Method and reaction device for preparing high-purity polyvinyl alcohol embolic microspheres with controllable particle size

Abstract

The present invention relates to the field of medical material technology, and in particular to a method and a reaction device for preparing high-purity polyvinyl alcohol embolic microspheres with controllable particle size. The advantages of using microwave technology to prepare polyvinyl alcohol embolic microspheres in the present application are: it is conducive to the preparation of a uniform suspension or emulsion, thereby effectively controlling the particle size and particle size distribution of the microspheres; while improving the efficiency of the cross-linking reaction; in addition, the phase stabilizer and other auxiliary agents used in the preparation process of the microspheres will be adsorbed in the pore size of the microspheres, and the adsorbed residues can be efficiently cleaned by microwave energy, thereby improving the purity of the product and ensuring its safety.

Description

Technical Field

[0001] The invention relates to the technical field of medical materials, and in particular to a method and a reaction device for preparing high-purity polyvinyl alcohol embolic microspheres with controllable particle size. Background Art

[0002] As the incidence of cancer continues to rise, the demand for various interventional oncology products and procedures has increased. According to GLOBOCAN2018, there were 609,596 new cases of liver cancer in Asia in 2018, and this number is expected to increase by 142,982 by 2025. Due to the advantages of minimally invasive surgery over traditional treatment procedures, such as fewer surgical complications, shorter hospital stays, less pain, smaller and more aesthetic incisions, lower risk of infection, and faster recovery, the demand for minimally invasive surgery in tumor treatment has increased significantly. Embolic agents have also developed rapidly, and various calibrated microspheres and biogels made of natural and synthetic polymers have been developed as flow-guided embolic agents. Currently available commercial embolic materials, including different polymer-based particles and hydrogels, are developed for intravascular embolization therapy. Embolic microspheres have been widely used as a new type of particle embolic agent. Existing microspheres can be divided into polyvinyl alcohol microspheres, starch microspheres, albumin microspheres, gelatin microspheres, polylactic acid microspheres, sodium alginate microspheres, chitosan microspheres, and ethyl fiber microspheres according to the materials used. Polyvinyl alcohol embolic microspheres occupy a major position in the embolic agent market due to their safety, uniform particle size, strong compressibility and non-degradability.

[0003] At present, polyvinyl alcohol embolic microspheres are generally prepared by reverse phase suspension polymerization process. The specific steps are: linear polyvinyl alcohol or functionalized polyvinyl alcohol is dissolved in water phase as the main chain molecule of the synthesis, dispersed in non-polar solvent as the oil phase to form a mixed suspension or emulsion, and then cross-linked and polymerized by a cross-linking agent to obtain polyvinyl alcohol hydrogel microspheres (the preparation chemical reaction formula is detailed in Figure 1 ). This method has the following disadvantages: (1) the preparation process of the suspension or emulsion is complicated and the process stability is poor; (2) the efficiency of cross-linking polymerization is low, which reduces the application efficiency of the polyvinyl alcohol microspheres; (3) phase stabilizers and other additives need to be added during the preparation process, which are not easy to be completely washed away and thus remain in the polyvinyl alcohol microspheres, resulting in reduced product purity and safety risks.

[0004] The heating principle of dielectric microwave heating is: when polar molecular dielectrics and non-polar molecular dielectrics are placed in a microwave electromagnetic field, dipoles will be formed in the dielectric material or the existing dipoles will be rearranged, and will swing at a speed of up to hundreds of millions of times per second with the high-frequency alternating electromagnetic field. In order for the molecules to rearrange with the direction of the constantly changing high-frequency electric field, they must overcome the interference and obstruction of the original thermal motion of the molecules and the interaction between the molecules, produce a friction-like effect, and achieve "stirring" at the molecular level, thereby generating a large amount of heat. It can be seen that conventional heating and microwave heating are two completely different heating methods; microwave heating is a "cold heat source". When it is generated and contacts an object, it is not a stream of hot air, but electromagnetic energy. It has a series of unique advantages that traditional heating does not have. Compared with the contact heating method, the three-dimensional heating method using microwaves can ensure the uniformity and stability of the two-phase system. At the same time, microwaves can accelerate the thermal motion of molecules, thereby improving the efficiency of olefin polymerization reactions. Patent CN100381363C discloses a method for preparing ferroferric oxide nanocrystals by using a microwave reactor in an alkaline solution and controlling the temperature and air pressure using ferric salt and ferrous salt as raw materials. Patent CN101337695B discloses a method for quickly preparing magnetic nanospheres in a non-aqueous solvent using a micro powder technology and using ferric salt as raw materials. The microspheres prepared by this method have uniform particle size distribution and controllable particle size.

[0005] Most hydrogel microspheres are prepared by cross-linking and curing into spheres through suspension polymerization. This solution is designed to solve the problem that the hydrogel microspheres contain a small amount of small molecule impurities that cannot form a three-dimensional cross-linked network structure due to insufficient cross-linking degree of the side chains; and the microsphere cleaning process generally uses purified water or sodium chloride solution to boil for more than 30 minutes, repeatedly, which is extremely cumbersome and the cleaning effect is not ideal, resulting in residual starting materials, which will cause the product purity to decrease. Summary of the invention

[0006] The purpose of the present invention is to provide a method and a reaction device for preparing high-purity polyvinyl alcohol embolic microspheres with controllable particle size, a target product with a three-dimensional cross-linked network structure of more macromolecules, and to use microwave technology to remove impurities wrapped in the hydrogel microspheres to obtain high-purity polymer hydrogel microspheres with a three-dimensional cross-linked network structure.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] The present invention provides a method and a reaction device for preparing high-purity polyvinyl alcohol embolic microspheres with controllable particle size, comprising the following steps:

[0009] S1: Dissolving polyvinyl alcohol: Add polyvinyl alcohol to the water phase kettle filled with purified water, turn on the stirring device of the water phase kettle, heat to 90-98°C, stir the solution to completely dissolve, and pass the circulating refrigerant into the kettle interlayer to cool the solution in the kettle to 20-30°C;

[0010] S2: Functionalization reaction: Add N-acrylamide acetaldehyde dimethyl acetal to the aqueous phase kettle containing the solution of step S1, then add hydrochloric acid to adjust the pH value to 1-2, and stir the reaction for 1-6 hours. Add sodium hydroxide solution to the reaction kettle to adjust the pH value of the solution to neutral;

[0011] S3: Preparation of aqueous solution: Sodium 2-acrylamide-2-methylpropanesulfonate and potassium persulfate are sequentially added to the aqueous phase kettle containing the solution of step S2, and stirred until completely dissolved;

[0012] S4: Preparation of oil phase solution: Add butyl acetate and cellulose acetate butyrate into the oil phase kettle, stir until cellulose acetate butyrate is completely dissolved in butyl acetate, and heat to 50-70°C;

[0013] S5: Cross-linking spheroidization reaction: The aqueous phase solution prepared in the aqueous phase kettle containing the solution of step S3 is transferred to the kettle containing the prepared oil phase solution through a pneumatic device, and the aqueous phase solution and the oil phase solution are formed into a stable suspension by the strong shear force of the stirring paddle. Tetramethylethylenediamine is added to cause free radical polymerization reaction in the aqueous phase, and at the same time, intermittent microwaves are started to maintain the temperature at 50-70°C. The reaction is stirred for 1-6 hours to allow the aqueous phase droplets to solidify rapidly, and then the microwave is turned off and naturally solidified for 1-6 hours. The curing reaction is completed. The reaction liquid is discharged from the kettle body, and the microspheres in the kettle body are collected to obtain the crude polyvinyl alcohol hydrogel microspheres;

[0014] S6: Washing of hydrogel microspheres: Add 1 to 5 times the volume of microspheres with butyl acetate, stir and heat with microwave radiation, then drain the liquid, and repeat the washing 1 to 5 times. Add 1 to 5 times the volume of microspheres with purified water, stir and heat with microwave radiation, then drain the liquid, and repeat the washing 1 to 5 times. Finally, wash repeatedly with injection water 1 to 5 times to obtain polyvinyl alcohol embolic microspheres and store them in physiological saline. The high-purity polyvinyl alcohol embolic microspheres obtained by this process can be used directly as embolic agents or as drug carriers for cationic drugs to obtain drug-mechanical combined drug-loaded embolic microspheres.

[0015] Preferably, the polyvinyl alcohol is preferably selected to have a 1,3-diol structure on the main chain of the embolic microsphere.

[0016] Preferably, the degree of polymerization of the polyvinyl alcohol is in the range of 1700 to 2400, and the degree of hydrolysis is in the range of 50 to 99; preferably, the degree of polymerization is 1700 and the degree of hydrolysis is 88.

[0017] Preferably, the weight ratio of the N-acrylamide acetaldehyde dimethyl acetal to polyvinyl alcohol is preferably 0.1 to 2:1;

[0018] The weight ratio of the sodium 2-acrylamide-2-methylpropane sulfonate to polyvinyl alcohol is preferably 0.1 to 2:1;

[0019] The weight ratio of potassium persulfate to polyvinyl alcohol is preferably 0.1-2:1.

[0020] Preferably, the weight ratio of the cellulose acetate butyrate to butyl acetate is preferably 0.01-0.1:1.

[0021] Preferably, the weight ratio of tetramethylethylenediamine to polyvinyl alcohol is preferably 0.1-2:1.

[0022] Preferably, the microwave radiation frequency of the cross-linking curing reaction is 2000-3000 Hz, and the temperature is controlled at 50-90°C.

[0023] The present invention also provides a reaction device for preparing high-purity polyvinyl alcohol embolic microspheres, which comprises a frame, a water phase kettle, an oil phase kettle, a semi-automatic control system, a controllable variable frequency microwave device, a driving motor, a stirring component, and a liquid inlet and outlet pipeline component;

[0024] The oil phase kettle is on the frame and includes a kettle cover provided with a feed inlet, a kettle body, and a lower kettle cover provided with a filter screen;

[0025] The water phase kettle and the oil phase kettle are connected by a pipeline, and the water phase kettle transports the water phase solution to the oil phase kettle through a power device;

[0026] The semi-automatic control system includes liquid inlet control, liquid discharge control, motor stirring control, microwave wavelength and start-up control.

[0027] The inlet and outlet pipeline assembly includes a power delivery device. The power delivery device is non-electrical power, including a pneumatic power device or a negative pressure power device and an electromagnetic control switch.

[0028] Compared with the prior art, the beneficial technical effects of the present invention are as follows: the advantages of using microwave technology to prepare polyvinyl alcohol embolic microspheres in the present application are: (1) it is conducive to the preparation of a uniform suspension or emulsion, thereby effectively controlling the particle size and particle size distribution of the microspheres; (2) improving the efficiency of the cross-linking reaction; (3) the phase stabilizer and other auxiliary agents used in the preparation of the microspheres will be adsorbed in the pores of the microspheres, and the microwave energy can efficiently clean the adsorbed residues, thereby improving the purity of the product and ensuring its safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The present invention will be further described below in conjunction with the accompanying drawings.

[0030] Figure 1 This is a schematic diagram of a reaction device for preparing high-purity polyvinyl alcohol embolic microspheres according to the present invention. DETAILED DESCRIPTION

[0031] This embodiment discloses a method for preparing high-purity polyvinyl alcohol embolic microspheres with controllable particle size, which is characterized by comprising the following steps:

[0032] S1: Dissolved polyvinyl alcohol

[0033] Add polyvinyl alcohol to an aqueous phase kettle containing purified water; turn on the built-in stirring mechanism of the aqueous phase kettle, heat the solution in the aqueous phase kettle to 90-98° C., and stir the solution to dissolve; after the polyvinyl alcohol in the aqueous phase kettle is completely dissolved, cool the solution in the kettle to 20-30° C.;

[0034] S2: Functionalization reaction

[0035] Add N-acrylamide acetaldehyde dimethyl acetal to the aqueous phase kettle containing the solution of step S1, and then add hydrochloric acid to adjust the pH value of the solution in the kettle to 1-2; then stir and react for 1-6 hours, and then add sodium hydroxide solution to the aqueous phase kettle to adjust its pH value to neutral;

[0036] S3: Preparation of aqueous solution

[0037] Add sodium 2-acrylamide-2-methylpropanesulfonate and potassium persulfate to the aqueous phase kettle of step S2 in sequence, and stir until completely dissolved;

[0038] S4: Preparation of oil phase solution

[0039] Add butyl acetate and cellulose acetate butyrate into the oil phase kettle, stir until cellulose acetate butyrate is completely dissolved in butyl acetate, and heat to 50-70°C;

[0040] S5: Cross-linking and spheroidization reaction

[0041] The aqueous phase solution prepared in the aqueous phase kettle containing the solution of step S3 is transferred to the prepared oil phase solution through a conveying device, and the aqueous phase solution and the oil phase solution are formed into a stable suspension by the strong shear force of the stirring paddle. Tetramethylethylenediamine is added to cause free radical polymerization reaction in the aqueous phase, and at the same time, intermittent microwaves are started to maintain the temperature at 50-70°C. The stirring reaction is allowed to react for 1-6 hours to allow the aqueous phase droplets to solidify rapidly, and then the microwave generator is turned off and naturally solidified for 1-6 hours to complete the curing reaction. The reaction liquid is discharged from the kettle body, and the microspheres in the kettle body are collected to obtain the crude polyvinyl alcohol hydrogel microspheres;

[0042] S6: Hydrogel microsphere cleaning

[0043] Add butyl acetate in an amount 1 to 5 times the volume of the polyvinyl alcohol hydrogel microspheres, stir and heat by microwave radiation, then drain the liquid, and repeat the above washing 1 to 5 times;

[0044] Add 1 to 5 times the volume of the microspheres with purified water, stir and heat with microwave radiation, then drain the liquid, and repeat the above washing 1 to 5 times;

[0045] Finally, the microspheres were washed repeatedly with water for injection for 1 to 5 times to obtain polyvinyl alcohol embolic microspheres which were stored in physiological saline.

[0046] The polyvinyl alcohol includes a 1,2-diol structure or a 1,3-diol structure on the main chain of the embolic microsphere.

[0047] The degree of polymerization of the polyvinyl alcohol is in the range of 1700-2400, and the degree of alcoholysis is in the range of 50-99.

[0048] The weight ratio of the N-acrylamide acetaldehyde dimethyl acetal to polyvinyl alcohol is preferably 0.1-2:1; the weight ratio of the sodium 2-acrylamide-2-methylpropane sulfonate to polyvinyl alcohol is preferably 0.1-2:1; and the weight ratio of the potassium persulfate to polyvinyl alcohol is preferably 0.1-2:1.

[0049] In this embodiment, the weight ratio of the cellulose acetate butyrate to butyl acetate is preferably 0.01-0.1:1.

[0050] The weight ratio of tetramethylethylenediamine to polyvinyl alcohol is preferably 0.1-2:1.

[0051] The microwave radiation frequency of the cross-linking curing reaction is 2000-3000 Hz, and the temperature is controlled at 50-90°C.

[0052] like Figure 1 As shown, the present invention also discloses a reaction device for preparing high-purity polyvinyl alcohol embolic microspheres, which comprises a water phase kettle and an oil phase kettle;

[0053] The water phase kettle and the oil phase kettle are connected through a delivery pipeline, and a delivery pump is installed on the delivery pipeline. The water phase kettle delivers the water phase solution to the oil phase kettle through a power device; stirring components are respectively arranged in the water phase kettle and the oil phase kettle;

[0054] The water phase kettle conveys raw materials through a liquid inlet pipeline assembly and a power device, and a solenoid valve is installed on the liquid inlet pipeline; the oil phase kettle is installed in the microwave device through a frame, wherein most of the oil phase kettle is in the cavity of the microwave generator, and the raw materials are conveyed through a liquid inlet pipeline assembly and a power device, and a solenoid valve is installed on the liquid inlet pipeline;

[0055] The electromagnetic valve, power device, delivery pump, microwave device, and stirring assembly are all regulated and controlled by a control system.

[0056] Specifically, the oil phase kettle is on the frame, and comprises a kettle cover with a feed port, a kettle body, and a lower kettle cover with a filter screen.

[0057] Specifically, the power transmission device is non-electrical power, which includes a pneumatic power device or a negative pressure power device and an electromagnetic control switch.

[0058] Implementation Example 1

[0059] Dissolution of polyvinyl alcohol: Add polyvinyl alcohol to the aqueous phase kettle filled with purified water, start stirring the aqueous phase kettle, heat to 95°C, maintain the temperature at 95°C and stir until the solution is completely transparent with no visible solid particles.

[0060] Functionalization reaction: Pass the circulating refrigerant to cool the solution in the kettle to 25°C, add N-acrylamide acetaldehyde dimethyl acetal to the reaction device, add hydrochloric acid to adjust the pH value to 1-2, and stir the reaction for 6 hours. Add sodium hydroxide solution to the reactor to adjust the pH value of the solution to 6-8 to terminate the reaction.

[0061] Preparation of aqueous solution: Add sodium 2-acrylamide-2-methylpropanesulfonate and potassium persulfate into the aqueous phase kettle in sequence and stir until completely dissolved.

[0062] Preparation of oil phase solution: Add butyl acetate and cellulose acetate butyrate into the oil phase kettle, stir until cellulose acetate butyrate is completely dissolved in butyl acetate, and heat to 55°C.

[0063] Cross-linking spheroidization reaction: The aqueous phase solution prepared in the aqueous phase kettle is transferred to the prepared oil phase solution through a pneumatic device, and the aqueous phase solution and the oil phase solution are formed into a stable suspension by the strong shear force of the stirring paddle. The stirring speed is reduced, and there is no coagulation and stratification of the aqueous phase. Tetramethylethylenediamine is added to the oil phase kettle to cause free radical polymerization of the aqueous phase. At the same time, the intermittent microwave is started to maintain the temperature at 55°C. The reaction is stirred for 6 hours to quickly solidify the aqueous phase droplets, and then the microwave is turned off. Natural curing for 1 hour, the curing reaction is completed. The reaction liquid is discharged from the kettle, and the microspheres in the kettle are collected to obtain the crude polyvinyl alcohol hydrogel microspheres.

[0064] Washing of hydrogel microspheres: Add butyl acetate twice the volume of microspheres, start the oil phase kettle to stir, start the microwave to radiate and heat the oil phase kettle solution for 3 minutes, then drain the liquid, and repeat the washing twice. Add purified water 5 times the volume of microspheres, start the oil phase kettle to stir, start the microwave to radiate and heat the oil phase kettle solution for 3 minutes, then drain the liquid, and repeat the washing twice. Finally, wash it twice with water for injection to obtain polyvinyl alcohol embolization microspheres and store them in physiological saline.

[0065]

[0066] Other embolic microsphere implementation examples

[0067] Implementation Example 2

[0068] Preparation of aqueous solution: Add gelatin to the aqueous kettle containing purified water, start stirring the aqueous kettle, heat to 70°C, maintain the temperature at 70°C and stir until the solution is completely transparent without visible solid particles, then introduce refrigerant to cool down to 15°C.

[0069] Preparation of oil phase solution: Add liquid paraffin and Span 80 into the oil phase kettle and stir evenly.

[0070] Cross-linking spheroidization reaction: The water phase solution prepared in the water phase kettle is transferred to the prepared oil phase solution through a pneumatic device, and the water phase solution and the oil phase solution are formed into a stable suspension by the strong shear force of the stirring paddle. The stirring speed is reduced, and there is no coagulation and stratification in the water phase. Formaldehyde is added to the oil phase kettle to make the gelatin undergo cross-linking polymerization reaction. At the same time, the intermittent microwave is started to maintain the temperature at 30°C. The reaction is stirred for 1 hour to make the water phase droplets solidify quickly, and then the microwave is turned off and naturally solidified for 1 hour. The curing reaction is completed. The reaction liquid is discharged from the kettle body, and the microspheres in the kettle body are collected to obtain the crude gelatin sponge hydrogel microspheres.

[0071] Washing of hydrogel microspheres: Add 2% Span 80 aqueous solution 5 times the volume of microspheres, start the oil phase kettle to stir, start the microwave to radiate and heat the oil phase kettle solution for 3 minutes, then drain the liquid, and repeat the washing twice. Add 5 times the volume of microspheres of purified water, start the oil phase kettle to stir, start the microwave to radiate and heat the oil phase kettle solution for 3 minutes, then drain the liquid, and wash twice. Finally, wash twice with injection water, and after drying, gelatin sponge embolization microspheres can be obtained.

[0072]

[0073]

[0074] Chemical reaction formula for the preparation of polyvinyl alcohol microspheres

[0075] In the description of the present invention, it should be understood that the terms "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside" and "outside" etc., indicating orientations or positional relationships, are based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as a limitation on the present invention.

[0076] The above embodiments are only descriptions of the preferred methods of the invention, and are not intended to limit the scope of the invention. Without departing from the design spirit of the invention, various modifications and improvements made to the technical solutions of the invention by ordinary technicians in this field should fall within the protection scope of the claims of the invention.

Claims

1. A method for preparing high-purity polyvinyl alcohol embolic microspheres with controllable particle size, characterized in that: The following steps are involved: S1. Dissolving polyvinyl alcohol: Add polyvinyl alcohol to the water phase kettle containing purified water, start stirring the water phase kettle, heat to 95°C, maintain the temperature at 95°C and stir until it is completely transparent and no solid particles are visible; S2, functionalization reaction: introducing circulating refrigerant to cool the solution in the kettle to 25°C, adding N-acrylamide acetaldehyde dimethyl acetal to the reaction device, and then adding hydrochloric acid to adjust the pH value to 1-2, stirring the reaction for 6 hours, adding sodium hydroxide solution to the reactor to adjust the pH value to 6-8, and terminating the reaction; S3, aqueous solution preparation: add sodium 2-acrylamide-2-methylpropanesulfonate and potassium persulfate into the aqueous phase kettle in sequence, and stir until completely dissolved; S4, preparation of oil phase solution: add butyl acetate and cellulose acetate butyrate into the oil phase kettle, stir until cellulose acetate butyrate is completely dissolved in butyl acetate, and heat to 55°C; S5, cross-linking spheroidization reaction: the aqueous phase solution prepared in the aqueous phase kettle is transferred to the prepared oil phase solution through a pneumatic device, and the aqueous phase solution and the oil phase solution are formed into a stable suspension by the strong shear force of the stirring paddle, and the stirring speed is reduced, and there is no agglomeration and stratification of the aqueous phase; tetramethylethylenediamine is added to the oil phase kettle to make the aqueous phase undergo free radical polymerization reaction, and the intermittent microwave is started to maintain the temperature at 55°C, and the reaction is stirred for 6 hours to make the aqueous phase droplets solidify quickly, and then the microwave is turned off and naturally solidified for 1 hour, and the curing reaction is completed; the reaction liquid is discharged from the kettle, and the microspheres in the kettle are collected to obtain the crude polyvinyl alcohol hydrogel microspheres; S6. Cleaning of hydrogel microspheres: add butyl acetate twice the volume of the microspheres, start the oil phase kettle to stir, start the microwave to radiate and heat the oil phase kettle solution for 3 minutes, then drain the liquid, and repeat the cleaning twice; add purified water five times the volume of the microspheres, start the oil phase kettle to stir, start the microwave to radiate and heat the oil phase kettle solution for 3 minutes, then drain the liquid, and repeat the cleaning twice; finally, repeat the cleaning twice with water for injection to obtain polyvinyl alcohol embolic microspheres and store them in physiological saline.

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