Self-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and preparation method thereof

Abstract

The invention relates to a self-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and a preparation method thereof. The preparation method comprises the following specific steps: providing polyvinyl alcohol with the weight-average molecular weight of 30000-80000 and an azo carboxylic acid derivative, and carrying out esterification coupling to obtain a polyvinyl alcohol intermediate capable of self-initiation crosslinking; the preparation method comprises the following steps: dissolving a self-initiated cross-linking polyvinyl alcohol intermediate and 2-acrylamide-2-sodium methylpropanesulfonate in water, uniformly mixing to form a water-phase solution, mixing the water-phase solution with the oil-phase solution to form a water-in-oil reversed-phase suspension polymerization system, heating, carrying out a stirring heating reaction, washing after the reaction is finished, and drying to obtain the water-in-oil reversed-phase suspension polymer. The self-initiated cross-linked polyvinyl alcohol drug-loaded embolism microspheres are obtained; wherein the oil phase solution is a mixed solution of butyl acetate and cellulose acetate butyrate. According to the preparation method, an additional cross-linking agent or a harmful initiator is not needed, the preparation process of the PVA microspheres is optimized, and the safety, biocompatibility and stability of the PVA microspheres are improved.

Description

Technical Field

[0001] The invention relates to the technical field of medical materials, and in particular to a self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microsphere and a preparation method thereof. Background Art

[0002] As interventional therapy becomes more mature, it is being used more and more widely in the field of medical technology. The principle of interventional therapy is to use a high-definition medical imaging device to guide a catheter into the tumor site in the human body through a small incision, and then infuse anti-tumor drugs through the blood supply artery or block the blood supply of the tumor tissue, so that the tumor will necrotize and shrink in a short period of time, achieving the purpose of treatment. In the current minimally invasive interventional treatment, embolic microspheres, as solid embolic agents, can effectively and accurately deliver drugs to the target site, reduce the diffusion of drugs throughout the body, and overcome the shortcomings of traditional liquid embolic agents.

[0003] In the prior art, commonly used embolic materials such as microspheres and microcapsules are mostly based on polymer materials, and polyvinyl alcohol (PVA) has become an ideal choice for embolic microsphere materials due to its good biocompatibility and non-toxicity. At present, polyvinyl alcohol (PVA) microspheres are one of the common embolic materials on the market. They are usually prepared by adding an emulsifier to the solution for emulsification, and then adding a cross-linking agent to solidify the solution to form micron-sized microspheres. However, the traditional PVA microsphere preparation process has some defects: the reaction is usually carried out by heating to initiate free radical thermal polymerization, which is not only time-consuming and energy-intensive, but also commonly used cross-linking agents such as glutaraldehyde may remain inside the microspheres, affecting their biocompatibility. In addition, the initiators used, such as azobisisobutyronitrile, may bring toxicity risks.

[0004] Therefore, the existing technology needs to be improved. Summary of the invention

[0005] In the prior art, the traditional PVA microsphere preparation process has some defects: the reaction is usually carried out by heating to initiate free radical thermal polymerization, which is not only time-consuming and energy-intensive, but also commonly used cross-linking agents such as glutaraldehyde may remain inside the microspheres, affecting their biocompatibility. Therefore, the present invention provides a self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microsphere and a preparation method thereof to solve the above problems.

[0006] In a first aspect, the present invention provides a method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres, which comprises the following specific steps: S1, providing polyvinyl alcohol with a weight average molecular weight of 30,000 to 80,000 and an azocarboxylic acid derivative, and obtaining a polyvinyl alcohol intermediate capable of self-initiated cross-linking through esterification coupling; S2, dissolving a self-initiating cross-linking polyvinyl alcohol intermediate and 2-acrylamide-2-methylpropanesulfonic acid sodium salt in water and mixing them evenly to form an aqueous phase solution, mixing the aqueous phase solution with an oil phase solution to form an oil-in-water reverse suspension polymerization system, heating and stirring to react, washing after the reaction is completed, and obtaining the self-initiating cross-linking polyvinyl alcohol drug-loaded embolic microspheres; Wherein, the oil phase solution is a mixed solution of butyl acetate and cellulose acetate butyrate.

[0007] In one implementation, in S1, the specific steps include: S11, adding the polyvinyl alcohol to a dimethyl sulfoxide solution and dissolving it completely at 70-90° C., then adding an azocarboxylic acid derivative, an acylating agent and a basic catalyst, and stirring the mixture at 40-70° C. for 20-24 hours; S12, after the reaction is completed, filtering the solution and adding a precipitant to the reaction system to precipitate the modified polyvinyl alcohol obtained by the reaction; S13, repeatedly performing ultrasonic washing with the precipitant, re-dissolving the modified polyvinyl alcohol in water, and freeze-drying for 2 to 4 days to obtain a polyvinyl alcohol intermediate capable of self-initiating cross-linking.

[0008] In one implementation, in S11, the azocarboxylic acid derivative includes one or more of azobiscyanovaleric acid and dimethyl azobisisobutyrate; the acylating agent is 1,3-dicyclohexylcarbodiimide; and the alkaline catalyst is tetramethylethylenediamine or 4-dimethylaminopyridine.

[0009] In one implementation, in S12, the precipitant is any one of ethyl acetate, ethanol and acetone.

[0010] In one implementation, the mass ratio of the polyvinyl alcohol, the azocarboxylic acid derivative, the acylating agent and the alkaline catalyst is 1:(0.01-0.5):(0.02-1):(0.01-1).

[0011] In one implementation, in S2, the mass ratio of the mixed solution of the self-crosslinkable polyvinyl alcohol intermediate, 2-acrylamide-2-methylpropane sulfonic acid sodium salt, butyl acetate and cellulose acetate butyrate is 1: (0.001-0.5): (1-10): (0.001-0.05).

[0012] In one implementation, in S2, the reaction temperature of the stirring and heating reaction is 45-60°C, the reaction time is 2.5-4 hours, and the stirring speed is 400-600 rpm.

[0013] In one implementation, in S2, washing after the reaction specifically includes: washing with butyl acetate, ethyl acetate and acetone in sequence.

[0014] In a second aspect, the present invention further provides a self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microsphere, which is prepared by any one of the preparation methods described above.

[0015] In one implementation, the particle size of the self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres is 1 to 2000 microns.

[0016] Beneficial effects: The present invention obtains a self-crosslinking polyvinyl alcohol intermediate through esterification coupling, and then blends it with 2-acrylamide-2-methylpropane sulfonic acid sodium salt, etc., and prepares drug-loaded embolic microspheres through a reverse suspension polymerization process. The prepared microspheres have the advantages of good mechanical strength, controllable size, high drug loading, etc., and are suitable for medical scenarios such as vascular embolism and tumor embolism; the self-crosslinking polyvinyl alcohol material is used to prepare the embolic microspheres, and the self-crosslinking mechanism is introduced, which improves the simplicity of the production process, does not require additional crosslinking agents or harmful initiators, optimizes the preparation process of PVA microspheres, and improves its safety, biocompatibility and stability, providing a more ideal embolic material for interventional therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a flow chart of the steps of the method for preparing the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided by the present invention; Figure 2 is a SEM electron micrograph of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 1; Figure 3 is a SEM electron micrograph of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 2; Figure 4 is a SEM electron micrograph of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 3; Figure 5 is a SEM electron micrograph of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 4; Figure 6 This is a SEM electron microscope image of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in the comparative example.

[0018] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the accompanying drawings and examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the description of the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" described below means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms is not necessarily for the same embodiment or example. Moreover, the technical features involved in each embodiment of the present invention can be combined with each other as long as they do not conflict with each other.

[0020] See also Figure 1 , Figure 1 The present invention provides a method for preparing self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres, which comprises the following specific steps: S1, providing polyvinyl alcohol with a weight average molecular weight of 30,000 to 80,000 and an azocarboxylic acid derivative, and obtaining a polyvinyl alcohol intermediate capable of self-initiated cross-linking through esterification coupling; S2, dissolving a self-initiating cross-linking polyvinyl alcohol intermediate and 2-acrylamide-2-methylpropanesulfonic acid sodium salt in water and mixing them evenly to form an aqueous phase solution, mixing the aqueous phase solution with an oil phase solution to form an oil-in-water reverse suspension polymerization system, heating and stirring to react, washing after the reaction is completed, and obtaining the self-initiating cross-linking polyvinyl alcohol drug-loaded embolic microspheres; Wherein, the oil phase solution is a mixed solution of butyl acetate and cellulose acetate butyrate.

[0021] The self-initiating cross-linking polyvinyl alcohol intermediate obtained by esterification coupling reduces the need for external initiators, simplifies the process steps, and improves the reaction efficiency. The self-initiating cross-linking polyvinyl alcohol intermediate obtained by esterification coupling reduces the need for external initiators, simplifies the process steps, and improves the reaction efficiency. The use of an oil-in-water reverse suspension polymerization system helps to form uniform microspheres and helps to control the particle size and morphology of the microspheres. Through precipitation, washing and other steps, multiple washing and purification can effectively remove unreacted residues to obtain high-purity products.

[0022] Specifically, in S1, the specific steps include: S11, adding the polyvinyl alcohol to a dimethyl sulfoxide solution and dissolving it completely at 70-90° C., then adding an azocarboxylic acid derivative, an acylating agent and a basic catalyst, and stirring the mixture at 40-70° C. for 20-24 hours; S12, after the reaction is completed, filtering the solution and adding a precipitant to the reaction system to precipitate the modified polyvinyl alcohol obtained by the reaction; S13, repeatedly performing ultrasonic washing with the precipitant, re-dissolving the modified polyvinyl alcohol in water, and freeze-drying for 2 to 4 days to obtain a polyvinyl alcohol intermediate capable of self-initiating cross-linking.

[0023] Specifically, in S11, the azocarboxylic acid derivative includes one or more of azobiscyanovaleric acid and dimethyl azobisisobutyrate. Azocarboxylic acid derivatives are thermal initiators that can decompose under heating conditions to generate free radicals, thereby initiating a crosslinking reaction. These free radicals promote the formation of a crosslinking network between PVA chains, giving the microspheres good stability and mechanical strength.

[0024] Specifically, the acylating agent is 1,3-dicyclohexylcarbodiimide (DCC). 1,3-Dicyclohexylcarbodiimide as an acylating agent can promote the esterification reaction of PVA and azocarboxylic acid derivatives to generate a PVA intermediate that can self-initiate cross-linking. Adding the acylating agent is a key chemical modification step, which enables PVA to have the ability of self-initiating cross-linking.

[0025] Specifically, the alkaline catalyst is tetramethylethylenediamine or 4-dimethylaminopyridine. The alkaline catalyst can improve the efficiency of the acylation reaction and accelerate the coupling reaction of PVA and azocarboxylic acid derivatives.

[0026] Furthermore, the mass ratio of the polyvinyl alcohol, azocarboxylic acid derivative, acylating agent and alkaline catalyst is 1: (0.01-0.5): (0.02-1): (0.01-1). Among them, polyvinyl alcohol (PVA) as the main film-forming polymer can provide a matrix for the microspheres, and its molecular weight is selected in the range of 30,000-80,000 to ensure its appropriate solubility and mechanical properties. Dimethyl sulfoxide (DMSO) as a solvent can efficiently dissolve PVA and other reactants to ensure uniform reaction.

[0027] In S12, the precipitant is any one of ethyl acetate, ethanol and acetone. The precipitant is used to precipitate the modified PVA generated by the reaction from the solution, which is convenient for separation and purification. In S13, ultrasonic washing can further remove unreacted substances and small molecule by-products to ensure the purity of the modified PVA.

[0028] Further, in S2, the mass ratio of the mixed solution of the self-initiating cross-linking polyvinyl alcohol intermediate, 2-acrylamide-2-methylpropane sulfonic acid sodium salt, butyl acetate and cellulose acetate butyrate is 1: (0.001~0.5): (1~10): (0.001~0.05). Among them, the self-initiating cross-linking polyvinyl alcohol intermediate is used as the main film-forming material to provide the matrix of the microsphere. Through the previous esterification coupling reaction, these polyvinyl alcohol molecules have been modified with azo groups, which can self-initiate cross-linking when heated to form a stable cross-linked network structure, ensuring the mechanical stability and chemical stability of the microspheres in the application. NaAMPS provides sulfonic acid groups, giving the final microsphere material good hydrophilicity and water absorption; it can also participate in the cross-linking reaction to further enhance the functionality and structural stability of the microspheres. In addition, NaAMPS also helps to adjust the viscosity of the solution in the aqueous phase to form a more stable suspension. Butyl acetate, as an oil phase solvent, provides a hydrophobic environment, which helps to form an oil-in-water reverse suspension polymerization system. The volatility and hydrophobicity of butyl acetate allow the water phase droplets to be evenly dispersed in the oil phase and easily washed away after the reaction. Cellulose acetate butyrate (CAB) acts as a thickener and stabilizer, increasing the viscosity of the oil phase, helping to disperse and stabilize the water phase droplets, preventing them from agglomerating, and helping to form uniformly sized, stable microspheres.

[0029] In general, 2-acrylamide-2-methylpropanesulfonic acid sodium salt (NaAMPS) can provide sulfonic acid groups, endow the final microsphere material with good hydrophilicity and water absorption, and at the same time help to form a stable oil-in-water reverse suspension polymerization system. The mixed solution of butyl acetate and cellulose acetate butyrate is used as the oil phase to form an oil-in-water reverse suspension polymerization system, ensuring that PVA and NaAMPS in the water phase are evenly dispersed in the oil phase. Cellulose acetate butyrate further increases the viscosity of the oil phase and stabilizes the suspension system.

[0030] Specifically, the reaction temperature of the stirring and heating reaction is 45-60°C, the reaction time is 2.5-4 hours, and the stirring speed is 400-600rpm. Washing after the reaction specifically includes: washing with butyl acetate, ethyl acetate and acetone in sequence. Among them, heating promotes the decomposition of the azo group in the polyvinyl alcohol intermediate, generates free radicals, and initiates a cross-linking reaction. Stirring ensures the uniform dispersion of the aqueous phase in the oil phase to form a stable suspension system. The appropriate temperature and stirring speed can ensure the uniformity of the reaction and the uniformity of the size of the microspheres. After the reaction is completed, the microspheres are washed with butyl acetate, ethyl acetate and acetone in sequence, which can remove unreacted monomers, oil phase solvents and other impurities, and ensure the purity and quality of the final product. Specifically, butyl acetate is used for preliminary washing to remove most of the oil phase solvent, and ethyl acetate is used for further washing to remove residual polymers and unreacted monomers; the acetone is used for final cleaning to ensure that all organic solvents and impurities are removed to obtain pure microspheres.

[0031] In a second aspect, the present invention further provides a self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microsphere, which is prepared by any one of the preparation methods described above. Specifically, the particle size of the self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microsphere is 1-2000 microns.

[0032] Example 1 S1: Catalytic synthesis of self-initiating cross-linking polyvinyl alcohol intermediates Add 100 ml of dimethyl sulfoxide and 10 g of polyvinyl alcohol with a weight average molecular weight of 67,000 to the reaction bottle, and heat to 80°C to completely dissolve the polyvinyl alcohol. Add 0.5 g of azobiscyanovaleric acid, 0.2 g of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminopyridine, and stir the reaction stably at 50°C for 24 hours. After the reaction is completed, filter out the precipitate to obtain a clear solution and then add precipitant acetone to the reaction system to precipitate the modified polyvinyl alcohol from the solution, then use acetone to ultrasonically clean it 3 times, redissolve it in water, and freeze-dry to obtain a polyvinyl alcohol intermediate that can self-initiate cross-linking.

[0033] S2: Preparation of polyvinyl alcohol embolic microspheres by inverse suspension polymerization 1g of polyvinyl alcohol intermediate and 10g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt were completely dissolved in 90g of deionized water to prepare an aqueous phase solution for use. 10g of cellulose acetate butyrate was added to 1000ml of butyl acetate and stirred to completely dissolve to prepare an oil phase solution for use.

[0034] The aqueous solution was added dropwise to the oily solution to form an oil-water mixed reaction system, and the temperature was raised to 50°C, the stirring speed was 400 rpm, and the reaction was stirred stably for 3 hours. After the reaction was completed, the reaction mixture was filtered to collect the microspheres, and then washed with butyl acetate, ethyl acetate and acetone in turn, and vacuum dried to obtain polyvinyl alcohol embolization microspheres. Figure 2 As shown, Figure 2 This is a SEM electron microscope image of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 1. The polyvinyl alcohol microspheres obtained in this example have complete spherical shape and uniform particle size distribution.

[0035] Example 2 S1: Catalytic synthesis of self-initiating cross-linking polyvinyl alcohol intermediates Add 200 ml of dimethyl sulfoxide and 20 g of polyvinyl alcohol with a weight average molecular weight of 67,000 to the reaction bottle, and heat to 80°C to completely dissolve the polyvinyl alcohol. Add 1 g of azobiscyanovaleric acid, 0.2 g of 1,3-dicyclohexylcarbodiimide and 0.2 g of 4-dimethylaminopyridine, and stir the reaction stably at 50°C for 24 hours. After the reaction is completed, filter out the precipitate to obtain a clear solution and then add precipitant acetone to the reaction system to precipitate the modified polyvinyl alcohol from the solution, then use acetone to ultrasonically clean it 3 times, redissolve it in water, and freeze-dry to obtain a polyvinyl alcohol intermediate that can self-initiate cross-linking.

[0036] S2: Preparation of polyvinyl alcohol embolic microspheres by inverse suspension polymerization 2g of polyvinyl alcohol intermediate and 20g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt were completely dissolved in 180g of deionized water to prepare an aqueous phase solution for use. 20g of cellulose acetate butyrate was added to 2000ml of butyl acetate and stirred to completely dissolve to prepare an oil phase solution for use.

[0037] The aqueous solution was added dropwise to the oily solution to form an oil-water mixed reaction system, and the temperature was raised to 50°C, the stirring speed was 600 rpm, and the reaction was stirred stably for 3 hours. After the reaction was completed, the reaction mixture was filtered to collect the microspheres, and then washed with butyl acetate, ethyl acetate and acetone in turn, and vacuum dried to obtain polyvinyl alcohol embolization microspheres. Figure 3 As shown, Figure 3 This is a SEM electron microscope image of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 2. The polyvinyl alcohol microspheres obtained in this example have complete spherical shape and uniform particle size distribution.

[0038] Example 3 S1: Catalytic synthesis of self-initiating cross-linking polyvinyl alcohol intermediates Add 100 ml of dimethyl sulfoxide and 10 g of polyvinyl alcohol with a weight average molecular weight of 67,000 to a reaction bottle, and heat to 80°C to completely dissolve the polyvinyl alcohol. Add 0.5 g of dimethyl azobisisobutyrate, 0.2 g of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminopyridine, and stir the reaction at 50°C for 24 hours. After the reaction is completed, filter out the precipitate to obtain a clear solution and then add precipitant acetone to the reaction system to precipitate the modified polyvinyl alcohol from the solution, then use acetone to ultrasonically clean it 3 times, redissolve it in water, and freeze-dry to obtain a polyvinyl alcohol intermediate that can self-initiate cross-linking.

[0039] S2: Preparation of polyvinyl alcohol embolic microspheres by inverse suspension polymerization 1g of polyvinyl alcohol intermediate and 10g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt were completely dissolved in 90g of deionized water to prepare an aqueous phase solution for use. 10g of cellulose acetate butyrate was added to 1000ml of butyl acetate and stirred to completely dissolve to prepare an oil phase solution for use.

[0040] The aqueous solution was added dropwise to the oily solution to form an oil-water mixed reaction system, and the temperature was raised to 50°C, the stirring speed was 400 rpm, and the reaction was stirred stably for 3 hours. After the reaction was completed, the reaction mixture was filtered to collect the microspheres, and then washed with butyl acetate, ethyl acetate and acetone in turn, and vacuum dried to obtain polyvinyl alcohol embolization microspheres. Figure 4 As shown, Figure 4 This is a SEM electron microscope image of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 3. The polyvinyl alcohol microspheres obtained in this example have complete spherical shape and uniform particle size distribution.

[0041] Example 4 S1: Catalytic synthesis of self-initiating cross-linking polyvinyl alcohol intermediates Add 100 ml of dimethyl sulfoxide and 10 g of polyvinyl alcohol with a weight average molecular weight of 47,000 to a reaction bottle, heat to 80°C to completely dissolve the polyvinyl alcohol. Add 0.5 g of dimethyl azobisisobutyrate, 0.2 g of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminopyridine, and stir stably at 50°C for 24 hours. After the reaction is completed, filter out the precipitate to obtain a clear solution and then add precipitant acetone to the reaction system to precipitate the modified polyvinyl alcohol from the solution, then use acetone to ultrasonically clean it 3 times, redissolve it in water, and freeze-dry to obtain a polyvinyl alcohol intermediate that can self-initiate cross-linking.

[0042] S2: Preparation of polyvinyl alcohol embolic microspheres by inverse suspension polymerization 2g of polyvinyl alcohol intermediate and 10g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt were completely dissolved in 90g of deionized water to prepare an aqueous phase solution for use. 10g of cellulose acetate butyrate was added to 1000ml of butyl acetate and stirred to completely dissolve to prepare an oil phase solution for use.

[0043] The aqueous solution was added dropwise to the oily solution to form an oil-water mixed reaction system, and the temperature was raised to 50°C, the stirring speed was 400 rpm, and the reaction was stirred stably for 3 hours. After the reaction was completed, the reaction mixture was filtered to collect the microspheres, and then washed with butyl acetate, ethyl acetate and acetone in turn, and vacuum dried to obtain polyvinyl alcohol embolization microspheres. Figure 5 As shown, Figure 5 This is a SEM electron microscope image of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in Example 4. The polyvinyl alcohol microspheres obtained in this example have complete spherical shape and uniform particle size distribution.

[0044] Comparative Example Preparation of polyvinyl alcohol microspheres by emulsification-chemical crosslinking method Place 10g of polyvinyl alcohol with a weight average molecular weight of 67,000 in 90ml of deionized water and stir at 80°C to completely dissolve the polyvinyl alcohol to obtain an anhydrous transparent polyvinyl alcohol solution. Measure 50ml of liquid paraffin, add 2g of emulsifier SP-80 to it, and stir at high speed to form a continuous oil phase for standby use. Then measure 10mL of polyvinyl alcohol solution and slowly add it dropwise to the oil phase (the oil-water volume ratio is 10:2), stir and emulsify at 70°C for 40min to obtain a uniformly dispersed oil-water mixed system. Subsequently, add 0.5mL of 50% glutaraldehyde and 0.4mL of 1moL / mL hydrochloric acid to the system, continue stirring for 3h, centrifuge, wash and dry to obtain polyvinyl alcohol microspheres. Figure 6 As shown, Figure 6 This is a SEM electron microscope image of the self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres provided in the comparative example. The polyvinyl alcohol microspheres obtained in this comparative example have irregular spherical shapes, many surface depressions, and some microspheres are sticky.

[0045] According to the experimental results of Examples 1 to 4 and the comparative example, it can be seen that the polyvinyl alcohol microspheres obtained by the preparation method provided by the present invention have a complete spherical shape and a uniform particle size distribution; the polyvinyl alcohol microspheres obtained in the comparative example have a relatively irregular spherical shape, many surface depressions, and some microspheres are sticky. The present invention improves the quality and morphology of polyvinyl alcohol microspheres through specific steps and conditions. Since the polyvinyl alcohol microspheres with complete spherical shape and uniform particle size distribution have better fluidity, dispersibility and stability in drug loading and embolization applications, they have higher practical value and effect in practical applications.

[0046] In summary, the present invention obtains a self-crosslinking polyvinyl alcohol intermediate through esterification coupling, and then blends it with 2-acrylamide-2-methylpropane sulfonic acid sodium salt, etc., and prepares drug-loaded embolic microspheres through a reverse suspension polymerization process. The prepared microspheres have the advantages of good mechanical strength, controllable size, high drug loading, etc., and are suitable for medical scenarios such as vascular embolism and tumor embolism; the self-crosslinking polyvinyl alcohol material is used to prepare the embolic microspheres, and the self-crosslinking mechanism is introduced, which improves the simplicity of the production process, does not require additional crosslinking agents or harmful initiators, optimizes the preparation process of PVA microspheres, and improves its safety, biocompatibility and stability, providing a more ideal embolic material for interventional therapy.

[0047] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for preparing self-initiated cross-linked polyvinyl alcohol drug-loaded embolic microspheres, characterized in that: The specific steps include: S1, providing polyvinyl alcohol with a weight average molecular weight of 30,000 to 80,000 and an azocarboxylic acid derivative, and obtaining a polyvinyl alcohol intermediate capable of self-initiated cross-linking through esterification coupling; S2, dissolving a self-initiating cross-linking polyvinyl alcohol intermediate and 2-acrylamide-2-methylpropanesulfonic acid sodium salt in water and mixing them evenly to form an aqueous phase solution, mixing the aqueous phase solution with an oil phase solution to form an oil-in-water reverse suspension polymerization system, heating and stirring to react, washing after the reaction is completed, and obtaining the self-initiating cross-linking polyvinyl alcohol drug-loaded embolic microspheres; Wherein, the oil phase solution is a mixed solution of butyl acetate and cellulose acetate butyrate.

2. The method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 1, characterized in that: In S1, the specific steps include: S11, adding the polyvinyl alcohol to a dimethyl sulfoxide solution and dissolving it completely at 70-90° C., then adding an azocarboxylic acid derivative, an acylating agent and a basic catalyst, and stirring the mixture at 40-70° C. for 20-24 hours; S12, after the reaction is completed, filtering the solution and adding a precipitant to the reaction system to precipitate the modified polyvinyl alcohol obtained by the reaction; S13, repeatedly performing ultrasonic washing with the precipitant, re-dissolving the modified polyvinyl alcohol in water, and freeze-drying for 2 to 4 days to obtain a polyvinyl alcohol intermediate capable of self-initiating cross-linking.

3. The method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 2, characterized in that: In S11, the azocarboxylic acid derivative includes one or more of azobiscyanovaleric acid and dimethyl azobisisobutyrate; the acylating agent is 1,3-dicyclohexylcarbodiimide; and the alkaline catalyst is tetramethylethylenediamine or 4-dimethylaminopyridine.

4. The method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 2, characterized in that: In S12, the precipitant is any one of ethyl acetate, ethanol and acetone.

5. The method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 2, characterized in that: The mass ratio of the polyvinyl alcohol, the azocarboxylic acid derivative, the acylating agent and the alkaline catalyst is 1:(0.01-0.5):(0.02-1):(0.01-1).

6. The method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 1, characterized in that: In S2, the mass ratio of the mixed solution of the self-crosslinkable polyvinyl alcohol intermediate, 2-acrylamide-2-methylpropane sulfonic acid sodium salt, butyl acetate and cellulose acetate butyrate is 1: (0.001-0.5): (1-10): (0.001-0.05).

7. The method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 1, characterized in that: In S2, the reaction temperature of the stirring and heating reaction is 45-60°C, the reaction time is 2.5-4 hours, and the stirring speed is 400-600 rpm.

8. The method for preparing self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 1, characterized in that: In S2, washing after the reaction specifically includes: washing with butyl acetate, ethyl acetate and acetone in sequence.

9. A self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microsphere, characterized in that: It is prepared by the preparation method according to any one of claims 1 to 8.

10. The self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres according to claim 9, characterized in that: The particle size of the self-initiating cross-linked polyvinyl alcohol drug-loaded embolic microspheres is 1 to 2000 microns.

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