Polyvinyl alcohol sponge particle for interventional therapy as well as preparation method and application of polyvinyl alcohol sponge particle

Abstract

The invention belongs to the technical field of medical materials, and provides polyvinyl alcohol sponge particles for interventional therapy as well as a preparation method and application of the polyvinyl alcohol sponge particles. The polyvinyl alcohol sponge particles are prepared from the following raw materials: polyvinyl alcohol, a foaming agent, a catalyst and a cross-linking agent, the foaming agent is one or more of hydrogenated lecithin, poloxamer 188, polysorbate 80 and polysorbate 85; the catalyst is one or more of hydrochloric acid, sulfuric acid, citric acid and tartaric acid; the cross-linking agent is one or more of formaldehyde, n-butyraldehyde, glutaraldehyde, salicylaldehyde and 5-hydroxymethylfurfural. The polyvinyl alcohol sponge particle has a relatively good chemical crosslinking structure, has excellent absorbability, suspension property and catheter passing performance, and meets clinical use requirements.

Description

Technical Field

[0001] The invention belongs to the technical field of medical materials and provides polyvinyl alcohol sponge particles for interventional treatment and a preparation method and application thereof. Background Art

[0002] Interventional therapy is a minimally invasive treatment that can be used in many fields such as tumors, cardiovascular, and neurology. In particular, it has been increasingly widely used in the treatment of vascular-rich cancer tumors such as liver cancer, kidney cancer, and uterine fibroids, as well as in the treatment of critical pulmonary vascular diseases such as hemoptysis.

[0003] Polyvinyl alcohol (PVA), the structural formula is -[CH 2 CH(OH)] n -, is a multifunctional water-soluble polymer material, which is widely used in the biomedical field because of its non-toxicity, non-irritation, excellent flexibility, ductility and good biocompatibility. For example, polyvinyl alcohol hydrogel can be used as ophthalmology, wound dressing, and artificial joints; polyvinyl alcohol microspheres can be used for drug sustained release; polyvinyl alcohol particles are used as particle embolic materials, which are delivered to the lesion site through blood vessels, block the blood flow of the lesion site, reduce or cut off the blood supply of tumors, aneurysms or arteriovenous fistulas, etc., so as to achieve the purpose of treatment, with the advantages of precise treatment and less trauma.

[0004] Chinese invention patent application CN107903428A discloses a method for preparing a medical polyvinyl alcohol sponge, which is prepared by directly mixing and stirring a polyvinyl alcohol aqueous solution with a cross-linking agent and a catalyst, and heat-insulating and shaping. The sponge has the advantages of good biocompatibility, porous and easy drainage, soft and compliant material, and no particle shedding. The main purpose is to have little irritation to the wound surface and reduce the foreign body sensation in clinical applications; the absorption and suspension properties are insufficient.

[0005] Chinese invention patent application CN103435832A discloses a polyvinyl alcohol liquid-absorbing sponge and a preparation method thereof, which is obtained by adding a cross-linking agent, a catalyst, a foaming agent, a pore-filling agent, an auxiliary foaming agent, a foam stabilizer and an emulsifier to a polyvinyl alcohol solution, and cross-linking and curing. The polyvinyl alcohol liquid-absorbing sponge has the characteristics of uniform pores, strong water absorption capacity, good flexibility and viscoelasticity, good biocompatibility, etc. However, its preparation process is complicated and requires the cooperation of multiple auxiliary materials such as a foaming agent, an auxiliary foaming agent, a foam stabilizer, and a pore-filling agent and an emulsifier to achieve uniform pores and improve liquid absorption, thereby increasing the preparation and raw material costs.

[0006] Chinese invention patent CN115624645B discloses a polyvinyl alcohol foam and a preparation method thereof, which is prepared with polyvinyl alcohol blends of different polymerization degrees and different alcoholysis degrees, crosslinking agents, catalysts, uniform foaming agents, foaming agents, pore-opening agents, and hydrophilic dispersants as main raw materials. It has a porous structure with large pores and small pores, good mechanical properties, antibacterial properties, and good biocompatibility; however, its penetration time is relatively long, which is more than 30 seconds; and the realization of its porous structure also requires the joint action of multiple auxiliary materials such as foaming agents, uniform foaming agents, and hydrophilic dispersants, and the preparation process is relatively complicated.

[0007] Currently, polyvinyl alcohol sponge particles still have defects such as difficulty in achieving a uniform pore structure, long absorption time, short suspension time, and easy clogging of the catheter during catheter delivery. These defects lead to multiple continuous shaking during surgery, inconvenient operation, and even surgical failure. It is necessary to conduct in-depth research on the coordination mechanism of foaming agents, catalysts, and cross-linking agents in the preparation process in order to achieve process savings while improving performance. Summary of the invention

[0008] The present invention aims at the problems existing in the prior art and provides a polyvinyl alcohol sponge particle for interventional treatment and a preparation method and application thereof. The preparation of the polyvinyl alcohol sponge particle of the present invention is to adjust the crosslinking degree of the water-soluble polymer material by effectively matching the raw material polyvinyl alcohol with a specific foaming agent, a catalyst and a crosslinking agent in an air foaming-catalytic curing system to form a porous polyvinyl alcohol sponge block, and then obtain the sponge particle by special freeze-drying treatment. The polyvinyl alcohol sponge particle has a short absorption time, a long suspension time, a significant catheter passing performance, and the performance is still stable after the aging test, and no blockage occurs when the catheter passes.

[0009] The technical solution of the present invention is as follows:

[0010] The present invention provides a polyvinyl alcohol sponge particle for interventional therapy, wherein the polyvinyl alcohol sponge particle is prepared from the following raw materials: polyvinyl alcohol, a foaming agent, a catalyst and a cross-linking agent;

[0011] The foaming agent is one or more of hydrogenated lecithin, poloxamer 188, polysorbate 80 and polysorbate 85;

[0012] The catalyst is one or more of hydrochloric acid, sulfuric acid, citric acid and tartaric acid;

[0013] The cross-linking agent is one or more of formaldehyde, n-butyraldehyde, glutaraldehyde, salicylaldehyde and 5-hydroxymethylfurfural;

[0014] The specific preparation method is as follows:

[0015] (1) adding polyvinyl alcohol and a foaming agent into water to prepare a polyvinyl alcohol solution and a foaming agent solution respectively;

[0016] (2) mixing the polyvinyl alcohol solution and the foaming agent solution, heating and stirring, and fully foaming;

[0017] (3) After the foaming is completed, a catalyst is added, mixed evenly, and the reaction is carried out by gradually reducing the temperature and stirring speed of the reaction system;

[0018] (4) finally adding a crosslinking agent, stirring and dispersing, and heat-insulating and curing;

[0019] (5) after the curing is completed, the reaction solution is neutralized and filtered to obtain a polyvinyl alcohol sponge;

[0020] (6) washing, crushing and drying the polyvinyl alcohol sponge to obtain the polyvinyl alcohol sponge particles;

[0021] The mass percentage of polyvinyl alcohol in the polyvinyl alcohol solution is 5 to 15%;

[0022] In step (6), the drying is specifically: mixing the washed and crushed polyvinyl alcohol sponge with water and then freeze-drying it.

[0023] Furthermore, the volume ratio of the polyvinyl alcohol sponge to water is 1:2-5.

[0024] Furthermore, the mass ratio of the polyvinyl alcohol, the foaming agent, the catalyst and the cross-linking agent is 1:0.05-0.3:1.5-3.5:0.7-1.8.

[0025] Furthermore, the molecular weight of the polyvinyl alcohol is 50,000-250,000, and the alcoholysis degree is ≥80%.

[0026] The present invention also provides a method for preparing polyvinyl alcohol sponge particles, comprising the following steps:

[0027] (1) adding polyvinyl alcohol and a foaming agent into water to prepare a polyvinyl alcohol solution and a foaming agent solution respectively;

[0028] (2) mixing the polyvinyl alcohol solution and the foaming agent solution, heating and stirring, and fully foaming;

[0029] (3) After the foaming is completed, add the catalyst, stir and mix evenly, and react by gradually reducing the temperature and stirring speed of the reaction system;

[0030] (4) finally adding a crosslinking agent, stirring and dispersing, and heat-insulating and curing;

[0031] (5) after the curing is completed, the reaction solution is neutralized and filtered to obtain a polyvinyl alcohol sponge;

[0032] (6) Washing, crushing and drying the polyvinyl alcohol sponge to obtain the polyvinyl alcohol sponge particles.

[0033] Furthermore, the mass proportion of polyvinyl alcohol in the polyvinyl alcohol solution is 5-15%.

[0034] Furthermore, the amount of the catalyst is 10-60% of the total mass of the polyvinyl alcohol and the foaming agent.

[0035] Furthermore, in step (2), the heating temperature is 50-90° C., the stirring speed is 200-800 rpm, and the foaming time is 15-120 min.

[0036] Furthermore, in step (3), the temperature is reduced by 5 to 10° C. every 10 to 20 minutes until it drops to 25 to 45° C.; and the stirring speed is reduced by 30 to 150 rpm every 5 to 30 minutes until it drops to 100 to 300 rpm.

[0037] Furthermore, in step (4), the insulation temperature is 25 to 45° C., and the insulation time is 12 to 36 hours.

[0038] Furthermore, in step (5), an alkaline substance is used to neutralize the reaction solution, and the alkaline substance is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate.

[0039] In some specific embodiments of the present invention, the device used for filtering in step (5) includes, but is not limited to: a centrifugal dehydrator, a bag filter, a filter press or a vacuum filter.

[0040] Furthermore, in step (6), the drying is specifically: mixing the washed and crushed polyvinyl alcohol sponge with water and then freeze-drying it.

[0041] Furthermore, the volume ratio of the polyvinyl alcohol sponge to water is 1:2-5.

[0042] Furthermore, the freeze drying is divided into a pre-freezing stage, a primary drying stage and a parsing drying stage.

[0043] In some preferred embodiments of the present invention, the initial temperature of the pre-freezing stage is -30°C to -40°C, and the pre-freezing holding time is 1 to 3 hours; then the temperature is raised to -15°C and maintained for 2 to 6 hours, and the vacuum degree is 40 to 80Pa.

[0044] In some preferred embodiments of the present invention, the initial temperature of the primary drying stage is -10 to -5°C, maintained for 2 to 8 hours, and the vacuum degree is 200 to 250 Pa.

[0045] In some preferred embodiments of the present invention, the temperature of the analytical drying stage is -5 to 5°C

[0046] In some preferred embodiments of the present invention, the starting temperature of the analytical drying stage is 0°C, maintained for 2 to 8 hours, and the vacuum degree is 200 to 250Pa; then the temperature is raised to 5-10°C, maintained for 6 to 15 hours, and the vacuum degree is 200 to 250Pa; then the temperature is raised by 5 to 10°C each time, maintained for 1 to 6 hours, and the vacuum degree is 200 to 250Pa; until the temperature is raised to 35°C, maintained for 2 to 6 hours, and the vacuum degree is 150 to 200Pa; finally, the temperature is raised to 37 to 50°C, maintained for 10 to 25 hours, and the vacuum degree is 0Pa.

[0047] In some preferred embodiments of the present invention, the heating rate during the entire freeze-drying process is 0.2-0.5°C / min.

[0048] In some specific embodiments of the present invention, the device used for pulverization in step (6) includes, but is not limited to: liquid nitrogen low-temperature freezing pulverization, knife mill, ball mill or air flow mill.

[0049] The invention also provides an application of polyvinyl alcohol sponge particles in embolic materials for interventional treatment.

[0050] Furthermore, the embolic material for interventional therapy includes any one of embolic materials for tumor, cardiovascular and nerve.

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] The raw material polyvinyl alcohol of the polyvinyl alcohol sponge particles of the present invention is non-toxic and non-irritating, and has excellent flexibility, ductility and biocompatibility. It can form a uniform chemical cross-linked structure and have suspension performance by combining with a specific foaming agent, a catalyst and a cross-linking agent, and controlling the concentration of the raw material itself. At the same time, a special drying method is adopted in the preparation process, and the obtained polyvinyl alcohol sponge particles have the characteristics of short absorption time, long suspension time, etc., and also have excellent catheter passing performance, meeting the clinical use requirements.

[0053] After aging for 90 days under the conditions of TAA=60° C. and relative humidity 60% RH, the absorption performance, suspension performance and catheter passing performance of the polyvinyl alcohol sponge particles of the present invention remain substantially unchanged, and the particles have excellent aging resistance.

[0054] The polyvinyl alcohol sponge particles of the present invention can be screened into different particle size ranges such as 50-150 μm, 100-300 μm, 250-400 μm, 300-500 μm, 500-700 μm, 700-1000 μm, 1000-1400 μm, 1400-2000 μm, 2000-2500 μm, etc., and can occlude tumor blood vessels of different calibers and different flow rates as needed, and have high practicality.

[0055] The polyvinyl alcohol sponge particles of the invention have simple process and easy-to-control operation conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 This is a microscopic image of the polyvinyl alcohol sponge particles after passing through the catheter in Example 1 of the present invention;

[0057] Figure 2 This is a microscopic image of the polyvinyl alcohol sponge particles after passing through the catheter in Comparative Example 6 of the present invention;

[0058] Figure 3 This is an image after delivery through a catheter in Example 1 of the present invention;

[0059] Figure 4 This is an image of comparative example 6 of the present invention after delivery through a catheter;

[0060] Figure 5 This is a schematic diagram of the implantation sites of the test article and the control article in Test Example 3 of the present invention. DETAILED DESCRIPTION

[0061] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited.

[0062] Example 1

[0063] A polyvinyl alcohol sponge wet granule, the preparation method is as follows:

[0064] (1) 1500 g of polyvinyl alcohol (molecular weight of 70,000-90,000, alcoholysis degree of 88%) was added to pure water, and the solution was stirred at 90° C. to obtain a polyvinyl alcohol solution (the mass percentage of polyvinyl alcohol was 10%);

[0065] (2) taking 225 g of hydrogenated lecithin and adding it into water to dissolve it, thereby obtaining a hydrogenated lecithin solution (the mass ratio of hydrogenated lecithin to polyvinyl alcohol is 0.15:1);

[0066] (3) Add the polyvinyl alcohol solution and the hydrogenated lecithin solution into the reaction kettle, raise the temperature to 75° C., stir at 500 rpm, and foam for 90 min;

[0067] (4) Measure 7500 mL of 37% hydrochloric acid and dilute it to 10000 mL (mass ratio of hydrochloric acid to polyvinyl alcohol: 2.2:1), add it to the reactor after cooling, continue stirring for 15 min, then reduce the temperature by 10°C and the rotation speed by 80 rpm every 20 min until the temperature drops to 35°C, and the stirring speed is 180 r / min;

[0068] (5) 1800 mL of formaldehyde (mass ratio of formaldehyde to polyvinyl alcohol: 0.8:1) was added to the reactor, stirred and dispersed for 20 min, then the stirring was stopped and the mixture was kept warm for 20 h;

[0069] (6) adding sodium bicarbonate solution to the reaction kettle to neutralize the reaction system, filtering out the reaction solution, taking out the sponge block, rinsing it several times, cutting it into small pieces using ceramic scissors, and pre-rinsing it in water;

[0070] (7) collecting small pieces of sponge and subjecting them to cryogenic freezing and pulverization by liquid nitrogen, collecting the pulverized sponge particles, dispersing the sponge particles in water, stirring and washing them several times, and filtering out water using a centrifugal dehydrator;

[0071] (8) freeze-drying the wet polyvinyl alcohol sponge particles at a volume ratio of 1:3 to water at a loading thickness of 10 mm to obtain the wet polyvinyl alcohol sponge particles;

[0072] Freeze drying parameters were as follows:

[0073] ① Pre-freezing stage: cool down to the pre-freezing temperature of -35℃ at a cooling rate of 0.5℃ / min, and keep the pre-freezing time for 2.5h; then heat up to -15℃ at a rate of 0.5℃ / min, keep for 2h, and the vacuum degree is 40Pa;

[0074] ② Primary drying stage: heating to -5℃ at a heating rate of 0.2℃ / min, holding time for 5h, vacuum degree 250Pa;

[0075] ③Analysis and drying stage: heat up to 0℃ at a heating rate of 0.5℃ / min, hold for 8h, vacuum degree 250Pa; then heat up to 5℃ at a rate of 0.5℃ / min, hold for 12h, vacuum degree 250Pa; then heat up at a rate of 0.25℃ / min, hold for 3h every time the temperature rises by 10℃, vacuum degree 250Pa; until the temperature rises to 35℃, hold for 6h, vacuum degree 150Pa; finally, heat up to 40℃ at a heating rate of 0.25℃ / min, hold for 15h, vacuum degree 0Pa.

[0076] Example 2

[0077] A polyvinyl alcohol sponge wet granule, the preparation method is as follows:

[0078] (1) 1200 g of polyvinyl alcohol (molecular weight of 90,000-120,000, alcoholysis degree of 88%) was added to pure water, and the solution was stirred at 90° C. to obtain a polyvinyl alcohol solution (the mass percentage of polyvinyl alcohol was 8%);

[0079] (2) taking 150 g of polysorbate 85 and adding it into water to dissolve it, thereby obtaining a polysorbate 85 solution (the mass ratio of polysorbate 85 to polyvinyl alcohol is 0.125:1);

[0080] (3) Add the polyvinyl alcohol solution and the polysorbate 85 solution into the reaction kettle, raise the temperature to 70°C, stir at 300 rpm, and foam for 60 min;

[0081] (4) Measure 2000 mL of sulfuric acid to prepare 10000 mL of 20% sulfuric acid solution (mass ratio of sulfuric acid to polyvinyl alcohol: 3.1:1), add it to the reactor after cooling, and continue stirring for 15 min. Then, reduce the temperature by 5°C and the rotation speed by 40 rpm every 15 min until the temperature drops to 30°C, and the stirring speed is 140 r / min;

[0082] (5) 1800 mL of glutaraldehyde (mass ratio of glutaraldehyde to polyvinyl alcohol: 1.5:1) was added to the reaction kettle, stirred and dispersed for 20 min, then the stirring was stopped and the mixture was kept warm for 30 h;

[0083] (6) adding sodium hydroxide solution to the reaction kettle to neutralize the reaction system, filtering out the reaction solution, taking out the sponge block, rinsing it several times, cutting it into small pieces using ceramic scissors, and pre-rinsing it in water;

[0084] (7) collecting small pieces of sponge and crushing them with a ball mill, collecting the crushed sponge particles, dispersing the sponge particles in water, stirring and washing them several times, and filtering out water with a vacuum filter;

[0085] (8) freeze-drying the wet polyvinyl alcohol sponge particles at a volume ratio of 1:2 to water at a loading thickness of 10 mm to obtain the wet polyvinyl alcohol sponge particles;

[0086] Freeze drying parameters were as follows:

[0087] ① Pre-freezing stage: cool down to the pre-freezing temperature of -40℃ at a cooling rate of 0.5℃ / min, and keep the pre-freezing time for 1.5h; then heat up to -15℃ at a rate of 0.2℃ / min, keep for 4h, and the vacuum degree is 80Pa;

[0088] ② Primary drying stage: heating to -5°C at a heating rate of 0.5°C / min, holding time for 3h, vacuum degree 200Pa;

[0089] ③ Analytical drying stage: Heat at a rate of 0.2 °C / min to 0 °C, hold for 3 h with a vacuum of 200 Pa; then heat at a rate of 0.2 °C / min to 5 °C, hold for 8 h with a vacuum of 200 Pa; then heat at a rate of 0.25 °C / min, hold for 2 h at every 5 °C increase with a vacuum of 200 Pa until the temperature reaches 35 °C, hold for 2 h with a vacuum of 180 Pa; finally, heat at a rate of 0.5 °C / min to 45 °C, hold for another 12 h with a vacuum of 0 Pa.

[0090] Example 3

[0091] A wet granule of polyvinyl alcohol sponge is prepared as follows:

[0092] (1) Take 2250 g of polyvinyl alcohol (molecular weight 70,000 - 100,000, degree of alcoholysis 94%) and add it to pure water, stir the solution at 85 °C to obtain a polyvinyl alcohol solution (mass percentage of polyvinyl alcohol is 15%);

[0093] (2) Take 135 g of polysorbate 80 and dissolve it in water to obtain a polysorbate 80 solution (mass ratio of polysorbate 80 to polyvinyl alcohol is 0.06:1);

[0094] (3) Add the polyvinyl alcohol solution and the polysorbate 80 solution to the reaction kettle, heat to 75 °C, stir at a speed of 500 rpm, and foam for 90 min;

[0095] (4) Measure 4000 g of citric acid and add it to water to prepare a 30% citric acid solution of 12000 mL (mass ratio of citric acid to polyvinyl alcohol is 1.78:1), cool it and add it to the reaction kettle, continuously stir for 30 min, then reduce the temperature by 5 °C every 10 min and reduce the rotation speed by 100 rpm until the temperature drops to 30 °C and the stirring speed is 100 r / min;

[0096] (5) Measure 1800 mL of n-butyraldehyde (mass ratio of n-butyraldehyde to polyvinyl alcohol is 1.8:1) and add it to the reaction kettle, stir and disperse for 20 min, then stop stirring and keep warm for 15 h;

[0097] (6) Add potassium carbonate solution to the reaction kettle to neutralize the reaction system, filter the reaction solution, take out the sponge block, wash it many times, cut it into small sponge pieces with a ceramic scissors, and soak and pre-wash it in water;

[0098] (7) Collect the small sponge pieces and crush them with a knife mill, collect the crushed sponge particles, disperse the sponge particles in water and stir and wash them many times, and filter out the water with a vacuum filter;

[0099] (8) freeze-drying the wet polyvinyl alcohol sponge particles at a volume ratio of 1:2 to water at a loading thickness of 15 mm to obtain the wet polyvinyl alcohol sponge particles;

[0100] Freeze drying parameters were as follows:

[0101] ① Pre-freezing stage: cool down to the pre-freezing temperature of -35℃ at a cooling rate of 0.5℃ / min, and keep the pre-freezing time for 3h; then heat up to -15℃ at a rate of 0.4℃ / min, keep for 5h, and the vacuum degree is 50Pa;

[0102] ② Primary drying stage: heating to -5℃ at a heating rate of 0.2℃ / min, holding time for 6h, vacuum degree 250Pa;

[0103] ③Analysis and drying stage: heat up to 0℃ at a heating rate of 0.2℃ / min, hold for 2h, vacuum degree 250Pa; then heat up to 5℃ at a rate of 0.5℃ / min, hold for 15h, vacuum degree 250Pa; then heat up at a rate of 0.5℃ / min, hold for 2h every time the temperature rises by 10℃, vacuum degree 250Pa; until the temperature rises to 35℃, hold for 6h, vacuum degree 150Pa; finally, heat up to 40℃ at a heating rate of 0.5℃ / min, hold for 12h, vacuum degree 0Pa.

[0104] Comparative Example 1

[0105] A polyvinyl alcohol sponge wet granule, the preparation method is as follows:

[0106] On the basis of Example 1, the 10% by mass polyvinyl alcohol solution is replaced with a 20% by mass polyvinyl alcohol solution, specifically: 1500g of polyvinyl alcohol is added to pure water, and the solution is stirred at 90°C to obtain a polyvinyl alcohol solution (the mass percentage of polyvinyl alcohol is 20%); the other steps are the same as in Example 1.

[0107] Comparative Example 2

[0108] A polyvinyl alcohol sponge wet granule, the preparation method is as follows:

[0109] On the basis of Example 1, the foaming agent is replaced with an equal mass of polyoxyethylene lauryl ether; specifically: 225g of polyoxyethylene lauryl ether is added into water and dissolved to obtain a polyoxyethylene lauryl ether solution (the mass percentage of polyoxyethylene lauryl ether is 1.5%); the other steps are the same as Example 1.

[0110] Comparative Example 3

[0111] A polyvinyl alcohol sponge wet granule, the preparation method is as follows:

[0112] On the basis of Example 1, the catalyst was replaced with a salicylic acid solution having the same mass concentration; specifically: 3300 g of salicylic acid was measured and formulated into 11000 mL of 30% salicylic acid solution (the mass ratio of salicylic acid to polyvinyl alcohol was 2.2:1); other steps were the same as in Example 1.

[0113] Comparative Example 4

[0114] A kind of wet polyvinyl alcohol sponge particles, the preparation method is as follows:

[0115] On the basis of Example 1, the crosslinking agent was replaced with an equal mass of vanillin; specifically: 1800 mL of vanillin solution (the mass ratio of vanillin to polyvinyl alcohol was 0.8:1) was added to the reaction kettle, stirred and dispersed for 20 min, then stirring was stopped and kept warm for 20 h; other steps were the same as in Example 1.

[0116] Comparative Example 5

[0117] A kind of wet polyvinyl alcohol sponge particles, the preparation method is as follows:

[0118] On the basis of Example 1, when the wet polyvinyl alcohol sponge particles were freeze-dried, water was not added, but the wet polyvinyl alcohol sponge particles were directly placed on the freezing tray and the freeze-drying procedure was carried out; other steps were the same as in Example 1.

[0119] Comparative Example 6

[0120] Commercially available competing polyvinyl alcohol particle embolization agents with a specification of 150 - 350 μm.

[0121] Test Example 1: Absorption, suspension and passing performance tests

[0122] (1) Test method for the absorption time of polyvinyl alcohol sponge particles:

[0123] The polyvinyl alcohol sponge particles prepared in the above-mentioned examples and comparative examples were screened, and the target particle size range was 150 - 350 μm. 100 mg of the screened sponge particles and 10 mL of contrast agent solution (the mass ratio of normal saline to iodixanol was 1:1) were added to a 20 mL syringe, the air was discharged from the syringe, the syringe plug was connected, the syringe was placed vertically and still, and the timing was started. When the color of the sponge particles changed from white to translucent completely, it was considered that the sponge particles were completely infiltrated, which was taken as the end point for measuring the absorption time, and this process was recorded as the absorption time.

[0124] (2) Test method for the suspension time of polyvinyl alcohol sponge particles:

[0125] Take the polyvinyl alcohol sponge particle syringe that has completed the absorption time measurement in (1), shake it vigorously 20 times within 10 seconds, and then let it stand for inspection. If no suspension is formed, that is, the suspension state is not reached (the microspheres are uniformly dispersed in the mixed waves and are considered to be in a suspended state), repeat the shaking and inspection until a suspension is observed, start timing, and continue to let the syringe stand until the suspension state disappears, then stop timing, and this time is recorded as the suspension time.

[0126] (3) Polyvinyl alcohol sponge particle catheter performance test method:

[0127] After the polyvinyl alcohol sponge particles in the syringe in (2) reach a suspended state again, connect the syringe to a 1mL syringe and a 1.7F catheter through a three-way valve, inject the particles into the 1mL syringe through the three-way valve, and then pass the particles through the catheter in a pulsed manner (the test needs to be performed under a catheter that simulates the curvature of human blood vessels). Observe whether the catheter is blocked during the transportation of the sponge particles, collect the particles after passing through the catheter, observe the particle morphology under a microscope, and examine the catheter passing performance.

[0128] The above tests were performed on the polyvinyl alcohol sponge particles prepared in the comparative examples of the embodiments, and the test results are summarized in Table 1.

[0129] Table 1 Test results of polyvinyl alcohol sponge embolization particle absorption time, suspension time, and catheter passing performance

[0130]

[0131]

[0132] Note: “ / ” indicates that it is impossible to obtain sponge particles with uniform performance and thus the absorption time test is not conducted, or it is impossible to achieve a suspension state and thus the catheter passing performance test is not conducted.

[0133] It can be seen from Table 1 that the absorption time, suspension time and catheter passing performance of the polyvinyl alcohol sponge embolic particles prepared in Examples 1 to 3 are all relatively good and have little difference; this indicates that the polyvinyl alcohol sponge particles prepared by the specific concentration of polyvinyl alcohol solution of the present invention in the cooperation of a specific foaming agent, a catalyst and a cross-linking agent have a shorter absorption time, a longer suspension time, and smooth catheter transportation without blockage, which can meet the use requirements; and there is no need to use auxiliary foaming agents, uniform foaming agents, foam stabilizers and emulsifiers, etc., the raw materials are simpler, and while saving costs and simplifying the process, a significant improvement in comprehensive performance is achieved.

[0134] Compared with Example 1, the polyvinyl alcohol content in Comparative Example 1 is increased, the product is colloid, has a compact structure, and has poor elastic recovery performance, resulting in an increase in its absorption time. In addition, the polyvinyl alcohol sponge particles can never reach a suspended state, floating above the liquid surface of the contrast agent solution, and because they cannot reach a suspended state, their catheter delivery cannot proceed smoothly.

[0135] Compared with Example 1, in Comparative Example 2, the foaming agent replaces hydrogenated lecithin with polyoxyethylene lauryl ether, and the foaming performance is slightly poor. The product is stratified, with the lower layer being dense and compact and the upper layer being loose and porous, and sponge particles with uniform performance cannot be obtained. Therefore, the suspension performance and catheter passing performance tests were not carried out.

[0136] Compared with Example 1, in Comparative Example 3, the catalyst hydrochloric acid solution was replaced with a salicylic acid solution, and the resulting sponge was relatively loose. Although the absorption time was faster, the suspension time was shorter. Multiple shaking was required during the delivery via the catheter, but no catheter blockage occurred during the delivery process.

[0137] Compared with Example 1, in Comparative Example 4, the cross-linking agent formaldehyde is replaced with vanillin, and the obtained sponge is relatively loose. Although the absorption time is faster, the suspension time is short. Multiple shaking is required during the delivery through the catheter, but there is no clogging of the catheter during the delivery process.

[0138] Compared with Example 1, in Comparative Example 5, the wet polyvinyl alcohol sponge particles were directly freeze-dried without adding water. The obtained sponge was denser and had a longer elastic compression recovery time. Although the absorption time was faster, the suspension time was longer. Multiple shaking was required during the catheter transportation process, and the catheter was blocked during the transportation process.

[0139] In addition, the morphology of the polyethylene sponge embolic particles of Example 1 of the present invention and the competitive polyvinyl alcohol granule embolic agent of Comparative Example 6 was observed by microscope. Figure 1 and Figure 2 The polyvinyl alcohol sponge particles prepared by the present invention have a morphology after being transported through a catheter. Figure 1 As shown in the figure, the particles have changed significantly; however, the commercially available product has blocked the catheter during delivery through the catheter. After the blockage, the particles that were cleared by multiple suction and pulling of the syringe were observed under a microscope, and obvious extrusion and merging of the particles were observed, such as Figure 2 shown.

[0140] The blockage of the polyethylene sponge embolic particles of Example 1 of the present invention and the competitive polyvinyl alcohol granule embolic agent of Comparative Example 6 after delivery through the catheter was compared. Figure 3 and Figure 4It can be seen that the competitor's polyvinyl alcohol granule embolic agent of comparative example 6 had obvious blockage after being delivered through the catheter, while the polyethylene sponge embolic particles of Example 1 of the present invention did not remain in the catheter and had excellent passing performance.

[0141] Test Example 2: Aging Performance Test

[0142] The particles of Example 1 were freeze-dried and sieved to obtain sponge particles with a particle size range of 150-350 μm. The sponge particles of Example 1 and Comparative Example 6 were respectively packed into 20 mL syringes at a filling amount of 100 mg / tube, and then placed in a comprehensive drug stability test box for aging for 90 days at TAA = 60°C and relative humidity 60% RH. The results are shown in Table 2.

[0143] Table 2 Comparison of absorption, suspension and catheter passing performance before and after aging

[0144]

[0145] As can be seen from the above table, after 90 days of accelerated aging, the absorption time and suspension time of the polyvinyl alcohol sponge particles in Example 1 were basically the same as before aging, and there was no clogging of the catheter during the catheter delivery process. In Comparative Example 6, the commercially available polyvinyl alcohol granule embolic agent with a specification of 150-350 μm was accelerated aged for 90 days, and the absorption time and suspension time were basically the same as before aging, but the catheter was still blocked during the catheter delivery process. It can be judged that the long-term storage of the polyvinyl alcohol sponge particles prepared by the present invention will not affect its absorption time, suspension time and catheter delivery capacity. Compared with the competing polyvinyl alcohol granule embolic agent, the catheter delivery performance of the polyvinyl alcohol sponge particles prepared by the present invention is significantly improved.

[0146] Test Example 3: Safety Test

[0147] In order to evaluate the safety of the test article, referring to GB / T16886.6-2022 Biological Evaluation of Medical Devices Part 6: Local Reaction Experiment after Implantation, the test article and the control article were implanted in the paraspinal muscles of the animals. Specifically, 3 New Zealand white rabbits (numbered 1001-1003) were implanted with a total of 12 test article (polyvinyl alcohol sponge particles prepared in Example 1, the implantation sites correspond to T1-T4) implantation sites and 12 control article (competitor polyvinyl alcohol particle embolic agent of Comparative Example 6, the implantation sites correspond to C1-C4) implantation sites. Each New Zealand white rabbit implantation site was as follows: Figure 5 After the implantation period, the animals were euthanized, and the implantation sites were exposed by autopsy. All implantation sites were collected and fixed for gross pathological observation and histopathological evaluation according to Table 3. The evaluation results are shown in Table 4.

[0148] Table 3 Grading table of local reaction after implantation

[0149] Final response score (points) Grading 0-2.9 No irritation or very slight irritation 3.0-8.9 Mild irritation 9.0-15.0 Moderate stimulation ≥15.1 Severe stimulation

[0150] Table 4 Results of local reaction degree after implantation

[0151] Score(points) Grading Example 1 0 No irritation or slight irritation Comparative Example 6 0 No irritation or slight irritation

[0152] All New Zealand white rabbits in this study survived until the end of the study. No abnormal clinical symptoms or weight changes were found during the observation period, and no macroscopic changes were observed in the planned autopsy.

[0153] After histopathological examination, the final reaction scores of the implantation sites of Example 1 and Comparative Example 6 were both: 0; the reaction grades were all: no irritation or very slight irritation; it can be seen that the polyvinyl alcohol sponge particles prepared by the present invention have the same safety as commercially available competing products.

[0154] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A polyvinyl alcohol sponge particle for interventional therapy, characterized in that: The polyvinyl alcohol sponge particles are prepared from the following raw materials: polyvinyl alcohol, a foaming agent, a catalyst and a cross-linking agent; The foaming agent is one or more of hydrogenated lecithin, poloxamer 188, polysorbate 80 and polysorbate 85; The catalyst is one or more of hydrochloric acid, sulfuric acid, citric acid and tartaric acid; The cross-linking agent is one or more of formaldehyde, n-butyraldehyde, glutaraldehyde, salicylaldehyde and 5-hydroxymethylfurfural; The specific preparation method is as follows: (1) adding polyvinyl alcohol and a foaming agent into water to prepare a polyvinyl alcohol solution and a foaming agent solution respectively; (2) mixing the polyvinyl alcohol solution and the foaming agent solution, heating and stirring, and fully foaming; (3) After the foaming is completed, a catalyst is added, mixed evenly, and the reaction is carried out by gradually reducing the temperature and stirring speed of the reaction system; (4) finally adding a crosslinking agent, stirring and dispersing, and heat-insulating and curing; (5) after the curing is completed, the reaction solution is neutralized and filtered to obtain a polyvinyl alcohol sponge; (6) washing, crushing and drying the polyvinyl alcohol sponge to obtain the polyvinyl alcohol sponge particles; The mass percentage of polyvinyl alcohol in the polyvinyl alcohol solution is 5 to 15%; In step (6), the drying is specifically: mixing the washed and crushed polyvinyl alcohol sponge with water and then freeze-drying it.

2. The polyvinyl alcohol sponge particles for interventional therapy according to claim 1, characterized in that: The mass ratio of the polyvinyl alcohol, the foaming agent, the catalyst and the cross-linking agent is 1: 0.05-0.3: 1.5-3.5: 0.7-1.8; And / or the molecular weight of the polyvinyl alcohol is 50,000-250,000, and the alcoholysis degree is ≥80%.

3. The polyvinyl alcohol sponge particles for interventional treatment according to claim 1, characterized in that: In step (6), the volume ratio of the polyvinyl alcohol sponge to water is 1:2-5.

4. The method for preparing polyvinyl alcohol sponge particles for interventional therapy according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) adding polyvinyl alcohol and a foaming agent into water to prepare a polyvinyl alcohol solution and a foaming agent solution respectively; (2) mixing the polyvinyl alcohol solution and the foaming agent solution, heating and stirring, and fully foaming; (3) After the foaming is completed, add the catalyst, stir and mix evenly, and react by gradually reducing the temperature and stirring speed of the reaction system; (4) finally adding a crosslinking agent, stirring and dispersing, and heat-insulating and curing; (5) after the curing is completed, the reaction solution is neutralized and filtered to obtain a polyvinyl alcohol sponge; (6) Washing, crushing and drying the polyvinyl alcohol sponge to obtain the polyvinyl alcohol sponge particles.

5. The preparation method according to claim 4, characterized in that: The weight percentage of polyvinyl alcohol in the polyvinyl alcohol solution is 5-15%; the amount of the catalyst is 10-60% of the total weight of the polyvinyl alcohol and the foaming agent.

6. The preparation method according to claim 4, characterized in that: In step (2), the heating temperature is 50-90° C., the stirring speed is 200-800 rpm, and the foaming time is 15-120 min; and / or In step (3), the step of gradually reducing the temperature and stirring speed of the reaction system is as follows: the temperature is reduced by 5 to 10°C every 10 to 20 minutes until it drops to 25 to 45°C; the stirring speed is reduced by 30 to 150 rpm every 5 to 30 minutes until it drops to 100 to 300 rpm; and / or In step (4), the insulation temperature is 25 to 45° C. and the insulation time is 12 to 36 hours.

7. The preparation method according to claim 4, characterized in that: In step (6), the drying is specifically: mixing the washed and crushed polyvinyl alcohol sponge with water and then freeze-drying; preferably, the volume ratio of the polyvinyl alcohol sponge to water is 1:2-5.

8. The preparation method according to claim 7, characterized in that: The freeze drying is divided into a pre-freezing stage, a primary drying stage and a desorption drying stage; the initial temperature of the pre-freezing stage is -30°C to -40°C, the initial temperature of the primary drying stage is -10 to -5°C, the starting temperature of the desorption drying stage is -5 to 5°C, and the terminal temperature is 37°C to 50°C.

9. Use of polyvinyl alcohol sponge particles in embolic materials for interventional therapy, characterized in that: The polyvinyl alcohol sponge particles are the polyvinyl alcohol sponge particles described in any one of claims 1 to 3 or the polyvinyl alcohol sponge particles prepared by the preparation method described in any one of claims 4 to 8.

10. The use according to claim 9, characterized in that: The embolic material for interventional therapy includes any one of embolic materials for tumor, cardiovascular and nerve.

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