WO2023226141A1

WO2023226141A1 - Drug-loaded bead and preparation method therefor

Info

Publication number: WO2023226141A1
Application number: PCT/CN2022/101633
Authority: WO
Inventors: 宁周雨; 顾晓雷; 李敏; 黄海
Original assignee: 苏州恒瑞迦俐生生物医药科技有限公司
Priority date: 2022-05-27
Filing date: 2022-06-27
Publication date: 2023-11-30
Also published as: CN115869457A

Abstract

A drug-loaded bead and a preparation method therefor, specifically relating to a drug-loaded embolic bead. The embolic bead is obtained by means of cross-linking polymerization of a polyhydroxy compound, an alkyl acetal derivative and an alkylsulfonic acid derivative. Moreover, the embolic bead can carry large molecule drugs and small molecule drugs together. The surface of the drug-loaded bead is smooth, the drug resistance of tumor cells caused by a single drug is reduced, drug loading capacity is improved, and a drug can be slowly released.

Description

Drug-loaded microsphere and preparation method thereof

priority statement

This application is a continuation application of the Chinese patent (Patent No. CN202210587813.X) submitted on February 2, 2021, and claims its priority. The entire content of which is hereby incorporated by reference.

Technical field

The present invention relates to the technical field of medical materials, and specifically relates to a drug-loaded microsphere and a preparation method thereof.

Background technique

Transcatheter arterial chemoembolization (TACE) is an interventional surgery that uses a catheter to inject embolism into the supply blood vessels of diseased organs to shrink the diseased location to achieve therapeutic purposes. For patients with hepatocellular carcinoma who currently cannot undergo tumor resection or liver transplantation, TACE has become the core method of liver cancer treatment. With the widespread application and rapid development of hepatic artery embolization technology, drug-eluting beads (DEB) have emerged as a new embolization agent.

Embolization microspheres can achieve the dual effects of physical embolization and chemotherapy at the same time after being loaded with drugs. Most of the drug-loaded microspheres currently on the market are single drugs. This not only easily causes tumor cells to develop drug resistance and reduces the therapeutic effect, but also causes the risk of a single drug. Addition of side effects. In addition, existing drug-loaded microspheres have a low loading capacity for some drugs and fail to meet clinical drug standards. Therefore, using a multi-drug combination method can solve the shortcomings of the existing technology.

The invention provides a drug-loaded microsphere and a preparation method thereof. The method can realize joint drug loading, increase the drug loading capacity, and prolong the drug release time; it can also reduce the drug resistance of tumor cells and reduce side effects on the human body.

Contents of the invention

The invention provides a drug-loaded microsphere and a preparation method thereof. The method can significantly increase the loading capacity of macromolecule drugs and small molecule drugs by embolization microspheres and prolong the release time of drugs in the embolization microspheres.

The present invention is achieved through the following technical solutions:

A drug-loaded microsphere. The drug-loaded microsphere includes polyhydroxy compounds, alkyl acetal derivatives, and alkyl sulfonic acid derivatives. The drug-loaded microsphere jointly encapsulates macromolecule drugs and small molecule drugs through electrostatic attraction. , drug-loaded microspheres are used in combination with transcatheter arterial chemoembolization.

Alkyl acetal derivatives include one or more of acrylamide alkyl dialkoxy acetal and N-acrylamide dimethoxyethyl acetal.

In another preferred embodiment, drug-loaded microspheres can simultaneously achieve the dual effects of physical embolization and chemotherapy.

In another preferred embodiment, the macromolecular drugs include one or more of PD-1 and bevacizumab, and the small molecule drugs include doxorubicin, irinotecan, epirubicin, and pirarubicin. one or more.

In another preferred example, the embolization microspheres contain negatively charged sulfonic acid groups in their own chemical structure, and can load positively charged macromolecule drugs and small molecule drugs through electrostatic adsorption.

A method for preparing drug-loaded microspheres, including the following steps:

(1) Preparation of functionalized macromolecular hydrogel: Heat the polyhydroxy polymer and dissolve it in purified water. After cooling, add alkyl acetal derivatives, stir and drop concentrated hydrochloric acid for reaction, collect the crude product, and Wash and dry to obtain the desired functionalized macromolecular hydrogel;

(2) Preparation of embolic microspheres: Dissolve alkyl sulfonic acid derivatives and potassium persulfate in water, mix evenly and then add the functionalized macromolecular hydrogel in step (1) to obtain a polymer monomer solution; Butyl acetate, cellulose acetate and nitrogen are passed into the reaction vessel, and polymer monomer solution and tetramethylethylenediamine are added to form an oil-water mixed reaction system. After the reaction is completed, it is washed with an organic solvent and dried to obtain the embolus microfiber. ball;

(3) Joint encapsulation of macromolecular drugs and small molecule drugs: Dissolve macromolecular drugs and small molecule drugs in purified water to obtain a drug mixture solution, and add embolization microspheres to soak the embolization microspheres in the drug mixture solution. , collect and dry after completion of loading to obtain drug-loaded microspheres.

In another preferred embodiment, the organic solvent includes butyl acetate, ethyl acetate, and acetone.

In another preferred embodiment, an axial flow stirring paddle is used for the stirring operation, and the stirring speed is 400-650 rpm.

In another preferred example, the ratio of functionalized macromolecular hydrogel to alkyl sulfonic acid derivatives is 1.00-0.12.

In another preferred example, when the polymer monomer solution is added, the reaction system temperature ranges from 40 to 60°C.

In another preferred embodiment, the polyvinyl alcohol is dissolved and then cooled to 10°C.

In another preferred example, the amounts of two drugs in the supernatant at different time points are measured, and the actual drug loading amount and actual drug loading efficiency of the drug-loaded microspheres for the two drugs can be accurately calculated through HPLC.

In another preferred example, the actual drug loading amount = the total drug dosage - the remaining drug amount in the supernatant.

In another preferred example, actual drug loading efficiency = actual drug loading amount/total drug dosage × 100%.

In another preferred example, cumulative release rate = cumulative drug release amount/drug loading amount × 100%.

Example data analysis results are as follows:

In Example 9, when doxorubicin and bevacizumab are combined for drug loading, within 60 minutes after drug loading, the drug loading efficiency reaches 98.0% and 53.2% respectively, and the drug loading amount reaches 29.4 mg and 31.9 mg respectively, which is in line with clinical practice. Medical applications require. In the drug release experiment, the cumulative release rate of drug-loaded microspheres after 48 hours was as low as 22.8%, which can slow the release of doxorubicin. In addition, the cumulative release rate of drug-loaded microspheres for bevacizumab after 48 hours The rate was 89.5%. In the previous experimental data of bevacizumab encapsulated in drug-loaded microspheres alone (Table 14), the release exceeded 90.0% in 2 hours. Therefore, combined encapsulation can better delay the release of bevacizumab antibodies. of release.

In Example 10, when doxorubicin and PD-1 are combined for drug loading, within 60 minutes after drug loading, the drug loading efficiency reaches 97.1% and 95.7% respectively, and the drug loading amount reaches 58.3 mg and 114.8 mg respectively, which is in line with clinical medicine. application needs. In the drug release experiment, the cumulative release rate of drug-loaded microspheres after 48 hours was as low as 24.7%, which can slowly release doxorubicin. In addition, the cumulative release rate of drug-loaded microspheres for PD-1 after 8 hours In the previous experimental data of PD-1 encapsulation in drug-loaded microspheres alone (Table 13), the release exceeded 90.0% in 1 hour. Therefore, combined encapsulation can better delay the release of PD-1 antibody.

In Example 11, when epirubicin and bevacizumab were combined for drug loading, within 60 minutes after drug loading, the drug loading efficiencies reached 85.6% and 53.9% respectively, and the drug loading amounts reached 51.4 mg and 64.7 mg respectively, which is consistent with Clinical medical application needs. In the drug release experiment, the cumulative release rate of drug-loaded microspheres was as low as 33.5% in 48 hours, which can slow the release of epirubicin. In addition, the cumulative release rate of drug-loaded microspheres in bevacizumab after 8 hours The release rate exceeds 90.0%. In the previous experimental data of bevacizumab encapsulated in drug-loaded microspheres alone (Table 14), the release rate exceeded 90.0% in 2 hours. Therefore, combined encapsulation can better delay bevacizumab. Antibody release.

In Example 12, when epirubicin and PD-1 are combined for drug loading, within 60 minutes after drug loading, the drug loading efficiency reaches 84.6% and 93.5% respectively, and the drug loading amount reaches 50.8mg and 112.2mg respectively, which is in line with clinical practice. Medical applications require. In the drug release experiment, the cumulative release rate of drug-loaded microspheres was as low as 34.2% in 48 hours, which can slow the release of epirubicin. In addition, the cumulative release rate of drug-loaded microspheres in PD-1 after 12 hours The rate exceeds 90.0%. In the previous experimental data of PD-1 encapsulated in drug-loaded microspheres alone (Table 13), the release exceeded 90.0% in 1 hour. Therefore, combined encapsulation can better delay the release of PD-1 antibody. .

The technical solution of the present invention has the following advantages:

(1) The preparation method of drug-loaded microspheres is simple and low-cost. The shape of the prepared drug-loaded microspheres is close to a perfect spherical shape, with a smooth surface and a compression deformation of more than 50%.

(2) The drug-loaded microspheres prepared by this method can efficiently encapsulate macromolecular protein drugs and small molecule chemotherapy drugs at the same time, increase the drug loading capacity, realize the joint effect of two drugs, and reduce the toxicity of a single drug to human chemotherapy. Side effects include reducing drug resistance of tumor cells.

(3) The drug-loaded microspheres prepared by this method can achieve sustained release of macromolecular protein drugs and small molecule chemotherapy drugs when combined with drug loading.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.

Preparation of functionalized macromolecular hydrogels

Example 1

Add 100g polyvinyl alcohol to the flask containing purified water, stir and disperse evenly. Heat to 96°C. After the polyvinyl alcohol is completely dissolved, cool down to below 25°C. Add 2g acrylamide alkyl dialkoxy acetal and 2g N-acrylamide dimethoxyethyl acetal and stir. After 10 minutes, 100 mL of concentrated hydrochloric acid was added dropwise to the solution. After the dropwise addition, stirring was continued for 6 hours. The crude product was then collected, washed and dried to obtain the desired functionalized macromolecular hydrogel.

Example 2

Add 200g polyvinyl alcohol to the flask containing purified water, stir and disperse evenly. Heat to 96°C. After the polyvinyl alcohol is completely dissolved, cool to below 25°C. Add 4g of acrylamide alkyl dialkoxy acetal and 4g of N-acrylamide dimethoxyethyl acetal. After stirring for 10 minutes, 200 mL of concentrated hydrochloric acid was added dropwise to the solution. After the dropwise addition, the reaction was continued to stir for 6 hours. The crude product was then collected, washed and dried to obtain the desired functionalized macromolecular hydrogel.

Preparation of polyvinyl alcohol embolization microspheres

Example 3

Add 6g sodium 2-acrylamide-2-methylpropanesulfonate and 5g potassium persulfate to the purified water in sequence. After dissolving and mixing evenly, add 50g of the functionalized macromolecular gel intermediate prepared in Example 1 and stir evenly. , to obtain a polymer monomer solution. Add 5g butyl acetate and 2.5g cellulose acetate, add nitrogen gas at the same time, stir and heat. Then add the above polymer monomer solution and tetramethylethylenediamine in sequence to form an oil-water mixed reaction system, and heat and stir for 3 hours. In this reaction, the stirring paddle is an axial flow stirring paddle, the stirring speed is 450 rpm, and the temperature of the reaction system is controlled at 40 to 60°C when the polymer monomer solution is added. After the reaction is completed, the reaction mixture is filtered to collect the microspheres, then washed with butyl acetate, ethyl acetate and acetone in sequence, and dried under vacuum to obtain polyvinyl alcohol embolized microspheres.

Example 4

Add 12g sodium 2-acrylamide-2-methylpropanesulfonate and 10g potassium persulfate to the purified water in sequence. After dissolving and mixing evenly, add 100g of the functionalized macromolecular gel intermediate prepared in Example 1 and stir evenly. , to obtain a polymer monomer solution. Add 10g of butyl acetate and 5g of cellulose acetate, add nitrogen gas at the same time, stir and heat, then add the above polymer monomer solution and tetramethylethylenediamine in sequence to form an oil-water mixed reaction system, heat and stir for 3 hours. In this reaction, the stirring paddle is an axial flow stirring paddle, the stirring speed is 450 rpm, and the temperature of the reaction system is controlled at 40 to 60°C when the polymer monomer solution is added. After the reaction is completed, the reaction mixture is filtered to collect the microspheres, then washed with butyl acetate, ethyl acetate and acetone in sequence, and dried under vacuum to obtain polyvinyl alcohol embolized microspheres.

Co-encapsulation of large molecule drugs and small molecule drugs by embolization microspheres

Example 5

Co-encapsulation of doxorubicin and bevacizumab in embolization microspheres: Take purified water, filter it with a 0.4 μm filter, prepare doxorubicin solution, and dilute bevacizumab injection to a concentration of 20 mg/mL and 4 mg respectively. /mL. Take 0.1g of embolization microspheres with the physiological saline removed and place it in a brown vial. According to the designed dosage, add 0.15mL and 1.5mL of the drug solution into the embolization microspheres. Gently shake the vial to fully mix the embolization microspheres and the drug. Evenly, start timing to load the medicine. Make 3 sets of samples in parallel for each sample. Extract the supernatant after loading for 5 minutes, 15 minutes, 30 minutes, and 1 hour. The remaining concentrations of the two drugs in the supernatant are measured by HPLC, and the drug loading efficiency and drug loading capacity of doxorubicin and bevacizumab are calculated. The results are as follows: As shown in Table 1.

Example 6

Co-encapsulation of doxorubicin and PD-1 by embolization microspheres: Take purified water, filter it with a 0.4 μm filter, prepare doxorubicin solution, and dilute PD-1 injection to a concentration of 20 mg/mL and 4 mg/mL respectively. . Take 0.1g of the embolization microspheres with the physiological saline removed and place it in a brown vial. Add 0.3 mL and 3.0 mL of the drug solution according to the designed dosage into the embolization microspheres. Gently shake the vial to fully mix the embolization microspheres and the drug. Evenly, start timing to load the medicine. Make 3 sets of samples in parallel for each sample. The supernatant was extracted after loading for 5 minutes, 15 minutes, 30 minutes, and 1 hour. The remaining concentrations of the two drugs in the supernatant were measured by HPLC, and the drug loading efficiency and drug loading capacity of doxorubicin and PD-1 were calculated. The results are as shown in the table 2 shown.

Example 7

Co-encapsulation of epirubicin and bevacizumab in embolic microspheres: Take purified water, filter it with a 0.4 μm filter, prepare epirubicin solution, and dilute bevacizumab injection, with concentrations of 20 mg/mL. and 4mg/mL. Take 0.1g of embolization microspheres with the physiological saline removed and place it in a brown vial. According to the designed dosage, add 0.3mL and 3.0mL of the drug solution into the microspheres. Gently shake the vial to fully mix the microspheres and the drug. Start timing drug loading. Make 3 sets of samples in parallel for each sample. Extract the supernatant after loading for 5 minutes, 15 minutes, 30 minutes, and 1 hour. The remaining concentrations of the two drugs in the supernatant were measured by HPLC, and the drug loading efficiency and drug loading capacity of epirubicin and bevacizumab were calculated. The results as shown in Table 3.

Example 8

Co-encapsulation of epirubicin and PD-1 in embolic microspheres: Take purified water, filter it with a 0.4 μm filter, prepare epirubicin solution, and dilute PD-1 injection, with concentrations of 20 mg/mL and 4 mg respectively. /mL. Take 0.1g of embolization microspheres with the physiological saline removed and place it in a brown vial. According to the designed dosage, add 0.3mL and 3.0mL of the drug solution into the microspheres. Gently shake the vial to fully mix the microspheres and the drug. Start timing drug loading. Make 3 sets of samples in parallel for each sample. Extract the supernatant after loading for 5 minutes, 15 minutes, 30 minutes, and 1 hour. The remaining concentrations of the two drugs in the supernatant are measured by HPLC, and the drug loading efficiency and drug loading capacity of epirubicin and PD-1 are calculated. The results are as follows: As shown in Table 4.

Study on simulated drug release in vitro from drug-loaded microspheres

Example 9

Experiment on the external release of doxorubicin and bevacizumab from drug-loaded microspheres: The drug-loaded microspheres obtained in Example 5 were tested in phosphate buffer saline (PBS, pH=7.4, 10mM) that simulated the physiological environment of the human body. Release, filter the supernatant of the drug-loaded microspheres, clean the surface with fresh phosphate buffer solution (PBS, pH 7.4, 10mM), weigh 0.2g and put it into 50mL of phosphate buffer solution (PBS, pH 7.4) , 10mM) in a sealed glass tube and placed in a 37°C incubator for release. Take out 4mL of release medium at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and then add the same volume of Fresh medium. The taken-out solution was sequentially measured by HPLC for the concentration of doxorubicin and bevacizumab in the release solution, and the cumulative release rates of the two drugs were calculated. Three sets of experiments were conducted in parallel. The results are shown in Table 5 and Table 6 respectively.

Example 10

In vitro drug release experiment of doxorubicin and PD-1 from drug-loaded microspheres: The drug-loaded microspheres obtained in Example 6 were released in phosphate buffer saline (PBS, pH=7.4, 10mM) that simulated the human physiological environment. , filter the supernatant from the drug-loaded microspheres, clean the surface with fresh phosphate buffer solution (PBS, pH 7.4, 10mM), weigh 0.2g and put it into 50mL of phosphate buffer solution (PBS, pH 7.4, 10mM). 10mM) in a sealed glass tube and placed in a 37°C incubator for release. Take out 4mL of release medium at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and then add the same volume of fresh medium. The taken-out solution was sequentially measured by HPLC for the concentration of doxorubicin and PD-1 in the release solution, and the cumulative release rates of the two drugs were calculated. Three sets of experiments were conducted in parallel. The results are shown in Tables 7 and 8 respectively.

Example 11

Experiment on the external release of epirubicin and bevacizumab from drug-loaded microspheres: The drug-loaded microspheres obtained in Example 7 were in phosphate buffer solution (PBS, pH=7.4, 10mM) that simulated the physiological environment of the human body. Release, filter the supernatant of the drug-loaded microspheres, clean the surface with fresh phosphate buffer solution (PBS, pH 7.4, 10mM), weigh 0.2g and put it into 50 mL of phosphate buffer solution (PBS, pH 7.4, 10mM). 7.4, 10mM) in a sealed glass tube and placed in a 37°C incubator for release. Take out 4mL of release medium at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and then add the same volume of fresh medium. The taken-out solution was sequentially measured by HPLC for the concentration of epirubicin and bevacizumab in the release solution, and the cumulative release rates of the two drugs were calculated. Three sets of experiments were conducted in parallel. The results are shown in Table 9 and Table 10 respectively. .

Example 12

In vitro drug release experiment of epirubicin and PD-1 from drug-loaded microspheres: The drug-loaded microspheres obtained in Example 7 were tested in phosphate buffer solution (PBS, pH=7.4, 10mM) that simulated the human physiological environment. Release, filter the supernatant of the drug-loaded microspheres, clean the surface with fresh phosphate buffer solution (PBS, pH 7.4, 10mM), weigh 0.2g and put it into 50mL of phosphate buffer solution (PBS, pH 7.4) , 10mM) in a sealed glass tube and placed in a 37°C incubator for release. Take out 4mL of release medium at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and then add the same volume of Fresh medium. The taken-out solution was sequentially measured by HPLC for the concentration of epirubicin and PD-1 in the release solution, and the cumulative release rates of the two drugs were calculated. Three sets of experiments were conducted in parallel. The results are shown in Table 11 and Table 12 respectively.

As shown in the table below, drug loading efficiency is abbreviated as DLE, drug loading capacity is abbreviated as DLC, and SD represents standard deviation.

Table 1 Drug loading efficiency and drug loading capacity of microspheres for doxorubicin and bevacizumab

Table 2 Drug loading efficiency and drug loading capacity of embolization microspheres for doxorubicin and PD-1

Table 3 Drug loading efficiency and drug loading capacity of embolization microspheres for epirubicin and bevacizumab

Table 4 Drug loading efficiency and drug loading capacity of embolization microspheres for epirubicin and PD-1

Table 5 Cumulative release rate of doxorubicin from drug-loaded microspheres

Table 6 Cumulative release rate of bevacizumab from drug-loaded microspheres

Table 7 Cumulative release rate of doxorubicin from drug-loaded microspheres

Table 8 Cumulative release rate of PD-1 from drug-loaded microspheres

Table 9 Cumulative release rate of epirubicin from drug-loaded microspheres

Table 10 Cumulative release rate of bevacizumab from drug-loaded microspheres

Table 11 Cumulative release rate of epirubicin from drug-loaded microspheres

Table 12 Cumulative release rate of PD-1 from drug-loaded microspheres

Table 13 Cumulative release rate of drug-loaded microspheres when PD-1 is loaded alone

Table 14 Cumulative release rate of bevacizumab when drug-loaded microspheres are encapsulated alone

Claims

A kind of drug-loaded microsphere. The drug-loaded microsphere includes polyhydroxy compounds, alkyl acetal derivatives, and alkyl sulfonic acid derivatives. It is characterized in that the drug-loaded microsphere jointly contains polyhydroxy compounds through electrostatic attraction. Carrying macromolecule drugs and small molecule drugs, the drug-loaded microspheres are used in combination with transcatheter arterial chemoembolization.
The drug-loaded microsphere according to claim 1, wherein the alkyl acetal derivatives include acrylamide alkyl dialkoxy acetal, N-acrylamide dimethoxyethyl acetal. One or more aldehydes.
The drug-loaded microsphere according to claim 1, characterized in that the drug-loaded microsphere can simultaneously achieve the dual effects of physical embolization and chemotherapy.
The drug-loaded microsphere according to claim 1, characterized in that the macromolecule drug includes one or more of PD-1 and bevacizumab, and the small molecule drug includes doxorubicin, iridine One or more of Kang, epirubicin, and pirarubicin.
The drug-loaded microsphere according to claim 1, characterized in that, in the electrostatic attraction, the drug-loaded microsphere is negatively charged, and the macromolecule drug and the small molecule drug are positively charged.
A method for preparing the drug-loaded microspheres, which is characterized in that it includes the following steps:

(1) Preparation of functionalized macromolecular hydrogel: Heat and dissolve the polyhydroxy polymer in purified water. After cooling, add the alkyl acetal derivative, stir and dropwise add concentrated hydrochloric acid to react, Collect the crude product, wash and dry to obtain the desired functionalized macromolecular hydrogel;

(2) Preparing embolic microspheres: Dissolve the alkyl sulfonic acid derivatives and potassium persulfate in water, mix evenly, and then add the functionalized macromolecular hydrogel in step (1) to obtain a polymer Monomer solution; pass butyl acetate, cellulose acetate and nitrogen into the reaction vessel, add the polymer monomer solution and tetramethylethylenediamine to form an oil-water mixed reaction system, wash with an organic solvent after the reaction is completed, The embolization microspheres are obtained by drying;

(3) Joint encapsulation of macromolecular drugs and small molecule drugs: Dissolve the macromolecular drugs and the small molecule drugs in the purified water to obtain a drug mixed solution, and add the embolization microspheres to make The embolization microspheres are soaked in the drug mixture solution, and after the loading is completed, they are collected and dried to obtain the drug-loaded microspheres.
The method for preparing the drug-loaded microspheres according to claim 6, wherein the organic solvent includes butyl acetate, ethyl acetate, and acetone.
A method for preparing the drug-loaded microspheres according to claim 6, characterized in that the stirring operation adopts an axial flow stirring paddle, and the stirring speed is 400-650 rpm.
The method for preparing the drug-loaded microspheres according to claim 6, wherein the ratio of the functionalized macromolecular hydrogel to the alkyl sulfonic acid derivative is 1.00-0.12.
A method for preparing the drug-loaded microspheres according to claim 6, characterized in that when the polymer monomer solution is added, the temperature range of the reaction system is 40-60°C.