermore, on the premise of not increasing auxiliary materials or process aids and not introducing other complex processes, the drug loading capacity and the encapsulation efficiency of the brexpiprazole microspheres are improved, and the slow-release effect is optimized.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a long-acting sustained-release microsphere of birepiperazole, its preparation method, and its application. Background Technology

[0002] Biriperazole, chemically named 7-[4-(4-benzo[B]thiophene-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone, is a third-generation atypical antipsychotic drug following aripiprazole. Biriperazole is a white or off-white crystal or crystalline powder, soluble in N-methylpyrrolidone, slightly soluble in N,N-dimethylacetamide, insoluble in methanol, extremely insoluble in ethanol, and almost insoluble in water. Due to its low solubility, biriperazole tablets prepared using existing processes often exhibit poor solubility and are difficult to dissolve; or the dissolution rate may differ from the original drug, leading to unstable drug quality. Furthermore, biriperazole is prone to crystallization; when prepared as microspheres, crystallization can cause a rapid release in the patient's body, resulting in a short-term increase in blood drug concentration and potentially causing local or systemic toxicity. On the other hand, psychiatric patients often exhibit poor compliance with oral medication administration, making it difficult to administer medication regularly and resulting in poor treatment outcomes. Therefore, there is a need to develop a long-acting sustained-release formulation of ibuprofen.

[0003] Patent CN116531379A, entitled "A Buripiperazole Sustained-Release Composition and Its Preparation Method and Application," discloses a strategy for achieving sustained release of buripiperazole by adjusting the composition of polylactic acid, polylactic acid-glycolic acid copolymer, and polycaprolactone. Patent CN118477048A, entitled "A Buripiperazole Sustained-Release Microsphere and Its Preparation Method," discloses a strategy for achieving sustained release of buripiperazole by adjusting the formulation of the oil and aqueous phases of buripiperazole.

[0004] Currently, there are few reports on achieving sustained release of birepiperazole from the perspective of optimizing the preparation process. Therefore, it is necessary to propose new methods and strategies to meet the needs of large-scale, standardized industrial production. Summary of the Invention

[0005] The purpose of this invention is to provide a long-acting sustained-release microsphere of birepiperazole, its preparation method, and its application, thereby partially solving or alleviating the above-mentioned deficiencies in the prior art. The specific technical solution adopted by this invention is as follows.

[0006] A first aspect of the present invention is to provide a method for preparing sustained-release microspheres.

[0007] A method for preparing birepiperazole long-acting sustained-release microspheres includes the following steps: S01: Add biriperazole and biodegradable polymeric carrier material to an organic solvent and dissolve them thoroughly. Filter the solution to obtain an oil phase solution containing the drug. S02: Mix the surfactant solution thoroughly with an excess of the organic solvent, let it stand, and filter the supernatant to obtain an aqueous solution; S03: Inject the oil phase solution and the aqueous phase solution into a pressure-type microfluidic device, setting the oil phase solution as the inner phase and the aqueous phase solution as the outer phase; adjust the flow rates of the inner and outer phases to obtain oil-in-water droplets at the outlet of the pressure-type microfluidic device; wherein the flow rate of the inner phase is set to v1, v1 is 10-2000 μL / min / channel, and the flow rate of the outer phase is set to v2, v2 is 50-10000 μL / min / channel; S04: During the preparation of the oil-in-water droplets, a (brief) pre-drying process is performed to solidify the oil-in-water droplets into microspheres. The pre-drying heating temperature is set to 25-45°C. The pre-drying includes stirring drying or chip drying. The pre-drying process is monitored, and the pre-drying is completed when the size of the oil-in-water droplets no longer shrinks significantly. S05: Perform formal drying on the microspheres obtained by pre-drying. Place the microspheres in a drying medium and stir until the solvent residue is less than 1%. The formal drying is completed. The drying medium includes the surfactant solution or an aqueous ethanol solution. Set the heating temperature for formal drying to 25-45℃. S06: Collect the completely solidified microspheres, wash them clean, and freeze-dry them to obtain the buripiperazole long-acting sustained-release microspheres.

[0008] In some preferred embodiments, v1 is 20-50 μL / min / channel and v2 is 200-500 μL / min / channel. More preferably, v1 is 25 μL / min / channel and v2 is 300 μL / min / channel.

[0009] Furthermore, the organic solvent includes dichloromethane, chloroform, or ethyl acetate.

[0010] In some preferred embodiments, the organic solvent is dichloromethane.

[0011] Furthermore, the surfactants include polyvinyl alcohol 1788, polyvinyl alcohol 1799, poloxamer F127, poloxamer F68, polyvinylpyrrolidone K12, polyvinylpyrrolidone K15, and polyvinylpyrrolidone K17.

[0012] In some preferred embodiments, the surfactant is polyvinyl alcohol 1788.

[0013] Furthermore, the biodegradable polymeric carrier material includes polylactic acid-glycolic acid copolymer, polylactic acid, or polycaprolactone.

[0014] In some preferred embodiments, the biodegradable polymeric carrier material is a polylactic acid-hydroxyacetic acid copolymer.

[0015] Furthermore, the stirring drying in the pre-drying process involves rapidly stirring the oil-in-water solution dropwise into a heated drying medium solution (to solidify it); the drying medium includes the surfactant solution or an aqueous ethanol solution.

[0016] In some preferred embodiments, the surfactant solution is a 0.5% polyvinyl alcohol solution; the ethanol aqueous solution is a 5.0% ethanol aqueous solution.

[0017] Furthermore, the chip drying in the pre-drying process involves passing the oil-in-water droplets into a preheated PDMS chip or a breathable PTFE chip, and using the mass and heat transfer effects of microfluidics to solidify the oil-in-water droplets.

[0018] As a preferred embodiment, the chip drying is performed using PDMS chip drying.

[0019] Furthermore, a large amount of the surfactant solution is introduced into the preheated chip to solidify the oil-in-water droplets.

[0020] Furthermore, a large amount of aqueous ethanol solution is added to the preheated chip to solidify the surface of the oil-in-water droplets.

[0021] In some preferred embodiments, the heating temperature for pre-drying and the heating temperature for formal drying are set to 20-40°C.

[0022] More preferably, the heating temperature for pre-drying is set to 25-40°C; and the heating temperature for formal drying is set to 20-40°C.

[0023] Furthermore, in the oil phase solution containing the drug, the concentration range of the biodegradable polymeric carrier material is 5%-10%; and the concentration range of buriperazole is 0.5%-5.0%.

[0024] In some preferred embodiments, the concentration range of the biodegradable polymeric carrier material includes 5%, 6%, 8%, or 10%; and the concentration range of buripiperazole includes 1%, 2%, or 5%.

[0025] Furthermore, in the oil phase solution containing the drug, the molecular weight of the biodegradable polymer carrier material ranges from 6000 to 100000 Da.

[0026] In some preferred embodiments, the molecular weight range of the biodegradable polymer carrier material includes 10,000-15,000 Da, 15,000-20,000 Da, 30,000-40,000 Da, or 50,000-60,000 Da.

[0027] Furthermore, when the added biodegradable polymeric carrier material is a polylactic acid-glycolic acid copolymer, it contains two monomers: lactide and glycolide; the ratio of lactide to glycolide is 50:50 to 85:15.

[0028] In some preferred embodiments, the ratio of lactide to glycolide includes 50:50 or 75:25.

[0029] In another aspect, the present invention also provides bripiprazole long-acting sustained-release microspheres prepared by the above preparation method; or bripiprazole long-acting sustained-release microspheres obtained by mixing carrier materials or microspheres in any proportion.

[0030] The present invention also provides applications of the above-mentioned birepiperazole long-acting sustained-release microspheres.

[0031] The above-mentioned birepiperazole long-acting sustained-release microspheres are used in the preparation of sustained-release antipsychotic drugs, wherein the mental illness includes adult major depressive disorder, schizophrenia, or dementia caused by Alzheimer's disease.

[0032] Beneficial technical effects: This invention provides a novel process for preparing long-acting sustained-release bripiprazole microspheres. Based on microfluidic control, this method innovatively proposes a stepwise drying process (i.e., pre-drying followed by formal drying), and optimizes the process conditions for this stepwise drying. This improves the drug loading and encapsulation efficiency of the bripiprazole microspheres without adding excipients or process aids or introducing other complex processes, and significantly optimizes the sustained-release effect. The final optimal microsphere sample exhibits a sustained-release effect for up to 90 days. When the long-acting sustained-release bripiprazole microspheres prepared using this invention are used to prepare antipsychotic drugs, it can greatly alleviate the problem of poor medication adherence and difficulty in regular medication use among psychiatric patients. Attached Figure Description

[0033] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. The elements or parts in the drawings are not necessarily drawn to scale. Obviously, the drawings described below are some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0034] Figure 1 This is a process diagram illustrating the preparation of birepiperazole microspheres according to the present invention; Figure 2 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 1 of the present invention. Figure 3 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 10 of the present invention. Figure 4 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 11 of the present invention. Figure 5 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 12 of the present invention. Figure 6 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 13 of the present invention. Figure 7 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 17 of the present invention. Figure 8 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 19 of the present invention. Figure 9 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 20 of the present invention. Figure 10 An optical microscope image (scale bar 80 μm) of the birepiperazole microspheres prepared in Experimental Example 21 of the present invention. Figure 11 This is an optical microscope image of the birepiperazole microspheres prepared in Comparative Example 1 of the present invention (scale bar is 80 μm). Figure 12 This is an optical microscope image of the birepiperazole microspheres prepared in Comparative Example 2 of the present invention (scale bar is 80 μm). Figure 13 These are the in vitro release curves for test examples 1-5 and 7-9 of the present invention; Figure 14The above are in vitro release curves for test examples 1, 17, 20, 22 and comparative example 2 of the present invention. Detailed Implementation

[0035] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0036] In this document, "and / or" includes any and all combinations of one or more of the listed related items.

[0037] In this article, "multiple" means two or more, that is, it includes two, three, four, five, etc.

[0038] As used in this specification, the term "about" typically means + / -5% of the value, more typically + / -4% of the value, more typically + / -3% of the value, more typically + / -2% of the value, even more typically + / -1% of the value, and even more typically + / -0.5% of the value.

[0039] In this specification, certain embodiments may be disclosed in a range-bound format. It should be understood that this "range-bound" description is merely for convenience and brevity and should not be construed as a rigid limitation on the disclosed range. Therefore, the description of a range should be considered as having specifically disclosed all possible subranges and the individual numerical values ​​within those ranges. For example, a description of the range 1-6 should be considered as having specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and the individual numbers within those ranges, such as 1, 2, 3, 4, 5, and 6. This rule applies regardless of the breadth of the range.

[0040] Definition of noun: The "pre-drying" mentioned in this invention refers to the drying of water-in-oil droplets containing irinotexaazole using a special process, so that the solvent contained in the droplets evaporates during the formation of microspheres, and the pre-drying is judged to be complete when the size of the microspheres no longer shrinks significantly.

[0041] The "formal drying" mentioned in this invention refers to thoroughly drying the pre-dried microspheres, and the drying is considered complete when the residual solvent content in the resulting microspheres is less than 1%.

[0042] Main reagents: Polylactic acid-glycolic acid copolymer (PLGA) was purchased from Evonik Specialty Chemicals Ltd.; dichloromethane was purchased from Nanjing Chemical Reagent Co., Ltd.; polyvinyl alcohol (PVA) was purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.; ethanol was purchased from Chengdu Kelong Chemical Co., Ltd.; polysorbate 80 was purchased from Nanjing Well Pharmaceutical Group Co., Ltd.; and phosphate buffer was purchased from Beijing Lanjieke Technology Co., Ltd.

[0043] Example 1 This embodiment provides an example of a method for preparing birepiperazole microspheres using microfluidic technology.

[0044] S01: Weigh out bripiprazole and polylactic acid-glycolic acid copolymer (PLGA) separately, add dichloromethane, and sonicate to fully dissolve them to obtain a reaction solution. Filter the above reaction solution with a needle nylon filter to obtain an oil phase solution for later use.

[0045] S02: Prepare a 0.5% (w / v) polyvinyl alcohol solution by adding excess dichloromethane and stirring for at least 30 minutes to ensure thorough mixing. Then let it stand overnight. Filter the supernatant to obtain the aqueous solution for later use.

[0046] S03: Inject the oil phase solution and aqueous phase solution into the pressure-type microfluidic device respectively. Figure 1 In this microfluidic device, the inner phase is an oil phase containing the drug, and the outer phase is an aqueous phase. By adjusting the flow rates of the oil and aqueous phases, the continuous phase (aqueous phase) in the microfluidic device shears the dispersed phase (oil phase) to obtain oil-in-water droplets. Figure 1 (Droplets in a tube).

[0047] S04: The method of regulating the internal phase flow rate, collecting the oil-in-water droplets for pre-drying, adjusting the droplet receiving time, adjusting the pre-drying temperature, and adjusting the pre-drying time, or the pre-drying process itself, is used to monitor the morphological changes of the droplets during pre-drying. The morphological changes of the droplets during pre-drying are mainly monitored by microscopic imaging. During the pre-drying process, the droplets gradually solidify to form microspheres, thus causing a significant change in droplet morphology. Pre-drying is complete when the droplet size no longer decreases significantly.

[0048] S05: During the shearing process, the collected droplets enter the pre-drying stage; the pre-drying process includes the following options: S0501: The microfluidic chip outlet is connected to a 0.5% polyvinyl alcohol solution, and stirred continuously at 100 rpm to rapidly evaporate dichloromethane and solidify the droplets, preventing drug migration and crystal formation. S0502: The microfluidic chip outlet is connected to a 5.0% ethanol aqueous solution and stirred continuously at 100 rpm to quickly dissolve dichloromethane and promote volatilization, solidify the droplets, and prevent drug migration and crystal formation. S0503: The microfluidic chip outlet is connected to the PDMS chip. Utilizing the efficient mass and heat transfer effect of microfluidics, dichloromethane evaporates rapidly, causing the droplets to solidify and preventing drug migration and crystal formation. S0504: The microfluidic chip outlet is connected to the PDMS chip, and mixed with a large amount of 0.5% polyvinyl alcohol solution in another channel in the chip. Utilizing the efficient mass and heat transfer effect of microfluidics, the dichloromethane in the droplet is rapidly diffused into the fresh solution and volatilized, causing the droplet to solidify and preventing the drug from migrating out and forming crystals. S0505: The microfluidic chip outlet is connected to the PDMS chip, and mixed with a large amount of 5.0% ethanol aqueous solution in another channel of the chip. Utilizing the efficient mass and heat transfer effect of microfluidics, the dichloromethane in the droplet is rapidly diffused into the fresh solution and volatilized, causing the droplet to solidify and preventing the drug from migrating out and forming crystals.

[0049] S06: Perform formal drying on the microspheres obtained from the pre-drying process. The drying medium for formal drying is 0.5% polyvinyl alcohol or 5.0% ethanol aqueous solution. Turn on heating and stirring, set the temperature control to 40±0.5℃, and the stirring speed to 100 rpm. Continue drying for 3 hours.

[0050] S07: Collect the completely dried microsphere product, wash with pure water, filter, and dry to obtain bripiprazole long-acting sustained-release microspheres.

[0051] Example 2 Based on the process conditions of Example 1, the formulation, monomer ratio, molecular weight and aqueous phase composition of biriperazole were screened and verified.

[0052] Table 1. Results of Formula Process Screening Remark: (1) In the prescription column, 30% represents the theoretical drug loading of biriperazole and 5% represents the concentration of polylactic acid-glycolic acid copolymer in the oil phase.

[0053] (2) LA and GA represent two monomers of polylactic acid-glycolic acid copolymer: LA represents lactide and GA represents glycolide; the ratio of the two monomers affects the properties of polylactic acid-glycolic acid copolymer.

[0054] (3) Molecular weight refers to the molecular weight of polylactic acid-hydroxyacetic acid copolymer.

[0055] (4) DL represents the drug loading of the microspheres; EE represents the encapsulation efficiency of the microspheres. Microspheres with drug crystals have lower encapsulation efficiency and drug loading.

[0056] Experimental Examples 1-9 were conducted under the same microfluidic control conditions: internal phase flow rate of 25 mL / h, external phase flow rate of 100-1000 mL / h, droplet collection time of 1 h, and S0504 pre-drying process. By adjusting the formulation and the type and molecular weight of polylactic acid-glycolic acid copolymer, bripiprazole microspheres with different release cycles were prepared.

[0057] Comparative Example 1 used the same microfluidic control conditions as Experimental Examples 1-9, but replaced the dichloromethane in the oil phase with ethyl acetate-benzyl alcohol to obtain bripiprazole microspheres.

[0058] The experimental results are analyzed as follows.

[0059] (1) As can be seen from Experiments 4-6, the concentration of polylactic acid-glycolic acid copolymer in the oil phase has a significant impact on the quality of the final drug-loaded microspheres. As the concentration of polylactic acid-glycolic acid copolymer in the oil phase increases, the drug loading and encapsulation efficiency of the prepared microspheres decrease, indicating that the concentration of polylactic acid-glycolic acid copolymer should not be too high in the microfluidic emulsion preparation system of the present invention.

[0060] (2) As can be seen from Comparative Example 1, when the dichloromethane in the oil phase is replaced with ethyl acetate-benzyl alcohol, it is impossible to prepare microspheres with uniform size, and the drug loading and encapsulation efficiency of the drug-loaded microspheres are both low. Furthermore, due to the difficulty in removing ethyl acetate-benzyl alcohol, the solvent residue is high.

[0061] Example 3 Based on the formulation and process conditions of Example 2, the microsphere preparation process, including internal phase flow rate, pre-drying temperature, pre-drying time, and drying method, was screened and verified.

[0062] Table 2 Results of preparation process screening Note: DL represents the drug loading of the microspheres; EE represents the encapsulation efficiency of the microspheres. Microspheres with drug crystals have lower encapsulation efficiency and drug loading.

[0063] As can be seen from Table 2, there is a significant correlation between microfluidic parameters and pre-drying effect: (1) In the test cases of pre-drying, the pre-drying S0501 and pre-drying S0502 processes had low solvent residue, high microsphere encapsulation rate and drug loading, and no obvious drug crystallization. The pre-drying S0504 and pre-drying S0505 processes utilized the efficient mass and heat transfer effect of microfluidics to enable the dichloromethane in the droplets to diffuse rapidly into the fresh solution and promote volatilization, further reducing the solvent residue.

[0064] (2) In the pre-drying test, the faster the internal phase flow rate, the more microspheres are produced in the same time period, the greater the difficulty of drying in the drying unit, and the more likely the microspheres are to crystallize. (3) In the test case of pre-drying, the longer the droplet collection time, the higher the concentration of microspheres in the drying unit, the lower the drying efficiency, and the more easily the microspheres crystallize. (4) In the test case of pre-drying, if the drying temperature is low, the internal solvent cannot evaporate quickly and the microspheres are prone to crystallization. If the drying temperature is high, the microspheres will deform. If the pre-drying time is short, the microspheres cannot be completely solidified and the microspheres are prone to crystallization.

[0065] (5) Compared with the control group that was not pre-dried, the microspheres showed obvious drug crystallization, and the drug loading and encapsulation efficiency were both low, and the solvent residue was high.

[0066] Example 4 This embodiment provides verification of the sustained-release effect of the birepiperazole microspheres prepared in Examples 2 and 3.

[0067] Experimental methods: A certain amount of microspheres was used for in vitro release assay. The release medium was phosphate buffer containing 1.0% (w / w) Tween 80, pH=7.2. The release conditions were a constant temperature water bath at 37℃ and a shaking speed of 150 rpm. During sampling, after the microspheres had completely settled, 5 ml of the upper release medium was collected, and the corresponding volume of release medium was added. The pH of the release medium was monitored to maintain it at approximately pH=7.2. The sample was analyzed by high-performance liquid chromatography (HPLC), the cumulative release percentage was calculated, and a release rate curve of cumulative release percentage versus time was plotted. The results are shown below. Figure 13 and Figure 14 .

[0068] Figure 13 The figures show the in vitro release curves for Examples 1-5 and 7-9. As demonstrated in Examples 1-3 and 7-9, the in vitro release behavior of birepiperazole long-acting sustained-release microspheres can be controlled by adjusting the molecular weight of the polylactic-co-glycolic acid copolymer and the molar ratio of lactide to glycolide, with a release period of 30-80 days. This suggests that a larger molecular weight of the polylactic-co-glycolic acid copolymer results in a longer release period, and a higher LA ratio also leads to a longer release period.

[0069] Figure 14 The figures show the in vitro release curves of Experimental Examples 1, 17, 20, 22 and Comparative Example 2. It can be seen from the figures that the in vitro release curves of microspheres with drug crystals are abnormal, and the drug cannot be completely released from the microspheres. Therefore, drug crystallization seriously affects the quality of microspheres. Controlling drug crystallization is essential in the preparation of birepiperazole long-acting microspheres.

[0070] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A method for preparing birepiperazole long-acting sustained-release microspheres, characterized in that, Includes the following steps: S01: Add biriperazole and biodegradable polymeric carrier material to an organic solvent and dissolve them thoroughly. Filter the solution to obtain an oil phase solution containing the drug. S02: Mix the surfactant solution thoroughly with an excess of the organic solvent, let it stand, and filter the supernatant to obtain an aqueous solution; S03: Inject the oil phase solution and the aqueous phase solution into a pressure-type microfluidic device, setting the oil phase solution as the inner phase and the aqueous phase solution as the outer phase; adjust the flow rates of the inner and outer phases to obtain oil-in-water droplets at the outlet of the pressure-type microfluidic device; wherein the flow rate of the inner phase is set to v1, v1 is 10-2000 μL / min / channel, and the flow rate of the outer phase is set to v2, v2 is 50-10000 μL / min / channel; S04: During the preparation of the oil-in-water droplets, pre-drying is performed to solidify the oil-in-water droplets into microspheres. The pre-drying heating temperature is set to 25-45℃. The pre-drying includes stirring drying or chip drying. The pre-drying process is monitored. When the size of the oil-in-water droplets no longer shrinks significantly, the pre-drying is completed. S05: Perform formal drying on the microspheres obtained by pre-drying. Place the microspheres in a drying medium and stir until the solvent residue is less than 1%. The formal drying is completed. The drying medium includes the surfactant solution or an aqueous ethanol solution. Set the heating temperature for formal drying to 25-45℃. S06: Collect the completely dried microspheres, wash them clean, and freeze-dry them to obtain the buripiperazole long-acting sustained-release microspheres.

2. The preparation method according to claim 1, characterized in that, The organic solvent includes dichloromethane, chloroform, or ethyl acetate; or the surfactant includes polyvinyl alcohol 1788, polyvinyl alcohol 1799, poloxamer F127, poloxamer F68, polyvinylpyrrolidone K12, polyvinylpyrrolidone K15, or polyvinylpyrrolidone K17; or the biodegradable polymeric carrier material includes polylactic acid-glycolic acid copolymer, polylactic acid, or polycaprolactone.

3. The preparation method according to claim 1, characterized in that, The pre-drying process involves rapidly stirring the oil-in-water solution dropwise into a heated drying medium solution; the drying medium includes the surfactant solution or an aqueous ethanol solution.

4. The preparation method according to claim 1, characterized in that, The chip drying process in the pre-drying stage involves passing the oil-in-water droplets into a preheated PDMS chip or a breathable PTFE chip, and using the mass and heat transfer effects of microfluidics to solidify the oil-in-water droplets.

5. The preparation method according to claim 4, characterized in that, A large amount of the surfactant solution is passed through the preheated chip to solidify the oil-in-water droplets.

6. The preparation method according to claim 4, characterized in that, A large amount of aqueous ethanol solution is added to the preheated chip to solidify the oil-in-water droplets.

7. The preparation method according to claim 1, characterized in that, In the oil phase solution containing the drug, the concentration range of the biodegradable polymeric carrier material is 5%-10%; the concentration range of buripiperazole is 0.5%-5.0%.

8. The preparation method according to claim 2, characterized in that, When the added biodegradable polymeric carrier material is a polylactic acid-glycolic acid copolymer, it contains two monomers: lactide and glycolide; the ratio of lactide to glycolide is 50:50 to 85:

15.

9. Buripiperazole long-acting sustained-release microspheres prepared by the preparation method according to any one of claims 1-8; or, buripiperazole long-acting sustained-release microspheres obtained by mixing carrier materials or microspheres in any proportion.

10. The use of the ibuprofen long-acting sustained-release microspheres according to claim 9 in the preparation of sustained-release antipsychotic drugs, characterized in that, The mental illnesses mentioned include adult major depressive disorder, schizophrenia, or dementia caused by Alzheimer's disease.

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