Embolism microsphere and preparation method thereof

Abstract

The invention discloses embolism microspheres and a preparation method thereof.The preparation method comprises the following steps that a stirring assembly is adopted for stirring a mixed solution in a reaction container, the mixed solution comprises an oil-phase solution and a water-phase solution, in the stirring process, the water-phase solution is dispersed into liquid drops in the oil-phase solution and subjected to a cross-linking reaction, and the oil-phase solution and the water-phase solution are mixed; after the reaction is finished, filtering, washing and drying to obtain embolism microspheres; the volume ratio of the oil phase solution to the water phase solution in the mixed solution is (3-9): 1; in the stirring process, the rotating speed of the stirring assembly ranges from 200 r / min to 500 r / min, the stirring assembly comprises a fixing rod and a plurality of paddle units, each paddle unit comprises a partition plate and a plurality of paddles located below the partition plate, and the paddles in each paddle unit are evenly arranged in the circumferential direction of the fixing rod at intervals. A through hole penetrating through the thickness direction of each paddle is formed in one end, far away from the fixed rod, of each paddle. According to the preparation method of the embolism microspheres, the production efficiency can be improved while the particle size of the embolism microspheres can be accurately regulated and controlled.

Description

Technical Field

[0001] The invention belongs to the technical field of medical materials, and specifically relates to an embolic microsphere and a preparation method thereof. Background Art

[0002] The transcatheter arterial embolization (TACE) treatment method has the advantages of less trauma, faster efficacy, and fewer side effects. This method has played an increasingly important role in clinical cancer treatment, especially in the treatment of advanced liver cancer. Its treatment principle is that doctors, with the assistance of imaging equipment, inject embolic agents into the blood vessels of tumor lesions through microcatheters to block blood supply, thereby achieving the purpose of "starving" the tumor. The performance of embolic agents will greatly affect the effect of embolization surgery. The embolic agents currently used in clinical practice include iodized oil, gelatin sponges, embolic microspheres and other products. Compared with iodized oil and gelatin sponges, embolic microspheres have good spherical morphology, strong degeneration ability, and are not easy to block catheters, which can achieve the advantage of permanent embolism.

[0003] During TACE treatment, if the particle size of the embolic microspheres used is too large, the level of the embolized artery will be higher, which may cause embolism of non-tumor blood vessels and damage normal tissues. In addition, microspheres that are too large are difficult to effectively block the ends of the diseased blood vessels, and the embolism is not thorough enough and is prone to recurrence. In addition, if the particle size of the embolic microspheres is too small, it is possible to cause microsphere drift. The existing method for preparing embolic microspheres has a wide particle size distribution and poor uniformity, which affects the efficacy of TACE treatment. Summary of the invention

[0004] In view of this, in order to overcome the defects of the prior art, the object of the present invention is to provide a method for preparing embolic microspheres, which can accurately control the particle size of the embolic microspheres.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] A method for preparing embolic microspheres comprises the following steps:

[0007] A stirring component is used to stir the mixed solution in the reaction container, wherein the mixed solution includes an oil phase solution and an aqueous phase solution. During the stirring process, the aqueous phase solution is dispersed into droplets in the oil phase solution and undergoes a cross-linking reaction. After the reaction is completed, the embolic microspheres are obtained by filtering, washing and drying. The volume ratio of the oil phase solution to the aqueous phase solution in the mixed solution is 3 to 9:1.

[0008] During the stirring process, the rotation speed of the stirring component is 200-500r / min. The stirring component includes a fixed rod and a plurality of blade units evenly spaced along the length direction of the fixed rod. Each of the blade units includes a partition and a plurality of blades located below the partition. The plurality of blades in each of the blade units are evenly spaced around the circumference of the fixed rod, and a through hole is provided at the end of each blade away from the fixed rod, which runs through the thickness direction thereof.

[0009] The present invention uses a stirring component with multiple paddle units to stir the mixed solution, and controls the rotation speed of the stirring component and the volume ratio of the oil phase solution to the water phase solution in the mixed solution to achieve regulation of the particle size of the embolic microspheres, thereby improving the uniformity of the prepared embolic microspheres.

[0010] Specifically, one of the main factors affecting the particle size distribution of embolic microspheres is the rotation speed of the stirring component. The shear force generated during the stirring process can disperse the continuous aqueous phase into droplets, and this shear force is the torsional force and shear force that the mixed solution is subjected to during the stirring process, which is reflected in the flow of the mixed solution. The setting of the through hole at one end of the paddle away from the fixed rod can strengthen the shear effect during the stirring process, but at the same time, the opening of the through hole will also form turbulence. The radial pulsation generated by the turbulence will accelerate the radial momentum, heat and mass transfer, making the flow of the mixed solution complicated and irregular. Therefore, it is necessary to control this turbulence to ensure that the particle size distribution of the prepared embolic microspheres is uniform. Preferably, the paddle unit of the present invention is provided with two or three to ensure that the influence of turbulence is not too large while having strong shear force.

[0011] According to some preferred implementation aspects of the present invention, the plurality of paddle units are close to the bottom end of the fixed rod, and during the stirring process, the plurality of paddle units are all located below the liquid surface of the mixed solution.

[0012] According to some preferred implementation aspects of the present invention, the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 60% to 90% of the liquid surface height of the mixed solution. The placement height of the multiple blade units in the stirring assembly in the mixed solution in the reaction container will affect the entire reaction system. The mechanical stirring method is used to prepare the embolic microspheres in the present invention. When the multiple blade units are immersed below the liquid surface of the mixed solution and the height from the bottom end of the fixed rod to the center of the bottom surface of the inner wall of the reaction container is high, the force generated by the rotation of the stirring assembly cannot be transmitted to the bottom of the mixed solution in the first time, and the shear force in the transmission process is continuously consumed by the mixed solution, which is easy to form downward turbulence, so that the stability of the entire reaction system is destroyed. Therefore, when the stirring assembly is placed, it is ensured that the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 60% to 90% of the liquid surface height of the mixed solution to ensure the stability of the reaction system; and as the height from the bottom end of the fixed rod to the center of the bottom surface of the inner wall of the reaction container gradually decreases, the shear force brought by the stirring is also greater.

[0013] According to some preferred implementation aspects of the present invention, one end of each blade is fixedly connected to the outer wall of the fixing rod, and each blade is tilted. The purpose of tilting the blade is to reduce vertical impact and avoid the blade from breaking during the stirring process.

[0014] According to some preferred implementation aspects of the present invention, a plurality of through holes are provided at one end of each blade away from the fixed rod, and the number of through holes on each blade gradually decreases from the side of the blade away from the fixed rod to the other side. The purpose of such a setting is to effectively increase the velocity gradient of the fluid, so that the liquid ejected from the through hole has a higher flow rate than the liquid flowing on both sides of the blade, collides with the liquid on both sides of the blade, and generates more small vortices in the flow field, which can strengthen the shear force brought by the blade.

[0015] According to some preferred embodiments of the present invention, the partition is circular in shape, a through hole is provided in the middle of the partition in the thickness direction, a connecting rod is fixedly provided in the through hole, and the connecting rod is fixedly connected to the fixed rod. The purpose of setting the partition is to stratify the mixed solution to reduce the influence of unstable turbulence generated during stirring on the particle size of the embolic microspheres.

[0016] According to some preferred implementation aspects of the present invention, the center of the through opening coincides with the center of the circle of the partition, the connecting rod is arranged along the radial direction of the partition, and the fixing rod passes through the centers of multiple partitions.

[0017] According to some preferred implementation aspects of the present invention, one end of each blade in each blade unit away from the fixing rod together forms a virtual circle, and the outer diameter of the partition is greater than or equal to the diameter of the virtual circle.

[0018] According to some preferred implementation aspects of the present invention, the rotation speed of the stirring assembly is controlled to be 400-500 r / min, the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 85%-90% of the liquid surface height of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 8-9:1, so as to prepare embolic microspheres with a particle size of 100-300 μm. When the volume ratio of the oil phase solution to the water phase solution is relatively large, that is, when the volume ratio of the oil phase to the water phase is relatively large, it means that less water phase is added, and when the water phase is dispersed into small droplets by shear force, the space in the oil phase is relatively large, which can reduce the situation of droplet fusion and enlargement caused by collision with other droplets during the rotation of the embolic microsphere droplets when the mixed solution is stirred and emulsified, so that the water phase can form stable small droplets under the action of the shear force generated by stirring, and the uniformity of the particle size of the embolic microspheres is ensured. For embolic microspheres with smaller particle sizes, the height from the bottom end of the fixed rod in the stirring assembly to the center of the bottom surface of the inner wall of the reaction vessel needs to be set lower, and the volume ratio of the oil phase solution to the water phase solution needs to be increased to increase the shear force brought by stirring. At the same time, the space of the oil phase in the reaction system is increased to prepare embolic microspheres with smaller particle sizes (100-300 μm).

[0019] According to some preferred embodiments of the present invention, the rotation speed of the stirring assembly is controlled to be 250-350 r / min, the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 60%-70% of the liquid surface height of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 3-4:1, so as to prepare embolic microspheres with a particle size of 300-500 μm.

[0020] According to some preferred embodiments of the present invention, the rotation speed of the stirring assembly is controlled to be 200-250 r / min, the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 60%-70% of the liquid surface height of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 3-4:1, so as to prepare embolic microspheres with a particle size of 500-700 μm.

[0021] According to some preferred embodiments of the present invention, the shape of the reaction container is spherical or cylindrical. In some embodiments of the present invention, when it is necessary to prepare embolic microspheres with a particle size of 100 to 300 μm, the shape of the reaction container is spherical. This is because the spatial distribution in the spherical reaction container is universally symmetrical, and the shear force generated by stirring can be more efficiently dispersed in the reaction container, so that the force of the mixed solution in the reaction container is more uniform, thereby making the particle size of the embolic microspheres smaller. In some other embodiments of the present invention, when it is necessary to prepare embolic microspheres with a particle size of 300 to 500 μm or 500 to 700 μm, the shape of the reaction container is cylindrical. This is because the cylindrical reaction container can easily achieve good axial force and radial force on the mixed solution inside it, and compared with the spherical reaction container, it can make the particle size of the prepared embolic microspheres larger.

[0022] According to some preferred implementation aspects of the present invention, the following steps are also included:

[0023] The embolic microspheres are dissolved in a first reaction solvent, and a modifier and an inorganic alkali solution are added thereto. The mixture is stirred evenly and heated to 40-80° C., and then iodide is added after constant temperature reaction for 4-8 hours. The constant temperature reaction is continued at 40-80° C. for 4-8 hours, and finally filtered and washed to obtain developable embolic microspheres.

[0024] The present invention also provides an embolic microsphere prepared by the above-mentioned preparation method.

[0025] Specifically, a method for preparing developable embolic microspheres of the present invention comprises the following steps:

[0026] A stirring component is used to stir the mixed solution in the reaction container at a speed of 200 to 500 r / min. The mixed solution includes an oil phase solution and an aqueous phase solution. During the stirring process, the aqueous phase solution is dispersed into droplets in the oil phase solution and undergoes a cross-linking reaction. After the reaction is completed, the embolic microspheres are obtained after filtering, washing and drying. The volume ratio of the oil phase solution to the aqueous phase solution in the mixed solution is 3 to 9:1.

[0027] The embolic microspheres are dissolved in the first reaction solvent, and a modifier and an inorganic alkali solution are added thereto, stirred evenly and heated to 40-80°C, and then iodide is added after isothermal reaction for 4-8 hours, and the isothermal reaction is continued at 40-80°C for 4-8 hours, and finally filtered and washed to obtain developable embolic microspheres. An epoxidation reaction can occur between the embolic microspheres and the modifier to form epoxy groups by grafting the hydroxyl groups on the embolic microspheres. The modified embolic microspheres can undergo an acetal reaction with the iodide to graft the acetal bond onto the modified embolic microspheres, so that the embolic microspheres can be developed. The addition of the inorganic alkali solution is to adjust the reaction environment to neutralize the acid generated during the reaction and ensure that the reaction environment is an alkaline environment. In addition, the iodine content of the developable embolic microspheres can be adjusted by changing the amount of iodide used.

[0028] According to some preferred embodiments of the present invention, the first reaction solvent is a combination of one or more of dimethyl sulfoxide, N-methylpyrrolidone, and tetrahydrofuran; the modifier is epichlorohydrin; the inorganic base is a combination of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate; the iodide contains a single or multiple hydroxyl groups, and the iodide is a combination of one or more of 2-iodobenzyl alcohol, 3-iodobenzyl alcohol, 4-iodobenzyl alcohol, 2,3,5-triiodobenzyl alcohol, or iohexol.

[0029] Traditional clinical use of embolic microspheres for treating tumors requires doctors to prepare contrast agents before surgery, and mix them evenly in a certain proportion before introducing them into the tumor blood vessels through a microcatheter. During the introduction process, relevant medical imaging equipment is needed to observe the position of the microspheres in the catheter to confirm that the microspheres have reached the target tumor blood vessels that need to be embolized, to prevent accidental embolism and serious adverse reactions. The entire surgical process requires a long preparation period, and doctors need to complete a lot of preliminary work, which brings a lot of trouble and risks to the treatment. After screening, the surface of the developable embolic microspheres is round and smooth, with good elasticity and flexibility; they are light yellow, do not require subsequent dyeing, and are visible under X-ray irradiation, which is convenient for doctors to operate during surgery and easier to grasp the degree of embolization, reducing the risk of adverse reactions.

[0030] The present invention also provides a developable embolic microsphere prepared by the preparation method as described above.

[0031] Due to the adoption of the above technical scheme, compared with the prior art, the benefits of the present invention are as follows: the preparation method of the embolic microspheres of the present invention, by using a stirring component with multiple blade units to stir the mixed solution, and controlling the rotation speed of the stirring component and the volume ratio of the oil phase solution to the water phase solution in the mixed solution, thereby achieving the regulation of the particle size of the embolic microspheres, which can not only improve the uniformity of the prepared embolic microspheres, but also improve the production efficiency and qualified rate of the embolic microspheres within the target particle size range, thereby effectively reducing the production cost of the enterprise. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0033] Figure 1 It is a schematic diagram of the three-dimensional structure of the stirring assembly in the preferred embodiment of the present invention;

[0034] Figure 2 This is a schematic diagram of the main structure of the stirring assembly in a preferred embodiment of the present invention;

[0035] Figure 3 It is a bottom view structural schematic diagram of the stirring assembly in the preferred embodiment of the present invention;

[0036] In the accompanying drawings, there are fixing rod-1, blade unit-2, partition-21, through-port-211, connecting rod-212, blade-22, and through-hole-221. DETAILED DESCRIPTION

[0037] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0038] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0039] The present invention provides a method for preparing embolic microspheres, comprising the following steps:

[0040] Dissolve the initiator and crosslinker in the modified water-soluble polymer intermediate solution, and stir at 25-30°C until the initiator and crosslinker are completely dissolved to obtain an aqueous phase solution. Add the second reaction solvent and surfactant into the reaction vessel, and introduce N 2 and stirring, so that the surfactant is dissolved in the second reaction solvent to obtain an oil phase solution, the oil phase solution is heated to 40-80°C and then kept at a constant temperature, then the aqueous phase solution and the organic base are added to the reaction container in sequence, and the volume ratio of the oil phase solution to the aqueous phase solution is controlled to be 3-9:1 to form an oil-water mixed solution, the height of the stirring component in the mixed solution in the reaction container is adjusted, the mixed solution is stirred at a temperature of 40-80°C using the stirring component, the speed of the stirring component is 200-500r / min, the aqueous phase solution is dispersed into multiple droplets in the oil phase solution under the stirring action of the stirring component and a cross-linking reaction occurs, the reaction time is 2-6h, after the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and after washing and vacuum drying, the embolic microspheres are obtained. Specifically, during the reaction, under the action of the cross-linking agent, the modified water-soluble polymer intermediates in the droplets produce chemical bonds with each other and are connected to each other, thereby cross-linking and polymerizing into embolic microspheres.

[0041] Among them, the initiator is a combination of one or more of potassium persulfate, ammonium persulfate or sodium persulfate; the cross-linking agent is a combination of one or more of 2-acrylamide-2-methylpropane sulfonic acid, sodium 2-acrylamide-2-methylpropane sulfonate, potassium 3-sulfopropyl acrylate or potassium 3-sulfopropyl methacrylate; the second reaction solvent is a combination of one or more of butyl acetate, ethyl acetate, liquid paraffin, soybean oil or cyclohexane; the surfactant is a combination of one or more of cellulose acetate butyrate, cellulose acetate, hydroxymethyl cellulose, Span 60, Span 80, Tween 60 or Tween 80; the organic base is tetramethylethylenediamine or tetraethylethylenediamine; the shape of the reaction container is spherical or cylindrical.

[0042] In addition, the modified water-soluble polymer intermediate is prepared by the following method:

[0043] Add a water-soluble polymer to a flask containing a specified amount of purified water, stir to disperse it evenly, heat to 50-100°C, dissolve the water-soluble polymer completely, and then cool to below 25°C, add a water-soluble molecule containing an aldehyde or acetal structure with an unsaturated bond, stir evenly, and then drop an inorganic acid into the solution. Continue stirring for more than 12 hours after the addition is completed; after the reaction is completed, use an alkaline solution to neutralize the pH of the reaction system to 6-10, and then concentrate to obtain a modified water-soluble polymer intermediate. Wherein, the water-soluble polymer is a combination of one or more of polyvinyl alcohol, polyethylene glycol and hydroxymethyl cellulose; the water-soluble molecule is a combination of one or more of N-(2,2-dimethoxyethyl)-2-acrylamide, 4-acrylamidobutyraldehyde dimethyl acetal or N-acrylamidoacetaldehyde; the inorganic acid is hydrochloric acid or sulfuric acid; the alkaline solution is sodium hydroxide; the molecular weight of the water-soluble polymer is 10,000-1,000,000, preferably 50,000-100,000.

[0044] Furthermore, if Figures 1 to 3 As shown, the stirring assembly in the present invention includes a fixed rod 1 and a plurality of blade units 2 evenly spaced along the length direction of the fixed rod 1, the plurality of blade units 2 are close to the bottom end of the fixed rod 1, and during the stirring process, the plurality of blade units 2 are all located below the liquid level of the mixed solution, and the distance from the bottom end of the fixed rod 1 to the liquid level of the mixed solution in the reaction container is set to account for 60% to 90% of the liquid level of the mixed solution. Preferably, the number of the blade units 2 is 2 or 3.

[0045] Each blade unit 2 includes a partition 21 and a plurality of blades 22 located below the partition 21, and each blade 22 is arranged at an angle; the plurality of blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1, and a plurality of through holes 221 are formed at one end of each blade 22 away from the fixed rod 1 and extending through the thickness thereof, and the other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0046] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 is enclosed together at one end away from the fixed rod 1 to form a virtual circle. The outer diameter of the partition 21 is greater than or equal to the diameter of the virtual circle. The partition 21 is arranged in this way to stratify the mixed solution to reduce the influence of the unstable turbulence generated during the stirring process on the particle size of the embolic microspheres. A through hole 211 is provided in the middle of the partition 21, which runs through the thickness direction thereof. A connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through hole 211; the center of the through hole 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the center of multiple partitions 21.

[0047] The present invention also provides embolic microspheres with a particle size of 100-300 μm, 300-500 μm and / or 500-700 μm prepared by the above preparation method, which can be used for TACE treatment.

[0048] The present invention also provides a method for preparing developable embolic microspheres, comprising the following steps:

[0049] Dissolve the initiator and crosslinker in the modified water-soluble polymer intermediate solution, and stir at 25-30°C until the initiator and crosslinker are completely dissolved to obtain an aqueous phase solution. Add the second reaction solvent and surfactant into the reaction vessel, and introduce N 2 and stirring to dissolve the surfactant in the second reaction solvent to obtain an oil phase solution, heating the oil phase solution to 40-80°C and maintaining a constant temperature, then sequentially adding an aqueous solution and an organic base to the reaction container, and controlling the volume ratio of the oil phase solution to the aqueous solution to be 3-9:1 to form an oil-water mixed solution, adjusting the height of the stirring component in the mixed solution in the reaction container, stirring the mixed solution at a temperature of 40-80°C using the stirring component, the rotation speed of the stirring component is 200-500r / min, the aqueous solution is dispersed into multiple droplets in the oil phase solution under the stirring action of the stirring component and a cross-linking reaction occurs, the reaction time is 2-6h, after the reaction is completed, filtering, washing and vacuum drying the reaction mixture to obtain embolic microspheres.

[0050] The embolic microspheres are then dissolved in the first reaction solvent, and a modifier and an inorganic alkali solution are added thereto. The mixture is stirred evenly and heated to 40-80°C. After constant temperature reaction for 4-8 hours, iodide is added and the constant temperature reaction is continued at 40-80°C for 4-8 hours. Finally, the developable embolic microspheres are obtained by filtration and washing.

[0051] Among them, the first reaction solvent is a combination of one or more of dimethyl sulfoxide, N-methylpyrrolidone, and tetrahydrofuran; the modifier is epichlorohydrin; the inorganic base is a combination of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; the iodide contains a single or multiple hydroxyl groups, and the iodide is a combination of one or more of 2-iodobenzyl alcohol, 3-iodobenzyl alcohol, 4-iodobenzyl alcohol, 2,3,5-triiodobenzyl alcohol or iohexol.

[0052] The present invention also provides a developable embolic microsphere prepared by the above preparation method, which has a round and smooth surface, good elasticity and flexibility, is light yellow, does not require subsequent dyeing treatment, and is visible under X-ray irradiation.

[0053] Example 1 A method for preparing embolic microspheres

[0054] This embodiment provides a method for preparing embolic microspheres, comprising the following steps:

[0055] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0056] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 90% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 450r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0057] The volume ratio of the oil phase solution to the water phase solution in this embodiment is 8.4:1. The stirring assembly in this embodiment includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1. The three blade units 2 are close to the bottom end of the fixed rod 1. Each blade unit 2 includes a partition 21 and four blades 22 located below the partition 21. Each blade 22 is tilted. The four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1. Each blade 22 is away from the fixed rod 1. One end of the rod 1 is provided with six through holes 221 penetrating through the thickness direction thereof. The six through holes 221 on each blade 22 are arranged in three rows, wherein the first row is provided with three through holes 221, the second row is provided with two through holes 221, and the third row is provided with one through hole 221. The three through holes 221 in the first row are located on the side of the blade 22 away from the fixed rod 1, and the multiple through holes 221 in the first row and the second row are arranged at intervals along the width direction of the blade 22; the other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0058] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0059] In the present embodiment, the prepared embolic microspheres are evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the counted embolic microspheres is greater than 1000). The statistical results show that the embolic microspheres with a particle size less than 100 μm account for 2%, the embolic microspheres with a particle size of 100-150 μm account for 10%, the embolic microspheres with a particle size of 150-250 μm account for 70%, the embolic microspheres with a particle size of 250-300 μm account for 15%, and the embolic microspheres with a particle size greater than 300 μm account for 3%. It can be seen that the particle size of the embolic microspheres prepared in the present embodiment is mainly 100-300 μm, among which the embolic microspheres with a particle size of 150-250 μm account for the largest proportion.

[0060] Example 2 A method for preparing embolic microspheres

[0061] This embodiment provides a method for preparing embolic microspheres, comprising the following steps:

[0062] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0063] In a 10L columnar reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 250r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0064] The volume ratio of the oil phase solution to the aqueous phase solution in this embodiment is 3.4:1. The stirring assembly in this embodiment includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1. The three blade units 2 are close to the bottom end of the fixed rod 1. Each blade unit 2 includes a partition 21 and four blades 22 located below the partition 21. Each blade 22 is tilted. The four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1. Each blade 22 is provided with six through holes 221 extending through its thickness direction at one end away from the fixed rod 1. The arrangement of the through holes 221 is the same as that in Example 1. The other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0065] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0066] In the present embodiment, the prepared embolic microspheres are evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the counted embolic microspheres is greater than 1000). The statistical results show that the embolic microspheres with a particle size less than 300 μm account for 1%, the embolic microspheres with a particle size of 300-350 μm account for 12%, the embolic microspheres with a particle size of 350-450 μm account for 71%, the embolic microspheres with a particle size of 450-500 μm account for 13%, and the embolic microspheres with a particle size greater than 500 μm account for 3%. It can be seen that the particle size of the embolic microspheres prepared in the present embodiment is mainly 300-500 μm, among which the embolic microspheres with a particle size of 350-450 μm account for the largest proportion.

[0067] Example 3 A method for preparing embolic microspheres

[0068] This embodiment provides a method for preparing embolic microspheres, comprising the following steps:

[0069] Dissolve 24 g of potassium persulfate in 340 g of water, and dissolve 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate in 1000 g of the modified water-soluble polymer intermediate. Stir at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate are completely dissolved to obtain an aqueous phase solution.

[0070] In a 10L columnar reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 200r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0071] The volume ratio of the oil phase solution to the aqueous phase solution in this embodiment is 3.4:1. The stirring assembly in this embodiment includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1. The three blade units 2 are close to the bottom end of the fixed rod 1. Each blade unit 2 includes a partition 21 and four blades 22 located below the partition 21. Each blade 22 is tilted. The four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1. Each blade 22 is provided with six through holes 221 extending through its thickness direction at one end away from the fixed rod 1. The arrangement of the through holes 221 is the same as that in Example 1. The other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0072] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0073] In the present embodiment, the prepared embolic microspheres are evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the counted embolic microspheres is greater than 1000). The statistical results show that the embolic microspheres with a particle size less than 500 μm account for 2%, the embolic microspheres with a particle size of 500-550 μm account for 10%, the embolic microspheres with a particle size of 550-650 μm account for 72%, the embolic microspheres with a particle size of 650-700 μm account for 14%, and the embolic microspheres with a particle size greater than 700 μm account for 2%. It can be seen that the particle size of the embolic microspheres prepared in the present embodiment is mainly 500-700 μm, among which the embolic microspheres with a particle size of 550-650 μm account for the largest proportion.

[0074] Example 4: A method for preparing a developable embolic microsphere

[0075] This embodiment provides a method for preparing developable embolic microspheres, comprising the following steps:

[0076] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0077] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 90% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 450r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0078] 10 g of embolic microspheres and 300 mL of dimethyl sulfoxide were added to a 500 mL round-bottom flask, the embolic microspheres were dissolved in dimethyl sulfoxide, and then 10 mL of epichlorohydrin and 10 mL of 1 mol / L NaOH solution were added thereto, stirred evenly, heated to 50°C and reacted at 50°C for 6 hours to modify the embolic microspheres. After reacting for 6 hours, 2 g of iohexol was added, and the reaction was continued at 50°C for 4 hours. After the reaction was completed, the reaction mixture was filtered and washed with dimethyl sulfoxide and water in turn to obtain developable embolic microspheres.

[0079] The volume ratio of the oil phase solution to the water phase solution in this embodiment is 8.4:1. The stirring assembly in this embodiment includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1. The three blade units 2 are close to the bottom end of the fixed rod 1. Each blade unit 2 includes a partition 21 and four blades 22 located below the partition 21. Each blade 22 is tilted. The four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1. Each blade 22 is away from the fixed rod 1. One end of the rod 1 is provided with six through holes 221 penetrating through the thickness direction thereof. The six through holes 221 on each blade 22 are arranged in three rows, wherein the first row is provided with three through holes 221, the second row is provided with two through holes 221, and the third row is provided with one through hole 221. The three through holes 221 in the first row are located on the side of the blade 22 away from the fixed rod 1, and the multiple through holes 221 in the first row and the second row are arranged at intervals along the width direction of the blade 22; the other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0080] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0081] In this embodiment, the element analysis test was performed on the developed embolic microspheres. The test results showed that the iodine content of the developed embolic microspheres in this embodiment was 5.5%.

[0082] Comparative Example 1-1 A method for preparing embolic microspheres

[0083] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0084] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0085] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 90% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 450r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0086] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 8.4:1, wherein the stirring assembly comprises a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 being close to the bottom end of the fixed rod 1, each paddle unit 2 comprising a partition 21 and four paddles 22 located below the partition 21, each paddle 22 being tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and no through hole 221 is provided at one end of each paddle 22 away from the fixed rod 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0087] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0088] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 100 μm accounted for 0, the embolic microspheres with a particle size of 100-150 μm accounted for 3%, the embolic microspheres with a particle size of 150-250 μm accounted for 50%, the embolic microspheres with a particle size of 250-300 μm accounted for 30%, and the embolic microspheres with a particle size greater than 300 μm accounted for 17%.

[0089] Comparative Example 1-2 A method for preparing embolic microspheres

[0090] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0091] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0092] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 90% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 450r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0093] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 8.4:1. The stirring assembly includes a fixed rod 1 and a paddle unit 2. The paddle unit 2 is close to the bottom end of the fixed rod 1. The paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21. Each paddle 22 is tilted. The four paddles 22 in the paddle unit 2 are evenly spaced around the circumference of the fixed rod 1. Six through holes 221 that penetrate the thickness direction of the paddle 22 are formed at one end away from the fixed rod 1. The setting of the through holes 221 on each paddle 22 is the same as that in Example 1. The other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0094] The partition 21 is circular in shape, and one end of each blade 22 in the blade unit 2 away from the fixed rod 1 together forms a virtual circle, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0095] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 100 μm accounted for 10%, the embolic microspheres with a particle size of 100-150 μm accounted for 10%, the embolic microspheres with a particle size of 150-250 μm accounted for 27%, the embolic microspheres with a particle size of 250-300 μm accounted for 27%, and the embolic microspheres with a particle size greater than 300 μm accounted for 26%.

[0096] Comparative Example 1-3 A method for preparing embolic microspheres

[0097] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0098] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0099] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 90% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 450r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0100] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 8.4:1. The stirring assembly includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1. The three blade units 2 are close to the bottom end of the fixed rod 1. Each blade unit 2 in this comparative example includes only four blades 22 without a partition 21, and each blade 22 is tilted. The four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1. Six through holes 221 are provided at one end of each blade 22 away from the fixed rod 1 and extend through the thickness direction thereof, and the other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0101] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 100 μm accounted for 0, the embolic microspheres with a particle size of 100-150 μm accounted for 0, the embolic microspheres with a particle size of 150-250 μm accounted for 0, the embolic microspheres with a particle size of 250-300 μm accounted for 14%, and the embolic microspheres with a particle size greater than 300 μm accounted for 86%.

[0102] Comparative Example 1-4 A method for preparing embolic microspheres

[0103] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0104] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0105] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 450r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0106] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 8.4:1, and the stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 are close to the bottom end of the fixed rod 1, each paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0107] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0108] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 100 μm accounted for 0, the embolic microspheres with a particle size of 100-150 μm accounted for 4%, the embolic microspheres with a particle size of 150-250 μm accounted for 16%, the embolic microspheres with a particle size of 250-300 μm accounted for 28%, and the embolic microspheres with a particle size greater than 300 μm accounted for 52%.

[0109] Comparative Example 1-5 A method for preparing embolic microspheres

[0110] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0111] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0112] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 90% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 250r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0113] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 8.4:1, and the stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 are close to the bottom end of the fixed rod 1, each paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0114] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0115] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 100 μm accounted for 0, the embolic microspheres with a particle size of 100-150 μm accounted for 0, the embolic microspheres with a particle size of 150-250 μm accounted for 0, the embolic microspheres with a particle size of 250-300 μm accounted for 33%, and the embolic microspheres with a particle size greater than 300 μm accounted for 67%.

[0116] Comparative Example 1-6 A method for preparing embolic microspheres

[0117] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0118] 10 g of potassium persulfate was dissolved in 140 g of water, 34 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 400 g of the modified water-soluble polymer intermediate, and the mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0119] In a 10L spherical reactor, 2400mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 571.4mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 90% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 450r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0120] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 4.2:1, and the stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 are close to the bottom end of the fixed rod 1, each paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0121] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0122] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 100 μm accounted for 0, the embolic microspheres with a particle size of 100-150 μm accounted for 4%, the embolic microspheres with a particle size of 150-250 μm accounted for 16%, the embolic microspheres with a particle size of 250-300 μm accounted for 47%, and the embolic microspheres with a particle size greater than 300 μm accounted for 33%.

[0123] Comparative Example 2-1 A method for preparing embolic microspheres

[0124] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0125] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0126] In a 10L columnar reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 250r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0127] The volume ratio of the oil phase solution to the water phase solution in this embodiment is 3.4:1. The stirring assembly in this embodiment includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1. The three blade units 2 are close to the bottom end of the fixed rod 1. Each blade unit 2 includes a partition 21 and four blades 22 located below the partition 21. Each blade 22 is tilted. The four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1. The end of each blade 22 away from the fixed rod 1 does not have a through hole 221, and the other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0128] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0129] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 300 μm accounted for 0, the embolic microspheres with a particle size of 300-350 μm accounted for 9%, the embolic microspheres with a particle size of 350-450 μm accounted for 43%, the embolic microspheres with a particle size of 450-500 μm accounted for 41%, and the embolic microspheres with a particle size greater than 500 μm accounted for 7%.

[0130] Comparative Example 2-2 A method for preparing embolic microspheres

[0131] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0132] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0133] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 250r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0134] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 3.4:1, and the stirring assembly includes a fixed rod 1 and a paddle unit 2, the paddle unit 2 is close to the bottom end of the fixed rod 1, the paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is arranged at an angle; the four paddles 22 in the paddle unit 2 are arranged evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 that penetrate the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0135] The partition 21 is circular in shape, and one end of each blade 22 in the blade unit 2 away from the fixed rod 1 together forms a virtual circle, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0136] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 300 μm accounted for 15%, the embolic microspheres with a particle size of 300-350 μm accounted for 23%, the embolic microspheres with a particle size of 350-450 μm accounted for 36%, the embolic microspheres with a particle size of 450-500 μm accounted for 12%, and the embolic microspheres with a particle size greater than 500 μm accounted for 14%.

[0137] Comparative Example 2-3 A method for preparing embolic microspheres

[0138] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0139] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0140] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 250r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0141] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 3.4:1, and the stirring assembly therein includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1, the three blade units 2 are close to the bottom end of the fixed rod 1, and each blade unit 2 in this comparative example includes only four blades 22 without a partition 21, and each blade 22 is tilted; the four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1; each blade 22 is provided with six through holes 221 running through its thickness direction at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0142] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 300 μm accounted for 3%, the embolic microspheres with a particle size of 300-350 μm accounted for 16%, the embolic microspheres with a particle size of 350-450 μm accounted for 31%, the embolic microspheres with a particle size of 450-500 μm accounted for 27%, and the embolic microspheres with a particle size greater than 500 μm accounted for 23%.

[0143] Comparative Example 2-4: A method for preparing embolic microspheres

[0144] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0145] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0146] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 50% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 250r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0147] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 3.4:1, and the stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 are close to the bottom end of the fixed rod 1, each paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0148] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0149] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 300 μm accounted for 0, the embolic microspheres with a particle size of 300-350 μm accounted for 3%, the embolic microspheres with a particle size of 350-450 μm accounted for 29%, the embolic microspheres with a particle size of 450-500 μm accounted for 37%, and the embolic microspheres with a particle size greater than 500 μm accounted for 31%.

[0150] Comparative Example 2-5: A method for preparing embolic microspheres

[0151] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0152] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0153] In a 10L spherical reactor, 2823.6mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 5.5mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 250r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0154] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 2:1, and the stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 are close to the bottom end of the fixed rod 1, each paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0155] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0156] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 300 μm accounted for 0, the embolic microspheres with a particle size of 300-350 μm accounted for 9%, the embolic microspheres with a particle size of 350-450 μm accounted for 19%, the embolic microspheres with a particle size of 450-500 μm accounted for 49%, and the embolic microspheres with a particle size greater than 500 μm accounted for 23%.

[0157] Comparative Example 3-1 A method for preparing embolic microspheres

[0158] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0159] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0160] In a 10L columnar reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 200r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0161] The volume ratio of the oil phase solution to the water phase solution in this embodiment is 3.4:1. The stirring assembly in this embodiment includes a fixed rod 1 and three blade units 2 evenly spaced along the length direction of the fixed rod 1. The three blade units 2 are close to the bottom end of the fixed rod 1. Each blade unit 2 includes a partition 21 and four blades 22 located below the partition 21. Each blade 22 is tilted. The four blades 22 in each blade unit 2 are evenly spaced around the circumference of the fixed rod 1. The end of each blade 22 away from the fixed rod 1 does not have a through hole 221, and the other end of each blade 22 is fixedly connected to the outer wall of the fixed rod 1.

[0162] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0163] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 500 μm accounted for 0, the embolic microspheres with a particle size of 500-550 μm accounted for 1%, the embolic microspheres with a particle size of 550-650 μm accounted for 42%, the embolic microspheres with a particle size of 650-700 μm accounted for 34%, and the embolic microspheres with a particle size greater than 700 μm accounted for 23%.

[0164] Comparative Example 3-2 A method for preparing embolic microspheres

[0165] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0166] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0167] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 200r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0168] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 3.4:1, and the stirring assembly includes a fixed rod 1 and a paddle unit 2, the paddle unit 2 is close to the bottom end of the fixed rod 1, the paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in the paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0169] The partition 21 is circular in shape, and one end of each blade 22 in the blade unit 2 away from the fixed rod 1 together forms a virtual circle, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0170] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 500 μm accounted for 0, the embolic microspheres with a particle size of 500-550 μm accounted for 0, the embolic microspheres with a particle size of 550-650 μm accounted for 29%, the embolic microspheres with a particle size of 650-700 μm accounted for 43%, and the embolic microspheres with a particle size greater than 700 μm accounted for 28%.

[0171] Comparative Example 3-3 A method for preparing embolic microspheres

[0172] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0173] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0174] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 200r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0175] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 3.4:1. The stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1. The three paddle units 2 are close to the bottom end of the fixed rod 1. Each paddle unit 2 in this comparative example includes only four paddles 22 without a partition 21, and each paddle 22 is tilted. The four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1. Six through holes 221 are provided at one end of each paddle 22 away from the fixed rod 1 and extend through the thickness direction thereof, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0176] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 500 μm accounted for 21%, the embolic microspheres with a particle size of 500-550 μm accounted for 30%, the embolic microspheres with a particle size of 550-650 μm accounted for 30%, the embolic microspheres with a particle size of 650-700 μm accounted for 19%, and the embolic microspheres with a particle size greater than 700 μm accounted for 0.

[0177] Comparative Example 3-4: A method for preparing embolic microspheres

[0178] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0179] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0180] In a 10L spherical reactor, 4800mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 50% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 200r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0181] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 3.4:1, and the stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 are close to the bottom end of the fixed rod 1, each paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0182] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0183] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 500 μm accounted for 0, the embolic microspheres with a particle size of 500-550 μm accounted for 3%, the embolic microspheres with a particle size of 550-650 μm accounted for 52%, the embolic microspheres with a particle size of 650-700 μm accounted for 27%, and the embolic microspheres with a particle size greater than 700 μm accounted for 18%.

[0184] Comparative Example 3-5: A method for preparing embolic microspheres

[0185] This comparative example provides a method for preparing embolic microspheres, comprising the following steps:

[0186] 24 g of potassium persulfate was dissolved in 340 g of water, and 82 g of a 50% aqueous solution of sodium 2-acrylamide-2-methylpropane sulfonate was dissolved in 1000 g of the modified water-soluble polymer intermediate. The mixture was stirred at 25° C. until the potassium persulfate and sodium 2-acrylamide-2-methylpropane sulfonate were completely dissolved to obtain an aqueous phase solution.

[0187] In a 10L spherical reactor, 2823.6mL of liquid paraffin and 80g of cellulose acetate butyrate were added, and N 2 Gas and stir to dissolve cellulose acetate butyrate in paraffin to obtain an oil phase solution, heat the oil phase solution to 60°C and keep constant temperature, then add 1411.8mL of aqueous phase solution to the reactor, stir for 5min, add 14mL of tetramethylethylenediamine to form an oil-water mixed solution, adjust the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction vessel to account for 70% of the liquid surface height of the mixed solution, and stir the mixed solution at a temperature of 60°C for 4h using the stirring assembly, and the speed of the stirring assembly is 200r / min. After the reaction is completed, the reaction mixture is filtered to collect the embolic microspheres, and washed with isopropanol and ethanol in turn and then vacuum dried to obtain the embolic microspheres.

[0188] The volume ratio of the oil phase solution to the aqueous phase solution in this comparative example is 2:1, and the stirring assembly includes a fixed rod 1 and three paddle units 2 evenly spaced along the length direction of the fixed rod 1, the three paddle units 2 are close to the bottom end of the fixed rod 1, each paddle unit 2 includes a partition 21 and four paddles 22 located below the partition 21, and each paddle 22 is tilted; the four paddles 22 in each paddle unit 2 are evenly spaced around the circumference of the fixed rod 1, and each paddle 22 is provided with six through holes 221 extending through the thickness direction thereof at one end away from the fixed rod 1, and the arrangement of the through holes 221 is the same as that in Example 1, and the other end of each paddle 22 is fixedly connected to the outer wall of the fixed rod 1.

[0189] The partition 21 is circular in shape, and each blade 22 in each blade unit 2 together forms a virtual circle at one end away from the fixed rod 1, and the outer diameter of the partition 21 is larger than the diameter of the virtual circle; a through opening 211 is opened in the middle of the partition 21 and runs through its thickness direction, and a connecting rod 212 fixedly connected to the fixed rod 1 is fixedly arranged in the through opening 211, and the center of the through opening 211 coincides with the center of the partition 21, and the connecting rod 212 is arranged along the radial direction of the partition 21, and the fixed rod 1 passes through the centers of multiple partitions 21.

[0190] In this comparative example, the prepared embolic microspheres were evenly dispersed in physiological saline to count the particle size distribution of the embolic microspheres (the count of the embolic microspheres was greater than 1000). The statistical results showed that the embolic microspheres with a particle size less than 500 μm accounted for 1%, the embolic microspheres with a particle size of 500-550 μm accounted for 3%, the embolic microspheres with a particle size of 550-650 μm accounted for 26%, the embolic microspheres with a particle size of 650-700 μm accounted for 41%, and the embolic microspheres with a particle size greater than 700 μm accounted for 29%.

[0191] Results and Discussion:

[0192] The following Table 1 is a summary table of the experimental conditions for preparing embolic microspheres in Examples 1 to 3 and Comparative Examples 1-1 to 1-6, Comparative Examples 2-1 to 2-5, and Comparative Examples 3-1 to 3-5; the following Table 2 is a statistical table of the particle size distribution of the embolic microspheres prepared in Example 1 and Comparative Examples 1-1 to 1-6; the following Table 3 is a statistical table of the particle size distribution of the embolic microspheres prepared in Example 2 and Comparative Examples 2-1 to 2-5; the following Table 4 is a statistical table of the particle size distribution of the embolic microspheres prepared in Example 3 and Comparative Examples 3-1 to 3-5.

[0193] Table 1 Summary of experimental conditions for preparing embolic microspheres

[0194]

[0195]

[0196] Table 2 Statistical table of particle size distribution of embolic microspheres in Example 1, Comparative Examples 1-1 to Comparative Examples 1-6

[0197]

[0198] It can be seen from Table 2 that: the embolic microspheres with a particle size in the range of 100 to 300 μm are defined as embolic microspheres with a qualified particle size, then the qualified rate of the embolic microspheres prepared in Example 1 is 95%, the qualified rate of the embolic microspheres prepared in Comparative Example 1-1 is 83%, the qualified rate of the embolic microspheres prepared in Comparative Example 1-2 is 64%, the qualified rate of the embolic microspheres prepared in Comparative Example 1-3 is 14%, the qualified rate of the embolic microspheres prepared in Comparative Example 1-4 is 48%, the qualified rate of the embolic microspheres prepared in Comparative Example 1-5 is 33%, and the qualified rate of the embolic microspheres prepared in Comparative Example 1-6 is 67%. The qualified rate of the embolic microspheres prepared in Example 1 is much higher than that of Comparative Examples 1-1 to Comparative Examples 1-6.

[0199] Table 3 Statistical table of particle size distribution of embolic microspheres in Example 2, Comparative Examples 2-1 to Comparative Examples 2-5

[0200]

[0201] It can be seen from Table 3 that the embolic microspheres with a particle size in the range of 300 to 500 μm are defined as embolic microspheres with a qualified particle size. The qualified rate of the embolic microspheres prepared in Example 2 is 94%, the qualified rate of the embolic microspheres prepared in Comparative Example 2-1 is 93%, the qualified rate of the embolic microspheres prepared in Comparative Example 2-2 is 71%, the qualified rate of the embolic microspheres prepared in Comparative Example 2-3 is 74%, the qualified rate of the embolic microspheres prepared in Comparative Example 2-4 is 69%, and the qualified rate of the embolic microspheres prepared in Comparative Example 2-5 is 77%. The qualified rate of the embolic microspheres prepared in Example 2 is much higher than that of Comparative Examples 2-1 to 2-5, and the qualified rate of Comparative Example 2-1 is 93%. The qualified rate of the prepared embolic microspheres is not much different from that of Example 2, but the pore sizes of the embolic microspheres prepared in Example 2 are mainly concentrated in the range of 350-450 μm, and the pore sizes of the embolic microspheres prepared in Comparative Example 2-1 are mainly concentrated in the range of 350-450 μm and 450-500 μm, and the distribution proportions of the embolic microspheres in the two ranges are relatively close. Compared with Example 2, the number of embolic microspheres with a particle size in the range of 450-500 μm in Comparative Example 2-1 is significantly increased. This is because the through hole 221 is not provided at one end of the paddle 22 in Comparative Example 2-1, which reduces the stirring shear force on the mixed solution and makes the particle size of the embolic microspheres larger.

[0202] Table 4 Statistical table of particle size distribution of embolic microspheres in Example 3, Comparative Examples 3-1 to Comparative Examples 3-5

[0203]

[0204]

[0205] It can be seen from Table 4 that: the embolic microspheres with a particle size in the range of 500 to 700 μm are defined as embolic microspheres with a qualified particle size, then the qualified rate of the embolic microspheres prepared in Example 3 is 96%, the qualified rate of the embolic microspheres prepared in Comparative Example 3-1 is 77%, the qualified rate of the embolic microspheres prepared in Comparative Example 3-2 is 72%, the qualified rate of the embolic microspheres prepared in Comparative Example 3-3 is 79%, the qualified rate of the embolic microspheres prepared in Comparative Example 3-4 is 82%, and the qualified rate of the embolic microspheres prepared in Comparative Example 3-5 is 70%. The qualified rate of the embolic microspheres prepared in Example 3 is much higher than that of Comparative Examples 3-1 to 3-5.

[0206] As can be seen from Tables 1 to 4 above, by using the stirring assembly of the present invention and controlling the rotation speed of the stirring assembly to 400 to 500 r / min, setting the distance from the bottom end of the fixed rod 1 to the liquid surface of the mixed solution in the reactor to account for 85% to 90% of the liquid surface height of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution to be 8 to 9:1, embolic microspheres with a particle size of mainly 100 to 300 μm can be prepared; controlling the rotation speed of the stirring assembly to 250 to 350 r / min, setting the distance from the bottom end of the fixed rod 1 to the liquid surface of the mixed solution in the reaction vessel to account for 85% to 90% of the liquid surface height of the mixed solution, and setting the volume ratio of the oil phase solution to the water phase solution in the mixed solution to be 8 to 9:1, embolic microspheres with a particle size of mainly 100 to 300 μm can be prepared. The distance accounts for 60% to 70% of the liquid level of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 3 to 4:1, and embolic microspheres with a particle size of mainly 300 to 500 μm can be prepared; the rotation speed of the stirring component is controlled to be 200 to 250 r / min, the distance from the bottom end of the fixed rod 1 to the liquid surface of the mixed solution in the reaction container accounts for 60% to 70% of the liquid level of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 3 to 4:1, and embolic microspheres with a particle size of mainly 500 to 700 μm can be prepared. It can be seen that in the present invention, through the structural design of the stirring component, combined with the control of the rotation speed of the stirring component during the stirring process, the control of the height from the bottom end of the fixed rod 1 of the stirring component to the liquid surface of the mixed solution, and the control of the volume ratio of the oil phase solution to the water phase solution in the reaction system, embolic microspheres with different target particle size ranges can be prepared respectively, which is conducive to improving the uniformity of the particle size distribution of the embolic microspheres.

[0207] It can be seen from Example 1 and Comparative Examples 1-1 to 1-4 and 1-6, from Example 2 and Comparative Examples 2-1 to 2-5, and from Example 3 and Comparative Examples 3-1 to 3-5 that, under the same other conditions, whether a through hole 221 is provided at the end of each paddle 22 away from the fixed rod 1, the number of paddle units 2, whether a partition 21 is provided in each paddle unit 2, the height from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution, and the volume ratio of the oil phase solution to the aqueous phase solution in the mixed solution will all affect the particle size of the prepared embolic microspheres. Specifically: (1) Stirring assembly structure: When the number of paddle units 2 in the stirring assembly decreases, the particle size distribution of the embolic microspheres becomes wider, and the number of embolic microspheres that are not within the target particle size range increases, resulting in a decrease in the yield of embolic microspheres of the target particle size; and when the through hole 221 is not provided at one end of the paddle 22, the stirring shear force on the mixed solution will be reduced, which will cause the particle size of the embolic microspheres to be larger; when there is no partition 21 in the paddle unit 2 of the stirring assembly, the disordered turbulence formed during stirring will affect the controllability of the particle size of the embolic microspheres. (2) Stirring assembly position: When the stirring assembly is set deeper in the mixed solution (i.e., the distance from the bottom end of the fixed rod 1 in the stirring assembly to the liquid surface of the mixed solution in the reaction container accounts for a greater percentage of the liquid surface height of the mixed solution), the particle size of the embolic microspheres will be smaller under the condition that other conditions remain unchanged. (3) Volume ratio of the oil phase solution to the aqueous phase solution in the mixed solution: When the volume ratio of the oil phase solution to the aqueous phase solution is too small, the probability of collision and re-fusion of the droplets formed after the aqueous phase solution is added to the oil phase solution increases, which makes the dispersion of the droplets worse, causing the embolic microspheres to stick together, thereby affecting the overall qualified rate of the microspheres.

[0208] It can be seen from Example 1 and Comparative Examples 1-5, and from Example 2 and Example 3 that, under the same other conditions, the rotation speed of the stirring assembly will also affect the particle size of the prepared embolic microspheres, and as the rotation speed gradually decreases, the particle size of the prepared embolic microspheres will gradually increase.

[0209] The present invention uses a stirring component with multiple paddle units 2 to stir the mixed solution, and controls the rotation speed of the stirring component, the volume ratio of the oil phase solution to the water phase solution in the mixed solution, and the position of the stirring component in the mixed solution to achieve regulation of the particle size of the embolic microspheres. This can not only improve the uniformity of the prepared embolic microspheres, but also improve the qualified rate of the embolic microspheres within the target particle size range.

[0210] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing embolic microspheres, characterized in that: The steps include: A stirring component is used to stir the mixed solution in the reaction container, wherein the mixed solution includes an oil phase solution and an aqueous phase solution. During the stirring process, the aqueous phase solution is dispersed into droplets in the oil phase solution and undergoes a cross-linking reaction. After the reaction is completed, the embolic microspheres are obtained by filtering, washing and drying. The volume ratio of the oil phase solution to the aqueous phase solution in the mixed solution is 3 to 9:

1. During the stirring process, the rotation speed of the stirring component is 200-500r / min. The stirring component includes a fixed rod and a plurality of blade units evenly spaced along the length direction of the fixed rod. Each of the blade units includes a partition and a plurality of blades located below the partition. The plurality of blades in each of the blade units are evenly spaced around the circumference of the fixed rod, and a through hole is provided at the end of each blade away from the fixed rod, which runs through the thickness direction thereof.

2. The preparation method according to claim 1, characterized in that: The plurality of paddle units are close to the bottom end of the fixed rod, and during the stirring process, the plurality of paddle units are all located below the liquid surface of the mixed solution.

3. The preparation method according to claim 2, characterized in that: The distance from the bottom end of the fixing rod to the liquid surface of the mixed solution in the reaction container accounts for 60% to 90% of the liquid surface height of the mixed solution.

4. The preparation method according to claim 1, characterized in that: One end of each of the blades is fixedly connected to the outer wall of the fixing rod, and each of the blades is arranged obliquely.

5. The preparation method according to claim 4, characterized in that: A plurality of through holes are formed at one end of each of the blades away from the fixing rod, and the number of the through holes on each of the blades gradually decreases from one side of the blade away from the fixing rod to the other side.

6. The preparation method according to claim 5, characterized in that: The partition is circular in shape, and a through opening penetrating through the partition in its thickness direction is opened in the middle of the partition. A connecting rod is fixedly arranged in the through opening, and the connecting rod is fixedly connected to the fixing rod.

7. The preparation method according to claim 6, characterized in that: The center of the through opening coincides with the center of the partition, the connecting rod is arranged along the radial direction of the partition, and the fixing rod passes through the centers of a plurality of the partitions.

8. The preparation method according to claim 7, characterized in that: One end of each blade in each blade unit away from the fixing rod together forms a virtual circle, and the outer diameter of the partition is greater than or equal to the diameter of the virtual circle.

9. The preparation method according to claim 8, characterized in that: The rotation speed of the stirring assembly is controlled to be 400-500 r / min, the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 85%-90% of the liquid surface height of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 8-9:1, so as to prepare embolic microspheres with a particle size of 100-300 μm.

10. The preparation method according to claim 8, characterized in that: The rotation speed of the stirring assembly is controlled to be 250-350 r / min, the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 60%-70% of the liquid surface height of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 3-4:1, so as to prepare embolic microspheres with a particle size of 300-500 μm.

11. The preparation method according to claim 8, characterized in that: The rotation speed of the stirring assembly is controlled to be 200-250 r / min, the distance from the bottom end of the fixed rod to the liquid surface of the mixed solution in the reaction container accounts for 60%-70% of the liquid surface height of the mixed solution, and the volume ratio of the oil phase solution to the water phase solution in the mixed solution is 3-4:1, so as to prepare embolic microspheres with a particle size of 500-700 μm.

12. The preparation method according to any one of claims 9 to 11, characterized in that: The reaction container is in a spherical or cylindrical shape.

13. The preparation method according to claim 1, characterized in that: The following steps are also included: The embolic microspheres are dissolved in a first reaction solvent, and a modifier and an inorganic alkali solution are added thereto. The mixture is stirred evenly and heated to 40-80° C., and then iodide is added after constant temperature reaction for 4-8 hours. The constant temperature reaction is continued at 40-80° C. for 4-8 hours, and finally filtered and washed to obtain developable embolic microspheres.

14. An embolic microsphere prepared by the preparation method according to any one of claims 1 to 13.

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