A system and method for preparing polyvinyl alcohol embolization microspheres with uniform particle size

Abstract

This invention discloses a system and method for preparing polyvinyl alcohol (PVA) embolization microspheres with uniform particle size, belonging to the field of embolization microsphere preparation technology. The microsphere preparation system comprises an in-situ dispersed phase mixing device, a dispersed phase fluid control device, and a microsphere generation and solidification device. The in-situ dispersed phase mixing device enables online real-time mixing of the PVA solution and catalyst, ensuring that the properties of the dispersed phase solution remain unchanged during large-scale microsphere preparation, thus guaranteeing the performance stability of the microsphere product. The dispersed phase fluid control device, by setting the dispersed phase flow rate and selecting feeding devices with different cross-sectional sizes, enables the dispersed phase to enter the continuous phase in the form of a stable liquid column, preparing PVA microspheres at a relatively low stirring speed. This invention significantly improves the particle size uniformity of PVA embolization microspheres and ensures the performance stability of the microsphere product, which is of great significance in the fields of biomedicine and medical devices.

Description

Technical Field

[0001] This invention belongs to the field of embolization microsphere preparation technology, specifically relating to a preparation system and method for polyvinyl alcohol embolization microspheres with uniform particle size. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] In recent years, polyvinyl alcohol (PVA) embolization microspheres have been increasingly widely used in interventional tumor therapy, and their properties and particle size are key factors affecting treatment efficacy. Stable, uniformly sized microspheres can embolize blood vessels of specific sizes, effectively avoiding incomplete embolization and misembolization, thus reducing complications. Currently, the main methods for preparing PVA embolization microspheres include emulsion crosslinking, spray drying, reverse suspension polymerization, and ion-induced polymerization. The resulting embolization microspheres are narrow or wide within a certain size range, such as the microsphere product DC... It is divided into several ranges, such as 100–300 μm, 300–500 μm, and 500–700 μm.

[0004] The emulsification crosslinking method involves adding a polyvinyl alcohol solution containing a catalyst as the dispersed phase to a continuous phase containing a surfactant under mechanical stirring, thereby obtaining embolic microspheres through emulsification crosslinking. This method is simple and easy to operate, but it has the following two main problems: (1) As the feeding time of the dispersed phase increases, the dispersed phase containing the catalyst will undergo a pre-crosslinking reaction, which will cause the viscosity of the dispersed phase to increase over time. This results in a large difference in the particle size and performance of the embolic microspheres at the beginning and end of the feeding process, increasing the uncertainty and instability of the microsphere product quality. (2) The dispersed phase is slowly added to the continuous phase by pouring. The microsphere formation process relies on the fluid shear force generated by mechanical stirring. The resulting microspheres have a wide particle size distribution, and the particle size is difficult to control. The repeatability between batches is poor, requiring manual screening. This results in low production efficiency and complex quality control.

[0005] The prior art CN 109988323A discloses "a method for rapid preparation of monodisperse polyvinyl alcohol microspheres at room temperature." This method uses a microchannel reactor, in which a mixed aqueous solution of polyvinyl alcohol, a crosslinking agent, and a catalyst, along with an oil phase, is pumped into the microchannel reactor to form water-in-oil droplets. A pre-crosslinking reaction takes place in the droplet pre-crosslinking curing zone, and deep crosslinking is performed in a collection bottle to obtain polyvinyl alcohol microspheres. However, the microchannel reactor is a microfluidic chip with a special channel structure. This method has a low dispersive phase feeding rate of 0.1-4 mL / h, resulting in low production efficiency and making it unsuitable for large-scale production of microspheres.

[0006] Furthermore, CN112569878B discloses "Equipment and Production Process for Preparing Polyvinyl Alcohol Embolizing Microspheres with Uniform Particle Size." This method involves adding a dispersed phase containing an aqueous initiator and a crosslinking agent, and a continuous phase containing an oil-phase initiator, to corresponding microreactors via a controller. Water-in-oil droplets are formed in the microreactors, and after solidification, polyvinyl alcohol embolizing microspheres are obtained. However, the microreactors consist of multiple microfluidic chips connected in parallel. This method is prone to microchannel blockage, affecting the stability of microsphere production. Moreover, no publicly disclosed commercially available production equipment exists.

[0007] Therefore, ensuring the stability of microsphere performance, controlling the particle size and particle size distribution of microspheres, and improving production efficiency are urgent problems to be solved in the current industrial preparation of polyvinyl alcohol embolization microspheres. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the purpose of this invention is to provide a polyvinyl alcohol embolization microsphere preparation system and preparation method with uniform particle size and stable performance.

[0009] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0010] In a first aspect, the present invention provides a system for preparing polyvinyl alcohol embolized microspheres, comprising: an in-situ mixing device for dispersed phase, a fluid control device for dispersed phase, and a device for generating and solidifying microspheres;

[0011] The dispersed phase in-situ mixing device consists of a first storage tank, a first pump, a second storage tank, a second pump, and a mixer. The first storage tank provides a storage space for a polyvinyl alcohol solution containing a crosslinking agent, and its outlet is connected to the inlet of the mixer via the first pump. The second storage tank provides a catalyst storage space, and its outlet is connected to the inlet of the mixer via the second pump. The mixer can be a static mixer or a dynamic mixer, preferably a static mixer.

[0012] The dispersed phase fluid control device includes a third pump, a flow meter, a pressure sensor, and a dispersed phase feeder connected in sequence;

[0013] The mixer outlet in the in-situ dispersed phase mixing device is connected to the inlet of the third pump in the dispersed phase fluid control device;

[0014] The outlet end of the dispersed phase feeder is a conical needle with a narrowed diameter structure along the fluid flow direction. The narrowed diameter ratio is 0.016-0.6, and the inner diameter of the small diameter end is 50-3000μm.

[0015] The outlet of the dispersed phase feeding device is located above or below the liquid level in the reactor of the microsphere generation and solidification device, preferably above the liquid level.

[0016] In some embodiments, viscosity ≤106 A polyvinyl alcohol solution with a viscosity >10 mPa·s was prepared using a static mixer. 6 A dynamic mixer was used to prepare a polyvinyl alcohol solution at mPa·s.

[0017] Preferably, the mixing element in the static mixer is a spiral element or an X-shaped element. The static mixer is an SK-type static mixer or an SV-type static mixer. The mixing element in the dynamic mixer is an actively rotating impeller, and it is a mixer with an external drive device.

[0018] In some embodiments, the first pump and the second pump are constant flow pumps, which are either injection pumps or peristaltic pumps.

[0019] Preferably, a peristaltic pump is used, with a flow rate range of 0.15 mL / min to 500 mL / min.

[0020] In some embodiments, the third pump is a constant flow pump, which is either an injection pump or a peristaltic pump.

[0021] Preferably, the peristaltic pump is a single-channel or multi-channel peristaltic pump, and the flow rate of the peristaltic pump is in the range of 0.15 mL / min to 500 mL / min.

[0022] In some embodiments, the flow meter is a differential pressure flow meter, an electromagnetic flow meter, or a mass flow meter. The flow meter has a range of 0.15 mL / min to 500 mL / min, and the pressure sensor is a liquid pressure sensor with a range of 0-50 N.

[0023] In some embodiments, the reactor is provided with a stirring paddle, which is an anchor-type, turbine-type, or propeller-type stirring paddle.

[0024] Preferably, the stirring paddle is a single-layer stirring paddle or a multi-layer stirring paddle.

[0025] The mechanical stirring speed is 50-500 rpm.

[0026] Secondly, the present invention provides a method for preparing embolic microspheres with uniform particle size, comprising the following steps:

[0027] Prepare a mixed solution of polyvinyl alcohol and crosslinking agent, and measure its viscosity;

[0028] When the viscosity of the mixed solution is ≤10 6 At a pressure of mPa·s, the mixed solution and the catalyst solution are mixed using a static mixer to obtain a dispersed phase;

[0029] When the viscosity of the mixed solution is >10 6 At a pressure of mPa·s, the mixed solution and the catalyst solution are mixed using a dynamic mixer to obtain a dispersed phase;

[0030] A third pump is used to inject the dispersed phase into the continuously stirred phase at low speed in the form of a liquid column jet, forming microdroplets;

[0031] Microdroplets are solidified, washed, dried, swollen, and sterilized to produce microspheres.

[0032] In some embodiments, the dispersed phase is polyvinyl alcohol, water, a crosslinking agent, and a catalyst; the continuous phase is a surfactant and an ester solvent.

[0033] In some embodiments, the mass fraction of polyvinyl alcohol in the dispersed phase is 1.0-30.0%, the mass fraction of the crosslinking agent in the dispersed phase is 0.1-10.0%, the mass fraction of the crosslinking agent in the polyvinyl alcohol is 0.5-20.0%, the volume fraction of the catalyst in the dispersed phase is 1.0-20.0%, and the volume fraction of the surfactant in the continuous phase is 1.0-20.0%.

[0034] In some embodiments, the crosslinking agent is a compound or polymer containing two or more acetal groups, wherein the acetal group has the structure -CO-NH-(CH2). m -CH-(OR1)2, where R1 is an aliphatic or aromatic group containing C1-C6, and m = 1-6. Specifically, including but not limited to N,N-di(methyl-(2,2-diethoxy)ethyl)dicarboxamide, N,N-di(2,2-diethoxyethyl)butadiamide, N,N-di(2,2-diethoxyethyl)pentadiamide, N,N-di(2,2-diethoxyethyl)butadiamide, maleic acid (N-methyl(2,2-diethoxy)ethyl)amide copolymer, etc.

[0035] In some embodiments, the catalyst is an acidic compound or polymer, including but not limited to sulfuric acid, hydrochloric acid, phosphoric acid, dichloroacetic acid, trifluoroacetic acid, benzenesulfonic acid, etc. The surfactant is an oil-soluble surfactant, including but not limited to sorbitol fatty acid esters, propylene glycol monolaurate, diethylene glycol fatty acid esters, cellulose acetate butyrate, etc.

[0036] In some embodiments, the dispersed phase flow rate ranges from 10 mL / min to 200 mL / min, and the liquid column pressure ranges from 1 to 20 N; the continuous phase stirring speed is 50 to 500 rpm; the microsphere crosslinking reaction temperature is 40 to 80 °C, and the curing time is 1 to 6 h.

[0037] In some embodiments, the size of polyvinyl alcohol microspheres prepared by feeding devices of different sizes can be controlled from 10 μm to 1200 μm, and the particle size uniformity is R. span <1.0(R span =(d 90 -d 10 ) / d 50 , where d90 ,d 10 ,d 50 The diameters, d, are the diameters of the microspheres when their volume occupies 90%, 10%, and 50% of the total volume, respectively. 50 That is, the volume average particle size.

[0038] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:

[0039] To address the problem that pre-crosslinking of the dispersed phase solution during the feeding process can easily lead to increased solution viscosity and affect the microsphere formation process and performance stability, this invention introduces an in-situ dispersed phase mixing device to achieve online real-time mixing of the polyvinyl alcohol solution and the catalyst. This ensures that the properties of the dispersed phase solution remain unchanged during the large-scale preparation of microspheres, thus guaranteeing the performance stability of the microsphere products.

[0040] To address the problems of uncontrollable microsphere formation and wide particle size distribution in existing mechanical stirring-based microsphere preparation methods, this invention introduces a dispersed phase fluid control device. This device enables quantitative feeding, controllable fluid state, adjustable fluid cross-sectional dimensions, and scalable fluid flux. Thus, by precisely adjusting the feeding rate of the dispersed phase, controlling the dispersed phase pressure and fluid state, and combining this with lower continuous phase shear force, controllable microsphere particle size is achieved, improving the uniformity of microsphere size.

[0041] This method requires no additional large equipment, is simple to operate, enables controllable preparation of microspheres at low stirring speeds, produces microspheres with narrow particle size distribution and good batch repeatability, and is suitable for the industrial preparation of embolization microspheres. Attached Figure Description

[0042] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0043] Figure 1 This is a schematic diagram of the embolization microsphere preparation system of the present invention;

[0044] Among them, 1-first storage tank; 2-first pump; 3-second pump; 4-second storage tank; 5-mixer; 6-in-situ mixing device for dispersed phase; 7-third pump; 8-flow meter; 9-pressure gauge; 10-three-way valve; 11-Luer connector; 12-dispersed phase feeding device; 13-dispersed phase fluid control device; 14-mechanical mixer; 15-stirring paddle; 16-reaction vessel; 17-continuous phase; 18-microsphere generation and solidification device.

[0045] Figure 2 This is a schematic diagram of the dispersed phase feeding device of the present invention;

[0046] Figure 3These are morphology and particle size distribution diagrams of the microspheres prepared in Example 5 and the comparative example of the present invention, wherein a is a morphology diagram of the microspheres prepared in the comparative example; b is a particle size distribution diagram of the microspheres prepared in the comparative example; c is a morphology diagram of the microspheres prepared in Example 5; and d is a particle size distribution diagram of the microspheres prepared in Example 5.

[0047] Figure 4 This is a diagram showing the morphology and particle size distribution of the microspheres prepared in Example 6 of this invention. Detailed Implementation

[0048] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0049] The present invention will be further described below with reference to the embodiments.

[0050] Example 1

[0051] This invention provides a system for preparing polyvinyl alcohol embolic microspheres with uniform particle size, such as... Figure 1 As shown, the system includes a dispersed phase in-situ mixing device 6, a dispersed phase fluid control device 13, and a microsphere generation and solidification device 18.

[0052] The in-situ dispersed phase mixing device 6 consists of a first storage tank 1, a first pump 2, a second storage tank 4, a second pump 3, and a mixer 5. The first storage tank 1 provides storage space for the polyvinyl alcohol solution, with a volume of 5L, and its outlet is connected to the inlet of the mixer 5 via the first pump 2. The second storage tank 4 provides storage space for the catalyst, with a volume of 2L, and its outlet is connected to the inlet of the mixer 5 via the second pump 3. The first pump 2 and the second pump 3 are peristaltic pumps with a flow rate range of 0.15mL / min-500mL / min. The mixer 5 is an SV-type static mixer with a hydraulic diameter of 5.0mm and a length of 1000mm.

[0053] The outlet of mixer 5 in dispersed phase mixing device 6 is connected to the inlet of third pump 7 in dispersed phase fluid control device 13.

[0054] The dispersed phase fluid control device 13 consists of a third pump 7, a flow meter 8, a pressure sensor 9, a three-way valve 10, a Luer connector 11, and a dispersed phase feeding device 12.

[0055] The third pump, 7, is a single-channel peristaltic pump with a flow rate range of 0.15 mL / min to 500 mL / min. The flow meter, 8, is a mass flow meter with a flow rate range of 0.15 mL / min to 500 mL / min. The pressure sensor is a liquid pressure sensor with a pressure range of 0-50 N. The outlet of the dispersed phase feed device 12 is a conical needle, such as... Figure 2 As shown, the structure has a narrowed diameter along the fluid flow direction, with a narrowing ratio of 0.032 and an inner diameter of 160 μm at the smaller diameter end. The outlet of the dispersed phase feeding device 12 is located above the liquid level inside the microsphere forming device.

[0056] The microsphere generation and solidification device 18 includes a mechanical stirring motor 14, a stirring paddle 15, a reaction vessel 16 containing a continuous phase, and a continuous phase 17. The mechanical stirring speed is 50 rpm, and the stirring paddle is an anchor-type multi-layer stirring paddle. The reaction vessel volume is 10 L.

[0057] Example 2

[0058] This invention provides a system for preparing polyvinyl alcohol embolized microspheres with uniform particle size, the structure of which is as described in Example 1, except that the mixer is a dynamic mixer with an actively rotating impeller.

[0059] Example 3

[0060] This invention provides a system for preparing polyvinyl alcohol embolization microspheres with uniform particle size, the structure of which is as described in Example 1, except that the diameter reduction ratio of the dispersed phase feeding device 12 is 0.16 and the inner diameter of the small diameter end is 800 μm.

[0061] Example 4

[0062] This invention provides a high-throughput, uniform-size polyvinyl alcohol embolization microsphere preparation system, with the structure as described in Example 1, except that the third pump 7 is a multi-channel peristaltic pump.

[0063] Example 5

[0064] This invention provides a method for preparing polyvinyl alcohol embolization microspheres using this microsphere preparation system.

[0065] Weigh 151.9 g of polyvinyl alcohol and 12.1 g of N,N'-bis(2,2-dimethoxyethyl)-1,4-butanediamide into a 1000 mL beaker to prepare a 10.7% polyvinyl alcohol aqueous solution. Dissolve the solution in a 95°C water bath. After cooling, measure the viscosity using a rheometer; the viscosity is 1327.08 ± 29.16 mPa·s. Add the solution to the first storage tank. Measure 216 mL of 1 mol / L hydrochloric acid and add it to the second storage tank.

[0066] A feeding device with a diameter of 400 μm was selected. After the microsphere preparation system was installed, the flow rates of the first and second pumps were set to 30 mL / min and 7.2 mL / min, respectively. The two phases were added to an SV-type static mixer with a hydraulic diameter of 5.0 mm and a length of 500 mm. The flow rate of the third pump was set to 40 mL / min. 5000 mL of butyl acetate and 125 mL of cellulose acetate solution as a stabilizer were added to a 10 L reactor to obtain a continuous phase. The temperature was set to 75 °C and the stirring speed was 100 rpm. The dispersed phase was introduced into the continuous phase in the form of a liquid column jet. Under the action of liquid column pressure and low fluid shear force, uniform microdroplets were formed. After reacting for 3 hours, the above mixed reaction system was naturally cooled, washed with ethyl acetate and ethanol, and vacuum dried to obtain embolized microspheres.

[0067] The dried microspheres were swollen, their morphology was observed, and the particle size and particle size distribution were statistically analyzed. The particle size distribution R was calculated. span The values ​​were used to obtain the morphology and particle size distribution of the microspheres, as shown below. Figure 3 As shown, c is a morphology diagram of the microspheres prepared in Example 5; d is a particle size distribution diagram of the microspheres prepared in Example 5.

[0068] Comparative Example

[0069] Similar to Example 5, the same dispersed and continuous phase formulations were used. The difference was that the dispersed phase solution was slowly poured into the continuous phase reactor using a pouring method. Under mechanical stirring, the dispersed phase was sheared into microdroplets. After reacting for 3 hours, the above mixed reaction system was naturally cooled, washed with ethyl acetate and ethanol, and vacuum dried to obtain embolic microspheres. The dried microspheres were swollen, their morphology was observed, and the particle size and particle size distribution were statistically analyzed. The particle size distribution R was calculated. span The values ​​were used to obtain the morphology and particle size distribution of the microspheres, as shown below. Figure 3 As shown, a is a morphology diagram of the microspheres prepared in the comparative example; b is a particle size distribution diagram of the microspheres prepared in the comparative example.

[0070] from Figure 3 As can be seen from the diagram, the polyvinyl alcohol microspheres prepared by the microsphere preparation system of this invention have a particle size of 375.25 ± 45.68 μm and a particle size distribution R0. span The particle size distribution was 0.29, with relatively uniform particle size distribution and no large microspheres were found. The polyvinyl alcohol microspheres prepared by the traditional mechanical stirring method had a particle size of 497.78±331.55 μm and a particle size distribution R. span The microspheres were 2.49 in size and unevenly distributed, with both larger and smaller microspheres present, with diameters of 1082.61 μm and 93.72 μm, respectively.

[0071] Example 6

[0072] This invention provides a method for preparing polyvinyl alcohol embolic microspheres using this microsphere preparation system. In this embodiment, the polyvinyl alcohol concentration is 6.9%, and the size of the dispersed phase feeding device is 1000 μm. The specific method is as follows:

[0073] Weigh 98.0 g of polyvinyl alcohol and 7.8 g of N,N'-bis(2,2-dimethoxyethyl)-1,4-butanediamide into a 1000 mL beaker to prepare a 6.9% polyvinyl alcohol aqueous solution. Dissolve the solution in a 95°C water bath. After cooling, measure the viscosity using a rheometer; the viscosity is 466.10 ± 17.15 mPa·s. Add the solution to the first storage tank. Measure 216 mL of 1 mol / L hydrochloric acid and add it to the second storage tank. A feeding device with a diameter of 1000 μm was selected. After the microsphere preparation system was installed, the flow rates of the first and second pumps were set to 30 mL / min and 7.2 mL / min, respectively. The two phases were added to an SV-type static mixer with a hydraulic diameter of 5.0 mm and a length of 500 mm. The flow rate of the third pump was set to 20 mL / min. 5000 mL of butyl acetate and 125 mL of cellulose acetate solution as a stabilizer were added to a 10 L reactor to obtain a continuous phase. The temperature was set to 65 °C and the stirring speed was 150 rpm. The dispersed phase was introduced into the continuous phase in the form of a liquid column jet. Under the action of liquid column pressure and low fluid shear force, uniform microdroplets were formed. After reacting for 3 hours, the above mixed reaction system was naturally cooled, washed with ethyl acetate and ethanol, and vacuum dried to obtain embolized microspheres.

[0074] The dried microspheres were swollen, their morphology was observed, and the particle size and particle size distribution were statistically analyzed. The particle size distribution R was calculated. span Value, result as Figure 4 As shown, the microspheres obtained had a particle size of 1159.45 ± 112.14 μm and a particle size distribution R0. span It is 0.23.

[0075] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A system for preparing polyvinyl alcohol embolic microspheres with uniform particle size, characterized in that, include: The dispersed phase in-situ mixing device, the dispersed phase fluid control device, and the microsphere generation and solidification device are provided. The outlet of the dispersed phase in-situ mixing device is connected to the inlet of the third pump in the dispersed phase fluid control device. The outlet of the dispersed phase fluid control device is located above the continuous phase liquid level in the microsphere generation and solidification device. The dispersed phase in-situ mixing device comprises a first storage tank, a first pump, a second storage tank, a second pump, and a mixer. The first storage tank provides storage space for a polyvinyl alcohol solution containing a crosslinking agent, and its outlet is connected to the inlet of the mixer through the first pump. The second storage tank provides storage space for a catalyst, and its outlet is connected to the inlet of the mixer through the second pump. The mixer is a liquid-liquid mixer, and the viscosity of the mixed solution of polyvinyl alcohol and crosslinking agent is ≤10. 6 At mPa·s, a static mixer is used; When viscosity > 10 6 At mPa·s, a dynamic mixer is used; The dispersed phase fluid control device includes a third pump, a flow meter, a pressure sensor, a three-way valve, a Luer connector, and a dispersed phase feeding device connected in sequence. The outlet end of the dispersed phase feeding device is a conical needle with a narrowed diameter structure along the fluid flow direction. The narrowed diameter ratio is 0.032-0.6, and the inner diameter of the small diameter end is 160-3000μm.

2. The microsphere preparation system according to claim 1, characterized in that, The first and second pumps are either syringe pumps or peristaltic pumps; The flow rate of the peristaltic pump ranges from 0.15 mL / min to 500 mL / min.

3. The microsphere preparation system according to claim 1, characterized in that, The static mixer is an SK type or SV type static mixer; The dynamic mixer is a dynamic mixer with an actively rotating impeller.

4. The microsphere preparation system according to claim 1, characterized in that, The third pump is either an injection pump or a peristaltic pump; The flow rate of the peristaltic pump ranges from 0.15 mL / min to 500 mL / min.

5. The microsphere preparation system according to claim 1, characterized in that, The flow meter is a differential pressure flow meter, an electromagnetic flow meter, or a mass flow meter, and the pressure sensor is a liquid pressure sensor.

6. The microsphere preparation system according to claim 1, characterized in that, The microsphere generation and solidification device is a reactor containing a stirring paddle and a circulating temperature control device, and the reactor is used to hold a continuous phase. The agitator is one of the following: anchor type, turbine type, or propeller type, and can be a single-layer or multi-layer agitator.

7. A method for preparing uniformly sized embolic microspheres using the microsphere preparation system according to any one of claims 1-6, characterized in that, Includes the following steps: Prepare a mixed solution of polyvinyl alcohol and crosslinking agent, and measure its viscosity; When the viscosity of the mixed solution is ≤10 6 At a pressure of mPa·s, the mixed solution and the catalyst solution are mixed using a static mixer to obtain a dispersed phase; When the viscosity of the mixed solution is >10 6 At a pressure of mPa·s, the mixed solution and the catalyst solution are mixed using a dynamic mixer to obtain a dispersed phase; A third pump is used to inject the dispersed phase into the continuously stirred phase at low speed in the form of a liquid column jet, forming microdroplets; Microdroplets are solidified, washed, dried, swollen, and sterilized to produce microspheres.

8. The method for preparing microspheres according to claim 7, characterized in that, The dispersed phase comprises polyvinyl alcohol, water, a crosslinking agent, and a catalyst; the continuous phase comprises a surfactant and an ester solvent; the mass fraction of polyvinyl alcohol in the dispersed phase is 1.0-30.0%, the mass fraction of the crosslinking agent in the dispersed phase is 0.1-10.0%, the mass fraction of the crosslinking agent in the polyvinyl alcohol is 0.5-20.0%, and the volume fraction of the catalyst in the dispersed phase is 1.0-20.0%; the volume fraction of the surfactant in the continuous phase is 1.0-20.0%.

9. The method for preparing microspheres according to claim 7, characterized in that, The crosslinking agent is a compound or polymer containing two or more acetal groups, wherein the acetal group has the structure -CO-NH-(CH2). m -CH-(OR1)2, where R1 is an aliphatic or aromatic group containing C1-C6, and m=1-6; The crosslinking agent includes N,N-di(methyl-(2,2-diethoxy)ethyl)dicarboxamide, N,N-di(2,2-diethoxyethyl)butadiamide, N,N-di(2,2-diethoxyethyl)pentadiamide, N,N-di(2,2-diethoxyethyl)butadiamide, or maleic acid (N-methyl(2,2-diethoxy)ethyl)amide copolymer.

10. The method for preparing microspheres according to claim 8, characterized in that, The catalyst is an acidic compound, including sulfuric acid, hydrochloric acid, phosphoric acid, dichloroacetic acid, trifluoroacetic acid, and benzenesulfonic acid; The surfactants mentioned are oil-soluble surfactants, including sorbitol fatty acid esters, propylene glycol monolaurate, diethylene glycol fatty acid esters, and cellulose acetate butyrate.

11. The method for preparing microspheres according to claim 7, characterized in that, The dispersed phase is jetted into the continuous phase in the form of a stable liquid column. The flow rate of the dispersed phase ranges from 10 mL / min to 200 mL / min, and the liquid column size is 160-3000 μm. The stirring speed of the continuous phase is 50-500 rpm. The crosslinking reaction temperature of the microspheres is 40-80℃, and the curing time is 1-6 h.

12. The method for preparing microspheres according to claim 7, characterized in that, The size of polyvinyl alcohol microspheres prepared by feeding devices of different sizes can be controlled from 10μm to 1200μm, and the particle size uniformity is high. span <1.0, R span =( d 90 - d 10 ) / d 50 , in, d 90 , d 10 , d 50 The figures represent the diameters when the microspheres occupy 90%, 10%, and 50% of the total volume, respectively.

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