CN116531379B - Bulleprazole sustained-release composition and preparation method and application thereof - Google Patents

Abstract

The present invention belongs to the field of pharmaceutical preparations, and relates to a brepirazole sustained-release composition and its preparation method and application. The microscopic morphology is a spherical particle with an average particle size of 10 to 30 μm, which is composed of a carrier and brepirazole, and the weight content of brepirazole in the spherical particles is 3 to 45%; the carrier is composed of 1 to 5 parts of polylactic acid, 2 to 10 parts of polylactic acid-glycolic acid copolymer and 1 to 6 parts of polycaprolactone according to the mass fraction; the ratio of lactic acid unit to glycolic acid unit in the polylactic acid-glycolic acid copolymer is 75:25 to 50:50. The brepirazole sustained-release composition provided by the present invention has a high drug loading, an average particle size that meets the standards for intramuscular or subcutaneous injection, a low burst rate, and can effectively achieve long-term sustained release of brepirazole, prolong the half-life of the drug in the body, reduce the fluctuation of blood drug concentration, improve the bioavailability of the drug, reduce the frequency of administration, improve the compliance of mental patients, and enhance the therapeutic effect.

Description

A breprazol sustained-release composition and its preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical preparations and relates to a brepazine sustained-release composition and a preparation method and application thereof.

Background Art

The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

Brepirapazole is a third-generation atypical antipsychotic drug after aripiprazole. According to the inventors' research, the only dosage forms of Brepirapazole on the market are tablets and orodisintegrating tablets. However, psychiatric patients usually show poor compliance with oral administration, which makes it difficult to administer the drug regularly, reducing the therapeutic effect. In addition, after administration of the above oral dosage forms, due to the first-pass effect including the influence of gastrointestinal enzymes and liver metabolism, the absorption of the drug is reduced, the bioavailability is low, and the blood drug concentration fluctuates greatly.

Summary of the invention

In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a brepizole sustained-release composition and a preparation method and application thereof. The brepizole sustained-release composition provided by the present invention has a high drug loading, an average particle size that meets the standards for intramuscular or subcutaneous injection, a low burst rate, and can effectively achieve long-term sustained release of brepizole, prolong the half-life of the drug in the body, reduce the fluctuation of blood drug concentration, improve the bioavailability of the drug, reduce the frequency of administration, improve the compliance of patients with mental illness, and enhance the treatment effect.

In order to achieve the above object, the technical solution of the present invention is:

On the one hand, a brepazine sustained-release composition has a microscopic morphology of spherical particles, and the average particle size of the spherical particles is 10 to 30 μm; the spherical particles are composed of a carrier and brepazole, brepazole is uniformly distributed in the carrier, and the weight content of brepazole in the spherical particles is 3 to 45%; the carrier is composed of 1 to 5 parts of polylactic acid, 2 to 10 parts of polylactic acid-glycolic acid copolymer and 1 to 6 parts of polycaprolactone in terms of mass fractions; the ratio of lactic acid units to glycolic acid units in the polylactic acid-glycolic acid copolymer is 75:25 to 50:50, the polylactic acid-glycolic acid copolymer is terminated with carboxylic acid, the weight average molecular weight of the polylactic acid is 20,000 to 40,000 Da, the weight average molecular weight of the polylactic acid-glycolic acid copolymer is 15,000 to 35,000 Da, and the weight average molecular weight of the polycaprolactone is 30,000 to 45,000 Da.

Polylactic acid is obtained by polymerization with lactic acid as the main raw material and has thermoplastic and biodegradable properties.

Poly(lactic acid-glycolic acid copolymer) is a biodegradable polymer material made of a certain proportion of lactic acid and glycolic acid. It has good biocompatibility and controllable degradation time. Its degradation products in the body are lactic acid and glycolic acid. The former is eventually excreted in the form of carbon dioxide and water, while the latter can participate in the tricarboxylic acid cycle or be excreted in urine.

Polycaprolactone is a polyester-based biodegradable hydrophobic polymer material with good biocompatibility and long-term degradation mechanism.

The present invention selects the above three polymer materials and adjusts the three ratios to prepare a sustained-release composition with an average particle size that meets the subcutaneous or intramuscular injection standards and has good drug release characteristics, which is used to prolong the half-life of the drug in the body, reduce the fluctuation of blood drug concentration, improve the bioavailability of the drug, reduce the frequency of administration, improve the compliance of psychiatric patients, and enhance the treatment effect.

For sustained-release compositions for injection, if the particle size is greater than 100 μm, there will be a problem of needle clogging, while if the particle size is less than 10 μm, it will be taken up by dendritic cells and macrophages. Therefore, sustained-release compositions with a particle size between 10-100 μm are suitable for administration by intramuscular or subcutaneous injection. The average particle size of the sustained-release composition of brepirazole provided by the present invention is 10 to 30 μm, and the composite meets the standards for intramuscular or subcutaneous injection. After testing, the sustained-release composition of brepirazole provided by the present invention has good needleability for a No. 5 needle (25G) with an inner diameter of 0.26 mm, which can further reduce the pain of the patient during injection.

On the other hand, a method for preparing the above-mentioned breprazol sustained-release composition comprises the following steps:

Adding polylactic acid, polylactic acid-co-glycolic acid, polycaprolactone and brepirazole into an organic solvent and mixing them evenly to obtain an oil phase, wherein the organic solvent is a volatile liquid organic substance that is immiscible with water;

dissolving polyvinyl alcohol into water to form an aqueous phase;

mixing the oil phase with the water phase to form an oil-in-water emulsion;

The organic solvent in the water-in-oil emulsion is removed by volatilization, and then centrifugation is performed to obtain a solidified composition, and the solidified composition is washed with water and vacuum-dried or freeze-dried to obtain the solidified composition.

In order to obtain a sustained-release composition with an average particle size that meets the standard for subcutaneous or intramuscular injection and has good drug release characteristics, its preparation method includes spray drying, membrane emulsification and emulsification. The preparation method has a significant effect on the encapsulation rate and particle size distribution of the sustained-release composition. Too low an encapsulation rate will lead to waste of raw materials and auxiliary materials in the preparation process of the sustained-release composition, increasing the preparation cost. The particle size of the sustained-release composition affects the stability after reconstitution and the needle permeability during injection. In addition, there is a linear relationship between the particle size of the sustained-release composition and its degradation rate. In a sustained-release composition with a smaller particle size, the acid degradation product can easily diffuse to the surface, while in a sustained-release composition with a larger particle size, the acid degradation product must move a longer distance to reach the surface, during which time the autocatalytic cycle of the degradation process of the sustained-release composition may be accelerated. Therefore, the control of the particle size distribution of the sustained-release composition is of great significance to ensure the sustained-release effect of the sustained-release composition. The spray drying method has a higher encapsulation rate for the sustained-release composition, but the particle size distribution is usually wider, and the installation and maintenance costs of the equipment are higher, and the cleaning after use is difficult. The particle size distribution of the sustained-release composition obtained by the membrane emulsification method is relatively narrow, but the equipment requirements are relatively high, requiring the mechanical strength of the membrane material to be sufficiently strong and the pore size to be stable. Therefore, the present invention adopts an emulsification method to prepare a brepazine sustained-release composition. The emulsification method uses physical means such as mechanical stirring, homogenization or ultrasound to uniformly disperse the droplets of the composition material containing the drug in a continuous phase that is immiscible with it, and further uses volatilization to remove the organic solvent in the droplets to solidify it to obtain a sustained-release composition. The brepazine sustained-release composition obtained by the emulsification method has a high encapsulation rate and a narrow particle size distribution, and has low requirements on equipment conditions, and is suitable for industrial production.

In a third aspect, a method for preparing a drug for assisting the treatment of major depressive disorder in adults, a drug for treating schizophrenia in adults, a drug for treating schizophrenia in children, a drug for improving schizophrenia in adults and/or a drug for improving schizophrenia in children is provided.

The beneficial effects of the present invention are:

1. The present invention uses polylactic acid, polylactic acid-glycolic acid copolymer and polycaprolactone as carrier materials. These polymer materials are biodegradable and biocompatible, so that the brepazine sustained-release composition has biocompatibility and sustained-release effect.

2. The breprazol sustained-release composition provided by the present invention is spherical, has a smooth surface with a few micropores, has no adhesion between the compositions, and has good fluidity and redispersibility.

3. The brepazine sustained-release composition provided by the present invention has a high drug loading and a large encapsulation rate (which can be greater than 95%), and a high raw material utilization rate, which can effectively save the preparation cost.

4. The brepizole sustained-release composition provided by the present invention has a low burst release rate at 37°C in vitro and can achieve a sustained-release effect of up to 3 weeks. Compared with brepizole tablets, it has the advantages of high bioavailability, greatly reducing the frequency of administration, and improving patient compliance.

5. The residual solvent and impurity contents of the breprazol sustained-release composition provided by the present invention comply with the guidelines and standards of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (Q3C).

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

FIG1 is an X-ray diffraction diagram of the brepizole sustained-release composition prepared in Example 1 of the present invention, wherein a is brepizole, b is the drug-loaded sustained-release composition, and c is the un-drug-loaded sustained-release composition;

FIG2 is a light microscopic image of the breprazol sustained-release composition prepared in Example 1 of the present invention, which is redissolved in deionized water, A: ×4, B: ×10, C: ×40, D: ×100;

FIG3 is a scanning electron micrograph of the breprazol sustained-release composition prepared in Example 1 of the present invention;

FIG4 is a scanning electron micrograph of the breprazol sustained-release composition prepared in Example 2 of the present invention;

FIG5 is a scanning electron micrograph of the breprazol sustained-release composition prepared in Example 3 of the present invention;

FIG6 is a scanning electron micrograph of the breprazol sustained-release composition prepared in Example 4 of the present invention;

FIG. 7 is an in vitro cumulative release curve at 37° C. of the breprazol sustained-release composition prepared in Example 13 of the present invention.

DETAILED DESCRIPTION

It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and/or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and/or combinations thereof.

In view of the problems of poor patient compliance, reduced drug absorption due to first-pass effect, low bioavailability and large fluctuations in blood drug concentration in existing brepazine dosage forms, the present invention proposes a brepazine sustained-release composition and a preparation method and application thereof.

A typical embodiment of the present invention provides a brepazine sustained-release composition, which has a microscopic morphology of spherical particles, and an average particle size of the spherical particles is 10 to 30 μm; the spherical particles are composed of a carrier and brepazole, and brepazole is uniformly distributed in the carrier, and the weight content of brepazole in the spherical particles is 3 to 45%; the carrier is composed of 1 to 5 parts of polylactic acid, 2 to 10 parts of polylactic acid-glycolic acid copolymer and 1 to 6 parts of polycaprolactone in terms of mass fractions; the ratio of lactic acid units to glycolic acid units in the polylactic acid-glycolic acid copolymer is 75:25 to 50:50, the polylactic acid-glycolic acid copolymer is terminated with carboxylic acid, the weight average molecular weight of the polylactic acid is 20,000 to 40,000 Da, the weight average molecular weight of the polylactic acid-glycolic acid copolymer is 15,000 to 35,000 Da, and the weight average molecular weight of the polycaprolactone is 30,000 to 45,000 Da.

In some embodiments, the mass ratio of polycaprolactone to polylactic-co-glycolic acid is 3.5-4.5: 10. Studies have shown that the drug loading rate is higher under this condition.

In some embodiments, the mass ratio of polylactic acid to polylactic acid-glycolic acid copolymer is 1.5 to 2.5: 10. Studies have shown that under this ratio, not only does it have a higher drug loading and a suitable average particle size, but it also has a more suitable mobile phase and redispersibility.

In some embodiments, polylactic acid is 1.5-2.5 parts, polylactic acid-co-glycolic acid is 10 parts, and polycaprolactone is 3-5 parts. Preferably, polylactic acid is 2 parts, polylactic acid-co-glycolic acid is 10 parts, and polycaprolactone is 4 parts.

The ratio of lactic acid units to glycolic acid units in the polylactic acid-glycolic acid copolymer can be 75:25 to 65:35, 65:35 to 50:50, 75:25, 65:35, 50:50, etc. In some embodiments, the ratio of lactic acid units to glycolic acid units in the polylactic acid-glycolic acid copolymer is 75:25 to 65:35; preferably 75:25. Studies have shown that the ratio of lactic acid units to glycolic acid units affects the burst rate and sustained release effect of the composition. When it fluctuates in the range of 75:25 to 65:35, as the content of lactic acid units increases, the burst rate decreases and the sustained release time is prolonged. When the ratio of lactic acid units to glycolic acid units is 75:25, the burst rate is lower and the sustained release effect is better.

In some embodiments, the weight content of breprazol in the spherical particles is 13-35%, preferably 28-33%, and more preferably 31.78%.

In some embodiments, the average particle size of the spherical particles is 11-20 μm, preferably 13-17 μm, and more preferably 14.6 μm.

Another embodiment of the present invention provides a method for preparing the above-mentioned breprazol sustained-release composition, comprising the following steps:

Adding polylactic acid, polylactic acid-co-glycolic acid, polycaprolactone and brepirazole into an organic solvent and mixing them evenly to obtain an oil phase, wherein the organic solvent is a volatile liquid organic substance that is immiscible with water;

dissolving polyvinyl alcohol into water to form an aqueous phase;

mixing the oil phase with the water phase to form an oil-in-water emulsion;

The organic solvent in the water-in-oil emulsion is removed by volatilization, and then centrifugation is performed to obtain a solidified composition, and the solidified composition is washed with water and vacuum-dried or freeze-dried to obtain the solidified composition.

In some embodiments, the organic solvent is dichloromethane. Studies have shown that when dichloromethane is used as the organic solvent, the preparation effect is better.

In one or more embodiments, the mass ratio of dichloromethane to brepazole is 44.2-132.5:1, more preferably 51-94.6:1, and further preferably 56.3:1.

In one or more embodiments, the ratio of the mass of brepizole, polylactic acid-co-glycolic acid and dichloromethane to the mass of brepizole and polylactic acid-co-glycolic acid is 15.7-45.2:1, preferably 18-32.5:1, and more preferably 19.8:1.

In one or more embodiments, the mass ratio of dichloromethane to poly(lactic acid-co-glycolic acid) is 22.1-66.3:1, more preferably 25.5-47.3:1, and further preferably 28.1:1.

In some embodiments, in the oil phase, the concentration of polylactic acid-glycolic acid copolymer is 2-6% (w/v, mass volume ratio), more preferably 2.8-5.2% (w/v, mass volume ratio), and further preferably 4.71% (w/v, mass volume ratio).

In some embodiments, in the oil phase, the mass ratio of polylactic acid, polylactic acid-co-glycolic acid and polycaprolactone is 1-5:10:1-6, preferably 2:10:3-5, and more preferably 1:5:2.

In some embodiments, the mass ratio of brepazole to the total mass of polylactic acid, polylactic acid-co-glycolic acid and polycaprolactone is 1:1-6, preferably 1:1.5-4, and more preferably 1:2.

In some embodiments, the concentration of polyvinyl alcohol in the aqueous phase is 0.1-0.9% (w/v), preferably 0.26-0.74% (w/v), and more preferably 0.61% (w/v).

In some embodiments, the volume ratio of the water phase to the oil phase is 50 to 150:1, more preferably 70.27 to 129.73:1, and further preferably 102.55:1.

In some embodiments, in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification, and the shear rate is 1500-4000rpm, preferably 1500-3000rpm, more preferably 2500-3000rpm, and more preferably 3000rpm. Studies have shown that the shear rate affects the average particle size of the composition. When the shear rate is 1500-3000rpm, the average particle size can be guaranteed to be 10-30μm. When the shear rate is 2500-3000rpm, especially 3000rpm, the average particle size can be guaranteed to be 10-20μm.

The shearing time also affects the average particle size of the composition. In one or more embodiments, the shearing time is 30 to 70 seconds, preferably 40 to 70 seconds, and more preferably 60 seconds. Studies have shown that when the shearing time is 60 seconds, the drug loading and encapsulation efficiency are higher.

In some embodiments, the method of volatilizing and removing the organic solvent in the oil-in-water emulsion is stirring. The stirring rate is 350-450 rpm and the stirring time is 3.5-4.5 hours.

In some embodiments, the solidified composition is washed with water and then freeze-dried.

A third embodiment of the present invention provides a use of the above-mentioned breprazol sustained-release composition in the preparation of a drug for auxiliary treatment of adult major depressive disorder, a drug for treating adult schizophrenia, a drug for treating childhood schizophrenia, a drug for improving adult schizophrenia and/or a drug for improving childhood schizophrenia.

Specifically, the dosage form of the drug is an injection.

In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

Example 1

4 mg of polylactic acid, 20 mg of polylactic acid-co-glycolic acid (75:25), 8 mg of polycaprolactone and 16 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 50 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the sustained-release composition obtained was 31.05%, the encapsulation efficiency was 93.15%, and the average particle size was 13.53 μm. X-ray diffraction results showed that brepazole was dispersed in the polylactic acid-glycolic acid copolymer in an amorphous form (Figure 1). The composition appeared as a white powder, without agglomeration or wall adhesion, and had good fluidity and redispersibility (Figure 2). The electron microscopic appearance of the composition (Figure 3) was a round and regular sphere with a smooth surface, and there was no adhesion between the compositions. The in vitro release of the composition (using the sample separation method, the microspheres of the composition were dispersed in a flask containing a release medium (pH 7.4 PBS, containing 0.5% (w/v) Tween 80 and 0.02% (w/v) sodium azide), incubated in an air bath oscillator (37°C, 100 rpm), and an appropriate amount of sample was collected at a predetermined time point and centrifuged to obtain the supernatant to detect the drug concentration. The precipitate was dispersed with an equal amount of release medium and then flushed back into the flask to draw the cumulative release curve of brepazole) had a burst rate of 2.14%, and the sustained release duration was 22 days.

The relevant material information of the composition of the present invention measured by high performance liquid chromatography is shown in Table 1 below:

Table 1 Information on related substances of the sustained-release composition

Table 1 shows that the content of related substances in the breprazol sustained-release composition prepared in this example meets the impurity standards for new drug preparations of ICH (Q3B).

Example 2

5.2 mg of polylactic acid, 26 mg of polylactic acid-co-glycolic acid (75:25), 10.4 mg of polycaprolactone and 20.8 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30,000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27,000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35,000 Da. The oil phase was poured into 35.14 mL of 0.74% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the obtained sustained-release composition is 30.14%, the encapsulation efficiency is 90.42%, and the average particle size is 20.27μm. The composition has the appearance of white powder, with partial agglomeration, poor fluidity but good redispersibility. The electron microscopic appearance of the composition (Figure 4) is a round and regular sphere with a smooth surface, but there is a certain aggregation phenomenon between the compositions. The 37°C in vitro release burst rate of the composition is 1.92%, and the sustained release duration is 25 days.

Example 3

4 mg of polylactic acid, 20 mg of polylactic acid-co-glycolic acid (75:25), 8 mg of polycaprolactone and 16 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30,000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27,000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35,000 Da. The oil phase was poured into 75 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at 3,000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the sustained-release composition obtained is 29.35%, the encapsulation efficiency is 88.05%, and the average particle size is 14.66μm. The composition has a white powder appearance, no agglomeration or wall adhesion, and good fluidity and redispersibility. The electron microscopic appearance of the composition (Figure 5) is a round and regular sphere with a smooth surface, and there is no adhesion between the compositions. The 37°C in vitro release burst rate of the composition is 2.38%, and the sustained release duration is 21 days.

Example 4

2.8 mg of polylactic acid, 14 mg of polylactic acid-glycolic acid copolymer (75:25), 5.6 mg of polycaprolactone and 11.2 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-glycolic acid copolymer was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 64.89 mL of 0.26% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the result.

Conclusion: The drug loading of the obtained sustained-release composition is 27.27%, the encapsulation efficiency is 81.81%, and the average particle size is 12.85μm. The composition has a white powder appearance, no agglomeration or wall adhesion, and good fluidity and redispersibility. The electron microscopic appearance of the composition (Figure 6) is a round and regular sphere with a smooth surface, and there is no adhesion between the compositions. The 37°C in vitro release burst rate of the composition is 1.74%, and the sustained release duration is 22 days.

Example 5

5.2 mg of polylactic acid, 26 mg of polylactic acid-co-glycolic acid (75:25), 10.4 mg of polycaprolactone and 20.8 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30,000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27,000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35,000 Da. The oil phase was poured into 64.89 mL of 0.26% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the sustained-release composition was 27.57%, the encapsulation efficiency was 82.71%, and the average particle size was 20.22 μm. The composition appeared as a white powder with obvious agglomeration, poor fluidity and redispersibility. The burst release rate of the composition at 37°C in vitro was 1.35%, and the sustained-release duration was 26 days.

Example 6

2.8 mg of polylactic acid, 14 mg of polylactic acid-glycolic acid copolymer (75:25), 5.6 mg of polycaprolactone and 11.2 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-glycolic acid copolymer was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 35.14 mL of 0.26% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the sustained-release composition was 26.35%, the encapsulation efficiency was 79.05%, and the average particle size was 17.53 μm. The composition appeared as a white powder, without agglomeration or wall adhesion, and had good fluidity and redispersibility. The burst release rate of the composition at 37°C in vitro was 1.35%, and the sustained-release duration was 24 days.

Example 7

5.2 mg of polylactic acid, 26 mg of polylactic acid-co-glycolic acid (75:25), 10.4 mg of polycaprolactone and 20.8 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30,000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27,000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35,000 Da. The oil phase was poured into 35.14 mL of 0.26% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the obtained sustained-release composition is 27.13%, the encapsulation efficiency is 81.39%, and the average particle size is 24.86μm. The composition has a white powder appearance, with obvious agglomeration and severe wall adhesion, and poor fluidity and redispersibility. The burst release rate of the composition at 37°C in vitro is 0.81%, and the sustained-release duration is 28 days.

Example 8

2mg polylactic acid, 10mg polylactic acid-glycolic acid copolymer (75:25), 4mg polycaprolactone and 8mg brepazole were ultrasonically dissolved in 0.5mL dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000Da, the weight average molecular weight of polylactic acid-glycolic acid copolymer was 27000Da, the intrinsic viscosity was 0.3dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000Da. The oil phase was poured into 50mL 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000rpm for 60s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at a speed of 400rpm with a magnetic stirrer for 4h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the result.

Conclusion: The drug loading of the sustained-release composition was 26.81%, the encapsulation efficiency was 80.43%, and the average particle size was 13.64 μm. The composition appeared as a white powder, without agglomeration or wall adhesion, and had good fluidity and redispersibility. The burst release rate of the composition at 37°C in vitro was 2.72%, and the sustained-release duration was 20 days.

Embodiment 9

6 mg of polylactic acid, 30 mg of polylactic acid-co-glycolic acid (75:25), 12 mg of polycaprolactone and 24 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 50 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the sustained-release composition was 30.26%, the encapsulation efficiency was 90.78%, and the average particle size was 21.66 μm. The composition appeared as a white powder, some of which were agglomerated, with poor fluidity but good redispersibility. The burst release rate of the composition at 37°C in vitro was 1.27%, and the sustained-release duration was 26 days.

Example 10

2.8 mg of polylactic acid, 14 mg of polylactic acid-glycolic acid copolymer (75:25), 5.6 mg of polycaprolactone and 11.2 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-glycolic acid copolymer was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 35.14 mL of 0.74% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

Conclusion: The drug loading of the sustained-release composition was 26.73%, the encapsulation efficiency was 80.19%, and the average particle size was 18.12 μm. The composition appeared as a white powder, without agglomeration or wall adhesion, and had good fluidity and redispersibility. The burst release rate of the composition at 37°C in vitro was 2.35%, and the sustained-release duration was 23 days.

Embodiment 11

2.8 mg of polylactic acid, 14 mg of polylactic acid-glycolic acid copolymer (75:25), 5.6 mg of polycaprolactone and 11.2 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-glycolic acid copolymer was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 64.89 mL of 0.74% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the result.

Conclusion: The drug loading of the sustained-release composition was 27.33%, the encapsulation efficiency was 81.99%, and the average particle size was 13.47 μm. The composition appeared as a white powder, without agglomeration or wall adhesion, and had good fluidity and redispersibility. The burst release rate of the composition at 37°C in vitro was 3.08%, and the sustained-release duration was 21 days.

The residual organic solvent dichloromethane content of the brepazine sustained-release composition in the above example was measured by gas chromatography to be 230-260 ppm, which was in compliance with the ICH (Q3C) standard.

Example 12: Selection of drug loading ratio

4 mg of polylactic acid, 20 mg of polylactic acid-co-glycolic acid (75:25), 8 mg of polycaprolactone and different amounts of brepazole (as shown in Table 2) were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 50 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the result.

The effects of different drug loading ratios on the sustained-release composition are shown in Table 2.

Table 2 Effects of different drug loading ratios on sustained-release compositions

Conclusion: The drug-loading ratio higher or lower than 1:2 will reduce the encapsulation efficiency of brepazole in the sustained-release composition.

Example 13: Selection of the ratio of lactic acid to glycolic acid in polylactic acid-glycolic acid copolymer

4 mg of polylactic acid, 20 mg of polylactic acid-glycolic acid copolymer (75:25 or 65:35 or 50:50), 8 mg of polycaprolactone and 16 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30000 Da, the weight average molecular weight of polylactic acid-glycolic acid copolymer was 27000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35000 Da. The oil phase was poured into 50 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at 3000 rpm for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

The effects of different poly(lactic acid-glycolic acid) copolymer models on the sustained-release composition are shown in Table 3.

Conclusion: The ratio of lactic acid to glycolic acid in polylactic acid-glycolic acid copolymer has a significant effect on the in vitro release characteristics of the sustained-release composition at 37°C (Figure 6). When the ratio of lactic acid to glycolic acid in the polylactic acid-glycolic acid copolymer in the sustained-release composition is 75:25, the burst release rate is the lowest and the sustained-release effect is the best.

Example 14: Selection of the ratio of three polymers in the composition

A certain mass of polylactic acid (A), 20 mg of polylactic acid-glycolic acid copolymer (75:25) (B), a certain mass of polycaprolactone (C) and brepazole equivalent to 1/2 of the mass of the three polymers are ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid is 30000 Da, the weight average molecular weight of polylactic acid-glycolic acid copolymer is 27000 Da, the intrinsic viscosity is 0.3 dL/g, the functional group end-capping is carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone is 35000 Da. The oil phase is poured into 50 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at different shear rates for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at a speed of 400 rpm with a magnetic stirrer for 4 hours to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition is collected by centrifugation, washed with deionized water and freeze-dried to obtain the result.

The effects of the three polymer ratios on the sustained-release composition are shown in Table 4.

Table 4 Effect of the ratio of three polymers on sustained-release composition

Conclusion: When the mass ratio of polycaprolactone to polylactic acid-glycolic acid copolymer in the composition is lower than 0.4, the drug loading of the obtained sustained-release composition is low, and exceeding 0.4 will lead to a decrease in the drug loading of the obtained sustained-release composition. Therefore, the optimal mass ratio of polycaprolactone to polylactic acid-glycolic acid copolymer in the composition is 0.4. The increase in the mass ratio of polylactic acid to polylactic acid-glycolic acid copolymer in the composition will lead to an increase in the drug loading and average particle size of the obtained sustained-release composition, but exceeding 0.2 will affect the fluidity and redispersibility of the obtained sustained-release composition. Therefore, the optimal mass ratio of polylactic acid to polylactic acid-glycolic acid copolymer in the composition is 0.2.

Example 15: Selection of shear rate for high-speed emulsifier

4 mg of polylactic acid, 20 mg of polylactic acid-co-glycolic acid (75:25), 8 mg of polycaprolactone and 16 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30,000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27,000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35,000 Da. The oil phase was poured into 50 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared at different shear rates for 60 s with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred at a speed of 400 rpm with a magnetic stirrer for 4 h to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

The effects of different shear rates on the sustained-release composition are shown in Table 5.

Table 5 Effect of different shear rates on sustained-release compositions

Conclusion: The shear rate mainly affects the average particle size of the sustained-release composition. A shear rate lower than 2000 rpm or higher than 3500 rpm will cause the average particle size of the sustained-release composition to be outside the range of 10 to 20 μm. Therefore, 3000 rpm is the optimal shear rate.

Example 16: Selection of shear time for high-speed emulsifier

4 mg of polylactic acid, 20 mg of polylactic acid-co-glycolic acid (75:25), 8 mg of polycaprolactone and 16 mg of brepazole were ultrasonically dissolved in 0.5 mL of dichloromethane to form an oil phase, wherein the weight average molecular weight of polylactic acid was 30,000 Da, the weight average molecular weight of polylactic acid-co-glycolic acid was 27,000 Da, the intrinsic viscosity was 0.3 dL/g, the functional group end-capping was carboxylic acid end-capping, and the weight average molecular weight of polycaprolactone was 35,000 Da. The oil phase was poured into 50 mL of 0.5% (w/v) polyvinyl alcohol aqueous solution, sheared for several seconds at 3,000 rpm with a high-speed emulsifier to form an oil-in-water emulsion, and further stirred for 4 hours at a speed of 400 rpm with a magnetic stirrer to volatilize the dichloromethane in the oil phase droplets to solidify the composition. The solidified composition was collected by centrifugation, washed with deionized water and freeze-dried to obtain the resultant.

The effects of different shearing times on the sustained-release composition are shown in Table 6.

Table 6 Effect of different shearing times on sustained-release compositions

Conclusion: Shearing time mainly affects the average particle size of the sustained-release composition. The average particle size of the sustained-release composition obtained when the shearing time is 30-70s is in the range of 10-20μm, while the drug loading capacity and encapsulation efficiency of the sustained-release composition obtained when the shearing time is 60s are higher. Therefore, 60s is the optimal shearing time.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (37)

1. A sustained-release composition of brepirazolide, characterized in that the microscopic morphology is spherical particles, the average particle size of the spherical particles is 10-30 μm; the spherical particles are composed of a carrier and brepirazolide, the brepirazolide is uniformly distributed in the carrier, and the weight content of brepirazolide in the spherical particles is 3-45%; The carrier is composed of polylactic acid, polylactic acid-glycolic acid copolymer and polycaprolactone; The mass ratios of the polylactic acid, polylactic acid-co-glycolic acid and polycaprolactone are 5:10:1, 1:10:3, 2:10:3, 5:10:3, 1:10:4 and 1:5:2; The ratio of lactic acid units to glycolic acid units in the polylactic acid-glycolic acid copolymer is 75:25; The polylactic acid-co-glycolic acid is terminated with carboxylic acid, the weight average molecular weight of the polylactic acid is 20000-40000Da, the weight average molecular weight of the polylactic acid-co-glycolic acid is 15000-35000Da, and the weight average molecular weight of the polycaprolactone is 30000-45000Da; The breprazol sustained-release composition meets the standards for intramuscular or subcutaneous injection. 2. The sustained-release composition of brepiraazole according to claim 1, wherein the weight content of brepiraazole in the spherical particles is 13-35%. 3. The sustained-release composition of brepizole according to claim 2, wherein the weight content of brepizole in the spherical particles is 28-33%. 4. The sustained-release composition of brepiraazole according to claim 3, wherein the weight content of brepiraazole in the spherical particles is 31.78%. 5. The sustained-release composition of brepazole according to claim 1, wherein the average particle size of the spherical particles is 11-20 μm. 6. The sustained-release composition of brepazole according to claim 5, wherein the average particle size of the spherical particles is 13-17 μm. 7. The sustained-release composition of brepazole according to claim 6, wherein the average particle size of the spherical particles is 14.6 μm. 8. A method for preparing the breprazol sustained-release composition according to claim 1, comprising the following steps: Adding polylactic acid, polylactic acid-co-glycolic acid, polycaprolactone and brepirazole into an organic solvent and mixing them evenly to obtain an oil phase, wherein the organic solvent is a volatile liquid organic substance that is immiscible with water; dissolving polyvinyl alcohol into water to form an aqueous phase; mixing the oil phase with the water phase to form an oil-in-water emulsion; The organic solvent in the oil-in-water emulsion is removed by volatilization, and then centrifuged to obtain a solidified composition, and the solidified composition is washed with water and vacuum-dried or freeze-dried to obtain; The organic solvent is dichloromethane; The mass ratio of brepazole to the total mass of polylactic acid, polylactic acid-co-glycolic acid and polycaprolactone is 1:2. 9. The method for preparing the brepaviridol sustained-release composition according to claim 8, wherein the mass ratio of dichloromethane to brepaviridol is 44.2-132.5:1. 10. The method for preparing the brepiraazole sustained-release composition according to claim 9, wherein the mass ratio of dichloromethane to brepiraazole is 51-94.6:1. 11. The method for preparing the brepiraazole sustained-release composition according to claim 10, wherein the mass ratio of dichloromethane to brepiraazole is 56.3:1. 12. The method for preparing a brepizole sustained-release composition according to claim 8, wherein the ratio of the mass of brepizole, polylactic acid-co-glycolic acid and dichloromethane to the mass of brepizole and polylactic acid-co-glycolic acid is 15.7-45.2:1. 13. The method for preparing a brepizole sustained-release composition according to claim 12, wherein the ratio of the mass of brepizole, polylactic acid-co-glycolic acid and dichloromethane to the mass of brepizole and polylactic acid-co-glycolic acid is 18-32.5:1. 14. The method for preparing a brepizole sustained-release composition according to claim 13, wherein the ratio of the mass of brepizole, polylactic acid-co-glycolic acid and dichloromethane to the mass of brepizole and polylactic acid-co-glycolic acid is 19.8:1. 15. The method for preparing the brepazole sustained-release composition according to claim 8, wherein the mass ratio of dichloromethane to polylactic acid-glycolic acid copolymer is 22.1-66.3:1. 16. The method for preparing the brepazole sustained-release composition according to claim 15, wherein the mass ratio of dichloromethane to polylactic acid-glycolic acid copolymer is 25.5-47.3:1. 17. The method for preparing the brepazole sustained-release composition according to claim 16, wherein the mass ratio of dichloromethane to polylactic acid-glycolic acid copolymer is 28.1:1. 18. The method for preparing the sustained-release brepazole composition according to claim 8, wherein the concentration of the polylactic acid-glycolic acid copolymer in the oil phase is 2-6% w/v. 19. The method for preparing the sustained-release brepazole composition according to claim 18, wherein the concentration of the polylactic acid-glycolic acid copolymer in the oil phase is 2.8-5.2% w/v. 20. The method for preparing the sustained-release brepazole composition according to claim 19, wherein the concentration of the polylactic acid-glycolic acid copolymer in the oil phase is 4.71% w/v. 21. The method for preparing the sustained-release brepazole composition according to claim 8, wherein the concentration of polyvinyl alcohol in the aqueous phase is 0.1-0.9% w/v. 22. The method for preparing the sustained-release brepazole composition according to claim 21, wherein the concentration of polyvinyl alcohol in the aqueous phase is 0.26-0.74% w/v. 23. The method for preparing the sustained-release brepazole composition according to claim 22, wherein the concentration of polyvinyl alcohol in the aqueous phase is 0.61% w/v. 24. The method for preparing the brepaviridol sustained-release composition according to claim 8, wherein the volume ratio of the aqueous phase to the oil phase is 50-150:1. 25. The method for preparing the brepaviridol sustained-release composition according to claim 24, wherein the volume ratio of the aqueous phase to the oil phase is 70.27-129.73:1. 26. The method for preparing the brepaviridol sustained-release composition according to claim 25, wherein the volume ratio of the aqueous phase to the oil phase is 102.55:1. 27. The method for preparing the sustained-release brepazole composition according to claim 8, characterized in that in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification at a shear rate of 1500-4000 rpm. 28. The method for preparing the sustained-release brepazole composition according to claim 27, characterized in that in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification at a shear rate of 1500-3000 rpm. 29. The method for preparing the brepaviridol sustained-release composition according to claim 27, wherein in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification at a shear rate of 2500-3000 rpm. 30. The method for preparing the sustained-release brepazole composition according to claim 29, characterized in that in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification at a shear rate of 3000 rpm. 31. The method for preparing the sustained-release brepazole composition according to claim 8, characterized in that in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification, and the shear time is 30-70 seconds. 32. The method for preparing the sustained-release brepazole composition according to claim 31, characterized in that in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification, and the shear time is 40-70 seconds. 33. The method for preparing the sustained-release brepazole composition according to claim 32, characterized in that in the process of preparing the oil-in-water emulsion, a high-speed emulsifier is used for shear emulsification, and the shear time is 60 seconds. 34. The method for preparing the sustained-release brepazole composition according to claim 8, wherein the method for volatilizing and removing the organic solvent in the oil-in-water emulsion is stirring. 35. The method for preparing the brepaviridol sustained-release composition according to claim 34, characterized in that the stirring rate is 350-450 rpm and the stirring time is 3.5-4.5 h. 36. The method for preparing the sustained-release composition of brepazine as claimed in claim 8, wherein the solidified composition is washed with water and then freeze-dried. 37. Use of the breprazol sustained-release composition according to any one of claims 1 to 7 in the preparation of a drug for assisting the treatment of adult major depressive disorder, a drug for treating adult schizophrenia, or a drug for improving adult schizophrenia.