CN115282322A

CN115282322A - Embolism microsphere and preparation method and application thereof

Info

Publication number: CN115282322A
Application number: CN202210886534.3A
Authority: CN
Inventors: 马亚丹; 潘杰
Original assignee: Hangzhou Minshun Medical Technology Co ltd
Current assignee: Hangzhou Minshun Medical Technology Co ltd
Priority date: 2022-07-26
Filing date: 2022-07-26
Publication date: 2022-11-04

Abstract

The invention discloses an embolic microsphere, a preparation method and application thereof. The embolism microsphere has a core-shell double-layer structure, an outer shell matrix contains a biocompatible high polymer material, and an inner shell matrix contains a monomer cross-linked body.

Description

Embolism microsphere and preparation method and application thereof

Technical Field

The invention relates to the technical field of medical high polymer materials. More particularly relates to a double-layer structure embolism microsphere capable of carrying medicine, a preparation method and application thereof.

Background

Transcatheter Arterial Chemoembolization (TACE) is a method of slowly delivering embolization material to the focal site via artery or vein by using microcatheter system to occlude blood supply vessel and interrupt blood supply, so as to control hemorrhage, treat tumor and vascular lesion. In recent years, microspheres as embolization materials become a novel material with rapid development and wide application, on one hand, sustained release and controlled release of drugs loaded with tumor chemotherapeutics, anesthetics and the like are carried out, and on the other hand, the microspheres can be used as carriers of macromolecular drugs such as proteins, polypeptides, vaccines and the like, and more attention is paid. Therefore, the further development of the multifunctional microsphere material has important significance in the clinical application of interventional therapy.

Patents CN105193735A, CN103977458B belong to traditional microspheres, and comprise polyvinyl alcohol embolism microspheres, bletilla striata microspheres, polylactic acid microspheres, albumin microspheres, etc., the series of microspheres belong to single layer microspheres, and can load drugs into the interior and surface of the microspheres through the action mechanisms of electrostatic interaction, macroporous adsorption, swelling adsorption, etc., but the single layer microspheres have burst release phenomenon, so that the drug concentration of the drugs at the focus is locally too high, which causes the disadvantages of drug toxicity, etc. With the development of science and technology, the double-layer microsphere is used as a novel microsphere, is suitable for the requirements of a sustained-release and controlled-release drug delivery system of a drug, overcomes some defects of the traditional single-layer microsphere, and better meets the requirements of a target organ on the drug. Two main preparation methods of the double-layer microsphere are provided, (1) one method is that the emulsion polymerization method is used for preparing polymer seed emulsion, then mixed monomers, a cross-linking agent and the like are added for initiating reaction, and layer-by-layer self-assembly is carried out through polyelectrolyte to generate polymerization reaction so as to form a core-shell structure. The method introduces precursor and electrolyte to increase residue and greatly increase biological risk. (2) The other method adopts a double emulsion drying method, two polymer materials are respectively dissolved, the medicine is added into the two polymer materials, and phase separation is generated by physical methods such as mechanical stirring or micro-fluidic, so that one polymer material is uniformly coated on the other polymer material to form the double-layer microsphere. The process needs long-time stirring or heating and other processes, the operation process is complicated, the medicament needs to be pre-embedded, and uncertain factors such as medicament failure, unstable polymer material, more toxicological substances and the like caused by combination of medical instruments exist.

Therefore, there is an urgent need in the art to provide a novel embolic microsphere capable of overcoming the technical defects, loading various drugs and realizing controlled and sustained release, and a preparation method thereof.

Disclosure of Invention

The invention aims to provide an embolization microsphere with a double-layer structure.

In a first aspect of the present invention, a embolic microsphere is provided, having a core-shell bilayer structure, wherein an outer shell matrix comprises a biocompatible polymer material and an inner shell matrix comprises a monomer cross-linked body.

In another embodiment, the microspheres are 40 to 1000 μm in diameter.

In one embodiment of the invention, the embolic microspheres with target specifications of 40-100 μm, 100-300 μm, 300-500 μm, 500-700 μm and the like can be obtained by sieving.

In another embodiment, the microspheres have smooth surfaces and uniform particle sizes.

In another embodiment, the microspheres carry a drug without burst release.

In another embodiment, the compression deformation rate of the microspheres reaches more than 50%, and the microspheres can be quickly recovered to the original shape without any damage after decompression.

In another embodiment, the biocompatible polymeric material comprises chitosan, polyurethane, polyvinyl alcohol, polyethylene glycol, polylactic acid, or a mixture thereof; and/or the monomers include salicylic acid, cysteine, sodium acrylamidopropanesulfonate, and mercapto PEG acrylamide.

In a second aspect of the present invention, there is provided a method for preparing an embolization microsphere according to the invention, as described above, the method comprising the steps of:

(1) Mixing a biocompatible polymer material, a monomer and a cross-linking agent to form a homogeneous liquid;

(2) Mixing a surfactant and an oil-soluble solvent to form an oil phase solvent;

(3) Mixing the homogeneous phase liquid and the oil phase solvent to form microspheres; and

(4) Crosslinking of the microspheres results in the embolization microspheres of the invention as described above.

In another embodiment, the weight ratio of the biocompatible polymeric material, the monomer and the cross-linking agent is 1-20:50-250:0.2-4.

In another embodiment, the weight ratio of the surfactant to the oil-soluble solvent in the reaction system is from 0.1 to 10:50-500.

In another embodiment, the step (1) is dispersed with ultrasound for more than 30 minutes to form a homogeneous liquid.

In another embodiment, the process parameters for microsphere production, step (3), are such that the microspheres are formed under shear forces at a speed of 100 to 400 rpm.

In a third aspect of the invention there is provided the use of an embolization microsphere according to the invention as described above in the preparation of an interventional embolization material.

Therefore, the invention provides a novel embolism microsphere which can be loaded with various medicines and can be controlled and slowly released and a preparation method thereof.

Drawings

FIG. 1 is a schematic diagram of the bilayer structure of the embolic microsphere provided by the present invention.

FIG. 2 is a schematic diagram of the schematic structure of the embolization microsphere provided by the present invention.

FIG. 3 shows the compression set test results of embolizing microspheres provided by the invention.

FIG. 4 shows that the invention provides microspheres with a particle size specification of 100-300 μm.

Fig. 5 is a graph of the release of embolic microspheres loaded with drug provided by the present invention.

FIG. 6 shows the surface condition of the microspheres with non-bilayer structure provided in example 5.

Detailed Description

The inventor unexpectedly discovers a monomer balance swelling method in research, in the method, an outer shell matrix selects a hydrophilic high molecular material and has reaction sites, an inner shell matrix selects a hydrophilic monomer with a target site structure, because molecular chains between adjacent points of the outer shell matrix are longer and have quite flexibility, a small molecular monomer can be drilled into a macromolecular grid, once an initiator is added, the monomer starts to be crosslinked to form a chemical bond, the polymer grid is expanded and swelled, and the molecular weight and the crosslinking degree of the outer shell matrix reach a balanced state after the crosslinking is carried out to a certain degree, so that the embolism microsphere provided by the invention is obtained. On the basis of this, the present invention has been completed.

Specifically, the invention provides an embolic microsphere which has a double-layer structure of a high polymer material embedded monomer, contains a high polymer material with excellent biocompatibility as an outer shell matrix of the double-layer structure, and contains a specifically-identified monomer as an inner shell matrix. The particle size of the microsphere is 40-1000 μm, and the particle size range is controllable, such as but not limited to 40-100 μm, 100-300 μm, 300-500 μm, 500-700 μm, 700-1000 μm and the like. The microsphere has smooth surface and excellent elastic property, and can not be broken after being compressed and deformed by 50 percent.

The polymer material with excellent biocompatibility contained in the shell matrix can be selected from hydrophilic polymer materials such as chitosan, polyurethane, polyvinyl alcohol, polyethylene glycol, polylactic acid and the like.

The monomer contained in the inner shell matrix is a hydrophilic monomer with a targeted site structure, can be specifically adsorbed with a medicament, is selected from groups with charges such as sulfydryl, amino, sulfonate and the like, and is preferably selected from specific monomers such as salicylic acid, cysteine, acrylamide propyl sulfonate, sulfydryl PEG acrylamide and the like.

The shell matrix is formed through weak acting forces such as hydrogen bonds among macromolecules, van der Waals force and the like; the inner shell matrix is cross-linked polymerized by chemical covalent bonds.

The connection part of the outer shell and the inner shell matrix is assembled by mutually penetrating the macromolecular long chain and the micromolecular monomer. See the schematic of fig. 2.

The preparation method of the embolism microsphere provided by the invention comprises the following steps:

firstly, mixing and dispersing a high polymer material, a monomer and a cross-linking agent to form a homogeneous liquid;

secondly, mixing the surfactant and the oil-soluble solvent to form an oil phase solvent;

thirdly, suspension polymerization is carried out on the homogeneous phase liquid and the oil phase solvent to form a microspherical object;

and fourthly, crosslinking the microspherical substance to obtain the embolism microsphere provided by the invention.

The order of the above-mentioned first step and second step may be interchanged or performed separately at the same time.

The weight ratio of the high molecular material, the monomer and the cross-linking agent used in the first step is 1-20:50-250:0.2 to 4; preferably 2 to 10:50-150:0.8-2.

If the proportion of the monomer exceeds the range, the prepared microspheres become hard, the compression set is unqualified, and the microspheres are more than 50 percent fragile. If the monomer ratio is below the range, the prepared microspheres become soft and sticky, and do not recover shape after compression.

The dispersion in the first step may be ultrasonic dispersion, and in one embodiment of the present invention, the ultrasonic dispersion is performed for 30 to 120 minutes.

In one embodiment of the present invention, in the first step, the polymer material, the monomer, and the crosslinking agent are mixed in a weight ratio of 1-20:50-250: feeding at a ratio of 0.2-4, stirring uniformly, and performing ultrasonic dispersion at 80Hz for more than 30 minutes, such as but not limited to 30-90 minutes, 60-120 minutes, etc., to form a homogeneous liquid.

In one embodiment of the present invention, the polymer material used in the first step is a biocompatible polymer material, which comprises chitosan, polyurethane, polyvinyl alcohol, polyethylene glycol, polylactic acid, or a mixture thereof; polyvinyl alcohol and polyethylene glycol are preferred.

In one embodiment of the present invention, the monomers used in the first step are hydrophilic monomers having a targeting site structure, including salicylic acid, cysteine, sodium acrylamidopropanesulfonate, and mercaptopeg acrylamide; sodium acrylamidopropanesulfonate and mercaptoPEG acrylamide are preferred.

In one embodiment of the present invention, the crosslinking agent used in the first step includes EDC/NHS, N-methylene bisacrylamide, ammonium persulfate/sodium bisulfite, ammonium sulfate/tetramethylethylenediamine, and the like.

The weight ratio of the surfactant to the oil-soluble solvent used in the second step is 0.1 to 10:50-500; preferably 1 to 5:50-200.

The surfactant can make the water phase microspheres in a round state, and the microspheres are not fused and agglomerated.

The second step may be carried out by mixing the surfactant and the oil-soluble solvent uniformly by methods conventional in the art, such as, but not limited to, stirring, shaking, sonication, and the like.

In one embodiment of the present invention, in the second step, the surfactant and the oil-soluble solvent are mixed in a ratio of 0.1 to 10: feeding materials in a proportion of 50-500, and uniformly stirring to obtain the oil phase solvent.

In one embodiment of the present invention, the surfactant used in the second step comprises tween-80, a surfactant for cellulose; cellulose acetate butyrate and tween 80 are preferred.

In one embodiment of the present invention, the oil-soluble solvent used in the second step includes liquid paraffin, vegetable oil, ethyl acetate, or a mixture thereof; preferably volatile ethyl acetate.

In one embodiment of the present invention, the third step is to slowly drop the homogeneous liquid into the oil phase solvent at a rotation speed of 100-400 rpm, and form microspheres under the action of a shearing force.

The rotating speed can influence the particle size distribution of the microspheres, the particle size of the microspheres depends on the shearing force of mechanical stirring, the larger the rotating speed is, the larger the shearing force is, the smaller the microspheres are, but due to the physical shearing action, the microspheres with various sizes from 40 to 1000 mu m can be generated under the same batch production condition, and the microspheres with the target particle size are obtained by screening through a screen. According to the particle size requirement, the proper rotating speed can be selected to obtain the proportion with the highest yield.

The fourth step may be carried out by any method conventional in the art, such as, but not limited to, UV light, heat, etc.

In an embodiment of the present invention, in the fourth step, after the microspheres are crosslinked, solid powdery microspheres are formed, and then the embolization microspheres provided by the present invention are obtained by post-treatment with an aqueous solution; the post-treatment may be conventional in the art, such as, but not limited to, drying, sieving, washing, sterilizing, and the like.

The preparation method provided by the invention can control the diameter of the obtained embolism microsphere, for example, the embolism microsphere with target diameter of 40-100 μm, 100-300 μm, 300-500 μm, 500-700 μm, 700-1000 μm and other specifications can be obtained, thereby fully meeting the clinical requirement.

In the process of synthesizing the microspheres, the particle sizes of the microspheres are distributed from 40 to 1000 μm, and are not in a single particle size distribution, and in order to obtain microspheres with particle sizes of 40 to 100 μm, 100 to 300 μm, 300 to 500 μm, 500 to 700 μm, 700 to 1000 μm and the like, the target microspheres can be screened by means of screening, for example, but not limited to, screening microspheres with different particle sizes by using screen meshes with different sizes. As shown in FIG. 4, the microspheres with the target particle size specification of 100-300 μm are screened out by a screen.

The embolism microsphere provided by the invention is composed of a specific monomer and an outer-layer high molecular material, wherein the monomer contains sulfydryl, amino, sulfonate and other charged groups, so that the specific adsorption on tumor and chemotherapeutic drugs is realized, and meanwhile, under the buffer condition of an outer-layer high molecular medium, on one hand, the biological safety of the apparatus is improved, and on the other hand, the slow release of the drugs is realized. The carried drugs include, but are not limited to, therapeutic drugs such as adriamycin, epirubicin, rapamycin, irinotecan, and the like.

The embolic microspheres loaded with drug do not exhibit burst release and can be released in a steady state, and in one embodiment of the invention, the in vitro drug release test shows an in vivo and in vitro release amount of about 5% in 1 hour and an in vitro release rate of about 35-45% in 6-72 hours.

The embolism microsphere provided by the invention can greatly improve the drug loading rate. At present, according to the clinical application of 25mg adriamycin/g microspheres, the drug loading rate of the bilayer structure microspheres provided by the invention is 45mg adriamycin/g microspheres, the drug loading rate can reach the clinical maximum demand, and the market demand can be fully met.

The embolism microsphere provided by the invention is not broken after being conveyed by a catheter, and meets the clinical requirements.

The embolism microsphere provided by the invention can also be used for high polymer material synthesis and implantation instruments.

As used herein, the "particle size" or "diameter" of the microspheres is used interchangeably and refers to the size of the microspheres, for example and without limitation, the diameter of the microspheres is measured using a microscope scale and the resulting value is referred to as the particle size.

Although numerical ranges and parameters setting forth the broad scope of the invention are approximate, the values set forth in the specific examples are presented as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the individual testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" indicates that the actual value falls within the acceptable standard error of the mean, as considered by those of skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values and percentages herein used (e.g. to describe amounts of material, length of time, temperature, operating conditions, quantitative ratios and the like) are to be understood as modified by the word "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, these numerical parameters are to be understood as meaning the number of significant digits and the number resulting from applying ordinary rounding techniques.

All features defined herein as numerical ranges or percentage ranges, such as values, amounts, levels and concentrations, are for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to cover and specifically disclose all possible subranges and individual numerical values (including integers and fractions) within the range.

Unless defined otherwise herein, the scientific and technical terms used herein have the same meaning as is commonly understood and used by one of ordinary skill in the art. Furthermore, as used herein, a singular noun covers a plural of that noun without conflicting context; the use of plural nouns also covers the singular form of such nouns.

To make the features and effects of the present invention comprehensible to those skilled in the art, general description and definitions are made below with reference to terms and expressions mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The theory or mechanism described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, i.e., the present disclosure may be practiced without limitation to any particular theory or mechanism.

The features mentioned above, or those mentioned in the embodiments, may be combined in any combination. All features disclosed in this specification may be combined in any combination, and all possible combinations are intended to be included within the scope of the specification as long as there is no conflict between such features and the combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.

The main advantages of the invention are:

1. the embolism microsphere provided by the invention has the advantages of controllable particle size, uniform dispersion, stable drug adsorption, proper rate release and the like.

2. The invention adopts a monomer equilibrium swelling method, polymer high molecular materials and monomers are interpenetrated, dispersed and swelled and then polymerized, and finally the one-step preparation of the microsphere with the double-layer structure is realized. Under the conditions of pH and ion buffer exchange of the high polymer material, stable adsorption and proper rate release of the medicine are realized, the clinical application point of the medicine-carrying microsphere is greatly improved, and the method has important significance for promoting the fields of high polymer material synthesis, implantation instruments, clinical application and the like.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight (g) of solute in 100ml of solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

Example 1

Synthesis of microspheres with bilayer structure

And (5) setting up devices such as a flask and a condenser pipe. Preparing an oil phase, weighing 800mL of liquid paraffin into a four-neck flask, starting stirring at a rotation speed of 200r/min, adding 5mL of Tween emulsifier, and uniformly stirring. Then 5g of chitosan, 80g of salicylic acid and 0.5g of crosslinking agent EDC/NHS are weighed in a beaker, stirred for 30min, and then subjected to ultrasonic treatment for 1h to be uniformly dispersed to form homogeneous liquid. And finally, dropping the water phase homogeneous liquid into an oil-soluble system in an injector mode, keeping the rotating speed at 200r/min, keeping the dropping time for 20min, starting to heat to 36 ℃, reacting for 24h, washing and screening to obtain microspheres with the particle size of 500-600 mu m, wherein the microspheres are round in appearance, good in dispersion phase and free of adhesion.

Example 2

Synthesis of microsphere with double-layer structure

And (4) setting up devices such as a flask, a condenser pipe and inert gas. Preparing an oil phase, weighing 1000mL of ethyl acetate into a four-neck flask, starting stirring at the rotating speed of 300r/min, adding 5mL of Tween emulsifier, and uniformly stirring. Then 10g of polyethylene glycol, 40g of sulfhydryl PEG acrylamide and 0.5g of ammonium persulfate/N, N-methylene bisacrylamide crosslinking agent are weighed in a beaker, stirred for 60min, and then subjected to ultrasonic treatment for 2h to be uniformly dispersed to form homogeneous liquid. And finally, dropping the water phase homogeneous liquid into an oil-soluble system in an injector mode, keeping the rotating speed at 300r/min, keeping the dropping time at 20min, starting to heat to 75 ℃, reacting for 6h, and mainly preparing and obtaining microspheres with the particle size of 100-300 mu m after washing and screening, wherein the microspheres are round in appearance, good in dispersion phase and free of adhesion.

Example 3

Synthesis of microsphere with double-layer structure

And setting up devices such as a flask, a condenser tube, a thermometer and the like. Preparing an oil phase, weighing 1000mL of ethyl acetate into a four-neck flask, starting stirring at a rotation speed of 400r/min, adding 5mL of a surfactant of cellulose acetate butyrate, and uniformly stirring. Then 10g of polyurethane, 25g of sodium acrylamidopropanesulfonate and 0.75g of a crosslinking agent of N, N-methylene-bisacrylamide are weighed in a beaker containing 50mL of water, stirred for 60min and subjected to ultrasonic treatment for 3h to be uniformly dispersed to form a homogeneous liquid. And finally, slowly dripping the water-phase homogeneous liquid into an oil-soluble system in a dripping mode, keeping the rotating speed at 300r/min, dripping for 20min, starting heating to 65 ℃, reacting for 4h, washing and screening to prepare the microspheres with the particle size of 100-300 mu m, round appearance, good dispersed phase and no adhesion.

Example 4

Compression set test

The mechanical properties of the microspheres of 100-300 μm obtained by screening in example 3 were tested using a texture analyzer system ta.xt.plus C.

And (3) testing conditions: setting a sensing force of 10g and a probe of 8mm, selecting a compression speed of 0.2mm/s, a compression deformation of 80%, a holding time of 10s and a return speed of 0.2mm/s.

The test results are shown in FIG. 3.

The result shows that the microspheres with 50% of compression set are not crushed, the mechanical curve is smooth, and the stage fluctuation does not occur, thereby proving the excellent compressibility of the microspheres.

Example 5

And setting up devices such as a flask, a condenser tube, a thermometer and the like. Preparing an oil phase, weighing 1000mL of ethyl acetate into a four-neck flask, starting stirring at a rotation speed of 400r/min, adding 5mL of a surfactant of cellulose acetate butyrate, and uniformly stirring. Then 10g of polyurethane, 25g of sodium acrylamidopropanesulfonate and 0.75g of a crosslinking agent of N, N-methylene-bisacrylamide are weighed in a beaker containing 50mL of water and stirred for 60min, and the homogeneous liquid is finished without adopting an ultrasonic mode. And finally, slowly dripping the water-phase homogeneous liquid into an oil-soluble system in a dripping mode, keeping the rotating speed at 300r/min, dripping for 20min, starting heating to 65 ℃, reacting for 4h, washing and screening to prepare microspheres with the particle size of 100-300 mu m, wherein the microspheres are round in appearance, but are not double-layer structure microspheres, and small particles can be seen on the surfaces of the microspheres, so that the microspheres are not smooth.

The result shows that the microspheres are prepared under the condition of no ultrasonic dispersion, and the prepared microspheres have non-double-layer structures, unsmooth surfaces and residual monomer blocky phenomena. See fig. 6.

Example 6

Drug loading Performance test

The 100-300 μm microspheres prepared in example 3 were tested for drug release rate, while commercially available polyvinylalcohol embolization microspheres (Callispheres, 100-300 μm) were purchased as a control.

1g of microspheres and 45mg of an adriamycin medicament are shaken up for adsorption, then, 100ml of PBS phosphate buffer solution with pH =7.4 is added into a conical flask to be used as a simulated in-vitro release, and the medicament concentration is respectively tested for 1h, 6h, 24h, 48h and 72h, and the test result is shown in figure 5.

The test result shows that the drug release ratio is 5% in 1h, the release rate is 10% in 6h, 17% in 24h, 26% in 48h and 36% in 72 h.

The data in figure 5 show that the competitive product microspheres have a rapid release phenomenon in 1h, reach a peak at 6h, are stable subsequently, and prove that the medicament release is rapid. In a 1h simulation system, the drug begins to be slowly released, the curve is relatively stable, the burst release phenomenon does not occur, the drug is released at a stable release rate within 6-72h along with the time, and the shell polymer material has good buffering capacity and the double-layer microsphere has stable drug slow control capacity.

The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.

Claims

1. The embolic microsphere is characterized by having a core-shell double-layer structure, wherein an outer shell matrix contains a biocompatible high polymer material, and an inner shell matrix contains a monomer cross-linked body.

2. The embolization microsphere of claim 1, wherein the microsphere is from 40 μ ι η to 1000 μ ι η in diameter.

3. The embolic microsphere of claim 1, wherein said microsphere has a smooth surface and a uniform particle size.

4. The embolic microsphere of claim 1, wherein the microsphere comprises no burst release of the drug.

5. The embolic microsphere of claim 1, wherein said microsphere has a compression set of greater than 50%, and after decompression, returns to its original shape quickly and without any breakage.

6. The embolic microsphere of any one of claims 1 to 5, wherein said biocompatible polymeric material comprises chitosan, polyurethane, polyvinyl alcohol, polyethylene glycol, polylactic acid, or a mixture thereof; and/or the monomers include salicylic acid, cysteine, sodium acrylamidopropanesulfonate, and mercapto PEG acrylamide.

7. A method for preparing an embolization microsphere according to any one of claims 1 to 6, wherein the method comprises the steps of:

(3) Mixing the homogeneous phase liquid and the oil phase solvent to form microspheres;

(4) Crosslinking the microspheres to obtain the embolization microspheres of any one of claims 1-6.

8. The method of claim 7, wherein the weight ratio of the biocompatible polymeric material, the monomer, and the cross-linking agent is 1-20:50-250:0.2-4.

9. The method of claim 7, wherein the step (1) comprises dispersing the mixture with ultrasound for 30 minutes or more to form a homogeneous liquid.

10. Use of an embolization microsphere according to any one of claims 1 to 6 in the preparation of an interventional embolization material.