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

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a long-acting sustained-release microsphere preparation containing olanzapine and a preparation method of the long-acting sustained-release microsphere preparation. The olanzapine long-acting sustained-release microsphere preparation is prepared by taking chitosan, sodium alginate and a pH sensitive polymer as carriers and a release regulator as auxiliary materials through an emulsification-curing process. By optimizing the prescription and the preparation process, the drug loading capacity of olanzapine is greater than 20%, the in-vitro release time is controlled to be 14-28 days, and the preparation is good in stability, simple in preparation process and suitable for industrial production, and provides a new choice for long-acting treatment of olanzapine.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a long-acting sustained-release microsphere preparation of olanzapine, a preparation method thereof, and an application thereof. Background Art

[0002] As an atypical antipsychotic drug, olanzapine is approved for the treatment of adult schizophrenia and bipolar type I disorder, and is significantly effective in controlling symptoms such as delusions, hallucinations, apathy, hostility, suspicion, and social impairment, and has become a first-line treatment drug for schizophrenia.

[0003] However, mental illnesses generally require long-term medication to maintain efficacy. However, currently marketed olanzapine preparations are all limited by the defects of traditional dosage forms: oral preparations have large fluctuations in blood drug concentration and low bioavailability due to the first-pass effect, and need to be administered 1-2 times a day. The phenomenon of patients missing or taking the wrong dose is common, and the compliance is poor; although ordinary injections have a fast onset of action, the drug has a short half-life and needs to be injected frequently to maintain an effective blood drug concentration, resulting in large fluctuations in blood drug concentration and increasing the risk of side effects such as extrapyramidal reactions.

[0004] Therefore, developing a long-acting preparation that can achieve slow release of olanzapine and prolong the action time is of great significance for improving the treatment effect and the quality of life of patients.

[0005] In the prior art, studies on olanzapine sustained-release preparations have been carried out.

[0006] CN116942677A provides a sustained-release pharmaceutical dosage form containing olanzapine or a pharmaceutically acceptable salt thereof, which is subcutaneously administered to the patient at a frequency of no more than once every 21 days, comprising olanzapine or a pharmaceutically acceptable salt thereof, and at least one biodegradable polymer such as polylactide, polyglycolide, poly(lactide-co-glycolide) copolymer, etc.

[0007] CN103417492A discloses a biodegradable microsphere preparation containing olanzapine and a preparation method thereof. The biodegradable microsphere preparation containing olanzapine includes the following components in weight percentages: olanzapine or its salt 10-50%, release regulator 0.5-20%, PLGA 30-89.5%, and can maintain a relatively stable drug concentration in the body for 14-45 days or more.

[0008] The above-mentioned preparations still have defects such as low drug loading, high burst release rate, uneven particle size distribution, poor long-term storage stability, and high requirements for production equipment and process control in the preparation process, and need to be improved by optimizing the formulation composition and preparation process, etc. Summary of the Invention

[0009] In view of the deficiencies of existing marketed olanzapine formulations, on the basis of in-depth research, the present invention further improves traditional formulations, mainly reflected in:

[0010] By reasonably designing the carrier composition and preparation process, the controlled release of olanzapine is achieved, the drug action time is extended to 2-4 weeks, the dosing frequency is reduced, and the patient's medication compliance is improved; at the same time, the drug loading and stability of the formulation are enhanced, and the risk of drug burst release and side effects are reduced.

[0011] To solve the slow-release problem, the present invention first prepares a sustained-release formulation by conventional methods. However, soon, the inventors found that although chitosan and sodium alginate, as natural polymer materials, have good biocompatibility, biodegradability and mucoadhesion, and are commonly used in drug sustained-release carriers, when used in the preparation of olanzapine sustained-release formulations, the drug release rate is difficult to accurately control, especially the targeted release ability is limited.

[0012] Accidentally, the inventors found that when a pH-sensitive polymer and a release regulator are introduced to construct a ternary synergistic carrier system, the above problems are effectively solved, and the resulting formulation has better drug loading, encapsulation efficiency and long-term stability. Moreover, the formulation has a wider pH-sensitive range and can simultaneously take into account the responses of multiple specific sites such as the gastrointestinal tract.

[0013] Specifically, the technical solution of the present invention is as follows:

[0014] First, provide an olanzapine sustained-release microsphere, the average particle size of the microsphere particles is 10-50 μm; the spherical particles are composed of a carrier and olanzapine; the carrier material is composed of a combination of chitosan, sodium alginate and a pH-sensitive polymer; the pH-sensitive polymer is selected from one or more of polyacrylic acid, polymethacrylic acid, and chitosan-polyethylene glycol graft copolymer.

[0015] Specifically, the degree of deacetylation of the chitosan is ≥85%, and the molecular weight is 50-150 kDa; the molecular weight of the sodium alginate is 10-50 kDa.

[0016] Furthermore, the olanzapine sustained-release microsphere also contains a release regulator, and the release regulator is one or more of glycerol, polyethylene glycol, and sorbitol.

[0017] Specifically, in terms of weight ratio, the olanzapine in the olanzapine sustained-release microsphere is 10%-30%, the carrier material is 60%-85%, and the release regulator is 5%-15%.

[0018] Furthermore, in terms of weight ratio, the carrier material is composed of 30%-50% chitosan, 20%-40% sodium alginate, and 10%-30% pH-sensitive polymer.

[0019] Furthermore, by selecting the above three polymer materials and adjusting the ratios of the three, the present invention can prepare a sustained-release composition with an average particle size meeting the subcutaneous or intramuscular injection standard and having good drug release characteristics, which is used to extend the half-life of the drug in the body.

[0020] Preferably, the release regulator is sorbitol.

[0021] Through verification, the microspheres prepared by the present invention have relatively uniform particle sizes. Specifically, the average particle size of the microspheres is 10 - 50 μm.

[0022] The olanzapine sustained-release preparation prepared by the present invention has a burst release rate of ≤10% within 24 hours, an in vitro release time of ≥14 days, and a drug loading of ≥20%.

[0023] Secondly, the present invention also provides a preparation method for the above olanzapine long-acting sustained-release microsphere preparation, which includes the following steps:

[0024] (1) Dissolve olanzapine in an organic solvent to form a drug-containing solution;

[0025] (2) Dissolve chitosan, sodium alginate, pH-sensitive polymer and release regulator in water to form an aqueous phase;

[0026] (3) After mixing the solution in step (1) with the aqueous phase in step (2), add a surfactant for emulsification and a curing agent for curing;

[0027] (4) Separate, wash and dry the microspheres to obtain the product.

[0028] To further improve the effect of the preparation, in one embodiment, the organic solvent in step (1) is preferably dichloromethane, N-methylpyrrolidone or dimethyl sulfoxide.

[0029] In another preferred embodiment, the surfactant in step (2) is polyvinyl alcohol or poloxamer, and the curing agent is a calcium chloride solution. Preferably, in terms of weight / volume ratio, the concentration of the calcium chloride solution as the curing agent is 1% - 5% w / v.

[0030] Furthermore, in the emulsification process of step (3), a high-speed homogenizer is used, with a rotation speed of 5000 - 10000 rpm and a time of 10 - 30 min; the drying method in step (4) is freeze-drying or spray-drying, and the freeze-drying conditions are -40 - -20°C, a vacuum degree of <10 mbar, and a time of 12 - 24 h.

[0031] The present invention also provides a dosage form of the above olanzapine microspheres, and the microspheres can be further prepared into a conventional pharmaceutical preparation with pharmaceutically acceptable excipients.

[0032] The present invention also provides a pharmaceutical use of the long-acting sustained-release microspheres of the above olanzapine microspheres in the preparation of drugs for adjuvant treatment of schizophrenia and bipolar disorder type I.

[0033] Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

[0034] (1) Improving patient compliance in taking medicine: It can slow down the release of olanzapine in the body, reduce the burst release rate within 24 hours to ≤10%, and the release period is 14 - 28 days, significantly prolonging the drug action time and reducing the dosing frequency, thereby improving the patient's compliance in taking medicine.

[0035] (2) Improving drug stability: It has been confirmed by examples that the olanzapine microspheres prepared by the present invention have good long-term stability.

[0036] (3) Improving drug safety: Since the release of the drug in the body is more stable, avoiding drastic fluctuations in drug concentration, thereby reducing drug side effects.

[0037] (4) The preparation conditions are simple and the production cost is reduced. Description of the Drawings

[0038] Figure 1 Results of the drug loading amount of each group with different carrier material types in Example 6;

[0039] Figure 2 Results of the burst release amount of each group with different carrier material types in Example 6;

[0040] Figure 3 Results of the cumulative drug release rate of each group at different pH stages with different weights of carrier materials in Example 6;

[0041] Figure 4 Results of the drug loading amount of each group with different weights of carrier materials in Example 6;

[0042] Figure 5 Results of the burst release amount of each group with different weights of carrier materials in Example 6;

[0043] Figure 6 Effect of the weight of carrier materials on T80 time in Example 6;

[0044] Figure 7 Results of the drug loading amount of each group with different types of release regulators in Example 7;

[0045] Figure 8 Results of the burst release amount of each group with different types of release regulators in Example 7. Detailed Embodiments

[0046] The present invention will be further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only for illustrating the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention fall within the scope of protection of the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0047] Example 1

[0048] Formulation:

[0049] Ingredient Dosage Olanzapine 300 mg Chitosan 392 mg Sodium alginate 294 mg Chitosan - polyethylene glycol copolymer 294 mg Sorbitol 120 mg

[0050] Preparation method:

[0051] (1) Dissolve olanzapine in 5 mL of dichloromethane to form a drug-containing solution;

[0052] (2) Dissolve chitosan, sodium alginate, pH-sensitive polymer and release regulator in 20 mL of water to form an aqueous phase;

[0053] (3) After mixing the solution in step (1) with the aqueous phase in step (2), add 1% w / v polyvinyl alcohol and emulsify in a high-speed homogenizer at a rotation speed of 10,000 rpm for 20 min, and add 5% calcium chloride solution to solidify the microspheres;

[0054] (4) Centrifuge to separate the microspheres, wash them 3 times with deionized water, and freeze-dry under the conditions of -30 °C, a vacuum of <10 mbar, and a time of 24 h to obtain white powdery microspheres.

[0055] The obtained microspheres are white powdery, with regular spherical shapes, uniform pore size distributions, a particle size distribution of 20 - 50 μm, and a drug loading and sustained release duration of 23 days.

[0056] Example 2

[0057] Formulation:

[0058] Ingredient Dosage Olanzapine 300 mg Chitosan 375 mg Sodium alginate 281 mg Chitosan - polyethylene glycol copolymer 281 mg Sorbitol 113 mg

[0059] Preparation method

[0060] (1) Dissolve olanzapine in 5 mL of dichloromethane to form a drug-containing solution;

[0061] (2) Dissolve chitosan, sodium alginate, pH-sensitive polymer and release regulator in 20 mL of water to form an aqueous phase;

[0062] (3) After mixing the solution in step (1) with the aqueous phase in step (2), add 3% w / v polyvinyl alcohol and emulsify in a high-speed homogenizer at a rotation speed of 8,000 rpm for 20 min, and add 3% calcium chloride solution to solidify the microspheres;

[0063] (4) Centrifuge the microspheres, wash them three times with deionized water, and freeze-dry them under the conditions of -30°C, a vacuum of <10 mbar, and a time of 12 h to obtain white powdery microspheres.

[0064] The obtained microspheres are white powdery, with regular spherical shapes, uniform pore size distributions, a particle size distribution of 20 - 45 μm, and a sustained release duration of 22 days.

[0065] Example 3

[0066] Formulation:

[0067] Ingredient Dosage Olanzapine 300 mg Chitosan 324 mg Sodium alginate 324 mg Chitosan - polyethylene glycol copolymer 278 mg Sorbitol 124 mg

[0068] Preparation method:

[0069] (1) Dissolve olanzapine in 5 mL of dichloromethane to form a drug-containing solution;

[0070] (2) Dissolve chitosan, sodium alginate, pH-sensitive polymer, and release regulator in 20 mL of water to form an aqueous phase;

[0071] (3) After mixing the solution in step (1) with the aqueous phase in step (2), add 5% w / v polyvinyl alcohol and emulsify it in a high-speed homogenizer. Set the rotation speed to 8000 rpm and the time to 20 min, and add 3% calcium chloride solution to solidify the microspheres;

[0072] (4) Centrifuge the microspheres, wash them three times with deionized water, and freeze-dry them under the conditions of -30°C, a vacuum of <10 mbar, and a time of 20 h to obtain white powdery microspheres.

[0073] The obtained microspheres are white powdery, with regular spherical shapes, uniform pore size distributions, a particle size distribution of 15 - 45 μm, and a sustained release duration of 21 days.

[0074] Example 4

[0075] Formulation:

[0076]

[0077]

[0078] Preparation method:

[0079] (1) Dissolve olanzapine in 5 mL of dichloromethane to form a drug-containing solution;

[0080] (2) Dissolve chitosan, sodium alginate, pH-sensitive polymer, and release regulator in 20 mL of water to form an aqueous phase;

[0081] (3) After mixing the solution in step (1) with the aqueous phase in step (2), 5% w / v polyvinyl alcohol was added and emulsified in a high-speed homogenizer at a rotation speed of 10,000 rpm for 30 min, and then 3% calcium chloride solution was added to solidify the microspheres.

[0082] (4) The microspheres were separated by centrifugation, washed 3 times with deionized water, and freeze-dried under the conditions of -30 °C, a vacuum degree of <10 mbar, and a time of 12 h to obtain white powdery microspheres.

[0083] The obtained microspheres were white powdery, with regular spherical shapes, uniform pore size distributions, a particle size distribution of 30 - 50 μm, and a sustained release duration of 26 days.

[0084] Example 5

[0085] Formulation:

[0086] Ingredient Dosage Olanzapine 300 mg Chitosan 360 mg Sodium alginate 1440 mg Chitosan - polyethylene glycol copolymer 216 mg Sorbitol 180 mg

[0087] Preparation method:

[0088] (1) Olanzapine was dissolved in 5 mL of dichloromethane to form a drug-containing solution.

[0089] (2) Chitosan, sodium alginate, pH-sensitive polymer, and release regulator were dissolved in 20 mL of water to form an aqueous phase.

[0090] (3) After mixing the solution in step (1) with the aqueous phase in step (2), 5% w / v polyvinyl alcohol was added and emulsified in a high-speed homogenizer at a rotation speed of 8,000 rpm for 20 min, and then 5% calcium chloride solution was added to solidify the microspheres.

[0091] (4) The microspheres were separated by centrifugation, washed 3 times with deionized water, and freeze-dried under the conditions of -30 °C, a vacuum degree of <10 mbar, and a time of 24 h to obtain white powdery microspheres.

[0092] The obtained microspheres were white powdery, with regular spherical shapes, uniform pore size distributions, a particle size distribution of 10 - 35 μm, and a sustained release duration of 19 days.

[0093] Example 6 Influence of the type and weight of the carrier material

[0094] Formulation:

[0095] Ingredient Dosage Olanzapine 250 mg Carrier material 700 mg Sorbitol 50 mg

[0096] Specifically, the type and dosage of the carrier material are as follows:

[0097] Grouping Carrier material type Group A1 Chitosan 40% + Sodium alginate 35% + Chitosan - polyethylene glycol copolymer 25% Group A2 PLGA(50:50) Group A3 Chitosan 50% + Sodium alginate 50% Group A4 Chitosan 70% + Polyacrylic acid 30% Group A5 Sodium alginate 60% + Polymethacrylic acid 40% Group A6 Chitosan - PEG graft copolymer Group A7 Chitosan Group A8 Sodium alginate

[0098] Preparation method:

[0099] (1) Dissolve olanzapine in 5 mL of dichloromethane to form a drug-containing solution;

[0100] (2) Dissolve the carrier material and the release regulator in 20 mL of water to form an aqueous phase;

[0101] (3) After mixing the solution in step (1) with the aqueous phase in step (2), add 5% w / v polyvinyl alcohol and emulsify it in a high-speed homogenizer. Set the rotation speed to 10,000 rpm and the time to 20 min, and then add 5% calcium chloride solution to solidify the microspheres;

[0102] (4) Centrifuge to separate the microspheres, wash them 3 times with deionized water, and freeze-dry them under the conditions of -30 °C, a vacuum of <10 mbar, and a time of 20 h to obtain white powdery microspheres.

[0103] Detection indexes:

[0104] (1) Drug loading and stability experiments:

[0105] The microspheres prepared in the examples are dispensed into vials, immediately sonicated in 0.1 M HCl solution for 30 min, centrifuged, and the supernatant is taken. The drug concentration is determined by HPLC.

[0106] The microspheres prepared in the examples are dispensed into vials, and the drug loading is detected after storing at 40 °C and 75% RH for 6 months.

[0107] The microspheres prepared in the examples are dispensed into vials, and the drug loading is detected after storing at 25 °C and 60% RH for 12 months. Statistically analyze the above experimental results as Figure 1 shown.

[0108] (2) Burst release rate:

[0109] The microspheres prepared in the examples are dispensed into vials, and the burst release of the drug within 24 h is determined by HPLC in pH 7.4 PBS solution immediately. The results are as Figure 2 shown.

[0110] (3) pH responsiveness:

[0111] The microspheres prepared in the examples are sequentially transferred to different pH media, and samples are taken at regular intervals to detect the release amount, and the targeted release characteristics of the microspheres at a specific pH are investigated. The release media are successively: hydrochloric acid solution with pH 1.2 (0 - 2 h), PBS solution with pH 6.8 (2 - 24 h), PBS solution with pH 7.4 (24 - 168 h). The results are as Figure 3 shown.

[0112] Experimental results:

[0113] Observation of the microspheres showed that the microspheres in group A1 were regular in shape, with a uniform pore size distribution on the surface and a particle size distribution of 15 - 40 μm. The morphologies of the other groups were inferior to that of group A1. In group A2, the pore size was uneven. In group A3, partial adhesion occurred. In groups A4 and A5, there were cracks on the surface and the structure was loose. The surface of group A6 was rough, and groups A7 and A8 showed severe adhesion. It can be seen from Figure 1 - 2 that the drug loading of group A1 was the highest, and the initial burst release rate in pH 7.4 PBS solution within 24 h was the lowest. After storage at 25℃ and 60% RH for 12 months, and after accelerated testing at 40℃ and 75% RH for 3 months, the decrease in drug loading of group A1 was relatively small, significantly better than that of other groups.

[0114] Figure 3 It was verified that group A1 could achieve low initial burst release, pH - targeted release, and long - acting sustained release compared with other groups.

[0115] Furthermore, we also conducted experiments on the dosage ratios of chitosan, sodium alginate, and chitosan - polyethylene glycol copolymer. The details are as follows:

[0116] Formulation:

[0117]

[0118]

[0119] Specifically, the types and dosages of the carrier materials are as follows:

[0120] Types and dosages of carrier materials Group A9 Chitosan 30% + Sodium alginate 45% + Chitosan - polyethylene glycol copolymer 25% Group A10 Chitosan 35% + Sodium alginate 35% + Chitosan - polyethylene glycol copolymer 30% Group A11 Chitosan 15% + Sodium alginate 35% + Chitosan - polyethylene glycol copolymer 50% Group A12 Chitosan 40% + Sodium alginate 15% + Chitosan - polyethylene glycol copolymer 45%

[0121] Preparation method:

[0122] (1) Dissolve olanzapine in 5 mL of dichloromethane to form a drug - containing solution;

[0123] (2) Dissolve the carrier material and the release regulator in 20 mL of water to form an aqueous phase;

[0124] (3) After mixing the solution in step (1) with the aqueous phase in step (2), add 5% w / v polyvinyl alcohol and emulsify with a high - speed homogenizer at a rotation speed of 10000 rpm for 25 min, and then add 5% calcium chloride solution to solidify the microspheres;

[0125] (4) Centrifuge to separate the microspheres, wash them 3 times with deionized water, and freeze - dry under the conditions of - 30℃, a vacuum degree of <10 mbar, and a time of 20 h to obtain white powdery microspheres.

[0126] Detection indexes:

[0127] (1) Drug loading:

[0128] Ultrasonic for 30 min in 0.1 M HCl solution, centrifuge and take the supernatant, and determine the drug concentration by HPLC. The results are as Figure 4 shown.

[0129] (2) Burst release rate:

[0130] Determine the drug burst release situation by HPLC in pH 7.4 PBS solution for 24 h. The results are as Figure 5 shown.

[0131] (3) In vitro release cycle

[0132] Determine the time when the cumulative drug release reaches 80% by HPLC in pH 7.4 PBS solution. The results are as Figure 6 shown.

[0133] Experimental results:

[0134] Groups A9 and A10 are spherical, regular and complete, with uniform pores; group A11 has a rough and irregular surface, and group A12 shows adhesion.

[0135] From Figure 4 it can be seen that the drug loading of groups A9 and A10 is similar, significantly higher than that of groups A11 and A12; from Figure 5 it can be seen that the 24-h burst release amount of groups A9 and A10 is similar, significantly lower than that of groups A11 and A12; from Figure 6 it can be seen that the T80 of group A9 is close to 18 days, that of group A10 is close to 14 days, that of group A11 is close to 9 days, and that of group A12 is close to 7 days. Considering comprehensively, the effect of group A10 is better.

[0136] Example 7 Influence of the type of release regulator

[0137] Formulation:

[0138] Ingredient Dosage Olanzapine 250 mg Carrier material 700 mg Release regulator 50 mg

[0139] Specifically, the types of release regulators are as follows:

[0140] Grouping Carrier material type Group B1 Sorbitol Group B2 Lactose Group B3 PEG400 Group B4 Glycerol Group B5 Poloxamer 188 Group B6 Glycerol monostearate Group B7 Sodium chloride Group B8 Mannitol

[0141] The preparation method is the same as that in Example 1.

[0142] Detection indexes:

[0143] (1) Drug loading:

[0144] Ultrasonic for 30 min in 0.1 M HCl solution, centrifuge and take the supernatant, and determine the drug concentration by HPLC. The results are as Figure 7 shown.

[0145] (2) Burst release rate:

[0146] The drug burst release situation was determined by HPLC in PBS solution at pH 7.4 for 24 h, and the results are as Figure 8 shown.

[0147] By morphological observation, the microspheres in group B1 had a smooth surface, uniform surface pore size, and a particle size distribution of 10 - 40 μm; the morphologies of the other groups were worse than that of group B1. In groups B2 and B5, partial adhesion was shown. In groups B3 and B4, pore collapse occurred. In group B6, the particle size distribution was wide; in groups B7 and B8, the microspheres ruptured and drug leakage occurred.

[0148] It can be seen from Figure 7 that the drug loading amount of group B1 was the highest, and the drug loadings of the other groups were significantly lower than that of group B1; Figure 8 indicating that the burst release rate of group B1 was the lowest at 24 h.

[0149] In summary, through improvement, the present invention can significantly slow down the release of olanzapine in vivo, reduce the 24-hour burst release rate to ≤10%, with a release period of 14 - 28 days, significantly prolong the drug action time, and have good long-term stability.

Claims

1. A long-acting sustained-release microsphere containing olanzapine, characterized in that, The sustained-release microspheres contain the following components: by weight ratio, olanzapine 10%-30%, carrier material 60%-85%, release regulator 5%-15%; the carrier material is composed of chitosan, sodium alginate, and a pH-sensitive polymer, and the pH-sensitive polymer is selected from one or more of polyacrylic acid, polymethacrylic acid, and chitosan-polyethylene glycol graft copolymer, and the release regulator is sorbitol.

2. The long-acting sustained-release microsphere according to claim 1, wherein By weight ratio, the carrier material is composed of 30%-50% chitosan, 20%-40% sodium alginate, and 10%-30% pH-sensitive polymer.

3. The long-acting sustained-release microsphere according to claim 1, wherein, The average particle size of the microspheres is 10-50 μm.

4. The long-acting sustained-release microsphere according to claim 1, wherein The burst release rate within 24 hours is ≤10%, the in vitro release time is ≥14 days, and the drug loading amount is ≥20%.

5. A method for preparing a long-acting sustained-release microsphere according to any one of claims 1-4, characterized in that, It includes the following steps: (1) Dissolve olanzapine in an organic solvent to form a drug-containing solution. (2) Dissolve chitosan, sodium alginate, pH-sensitive polymer, and release regulator in water to form an aqueous phase. (3) After mixing the solution in step (1) with the aqueous phase in step (2), add a surfactant for emulsification and a curing agent for curing. (4) Separate, wash, and dry to obtain the microspheres.

6. The preparation method according to claim 5, characterized in that, The organic solvent in step (1) is dichloromethane, N-methylpyrrolidone, or dimethyl sulfoxide.

7. The preparation method according to claim 5, characterized in that, The surfactant in step (2) is polyvinyl alcohol or poloxamer, and the curing agent is a calcium chloride solution. Preferably, by weight / volume ratio, the concentration of the calcium chloride solution as the curing agent is 1%-5% w / v.

8. The preparation method according to claim 5, characterized in that, In the emulsification process of step (3), a high-speed homogenizer is used, with a rotation speed of 5000-10000 rpm and a time of 10-30 min.

9. The preparation method according to claim 5, characterized in that, The drying method in step (4) is freeze-drying or spray-drying. The freeze-drying conditions are -40--20°C, a vacuum degree <10 mbar, and a time of 12-24 h.

10. Use of a long-acting sustained-release microsphere as described in any one of claims 1-4 in the preparation of a drug for adjuvant treatment of schizophrenia and bipolar type I disorder.

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