A modified filler for hemoperfusion and its preparation method

Abstract

The present invention relates to the technical field of hemoperfusion, and particularly relates to a modified filler for hemoperfusion and a preparation method thereof, including: S1. Performing argon plasma coating on pretreated polystyrene resin to obtain plasma-coated resin; S2. Adding the plasma-coated resin into an acrylic acid solution and irradiating with ultraviolet light to obtain modified plasma-coated resin; S3. Dispersing 6-monamino-β-cyclodextrin in an ethanol aqueous solution, adding phenyl isothiocyanate and triethylamine, and reacting to obtain modified cyclodextrin; S4. Mixing the modified cyclodextrin, the modified plasma-coated resin and potassium dihydrogen phosphate uniformly in deionized water, heating and reacting, and after the reaction is completed, washing and drying to obtain the modified filler for hemoperfusion. The modified filler for hemoperfusion prepared by the present invention can improve the clearance rate of uric acid, and at the same time has little influence on other substance components in the blood, and has stronger specificity.

Description

Technical Field

[0001] The present invention relates to the technical field of hemoperfusion, and particularly relates to a modified filler for hemoperfusion and a preparation method thereof. Background Art

[0002] Hyperuricemia is a common metabolic disease, which is mainly caused by excessive production and insufficient excretion of uric acid in the body. The reasons for excessive production of uric acid in the body include congenital purine metabolism disorders, as well as secondary hyperuricemia caused by kidney diseases and myeloproliferative diseases. Reduced glomerular filtration rate, increased tubular reabsorption, and impaired tubular secretion function are the main reasons for reduced uric acid excretion. Long-term hyperuricemia can cause acute gouty arthritis, form uric acid stones in the urinary system, and cause renal colic, hematuria, and acute renal failure after obstruction. Oral medications are currently the main treatment means for hyperuricemia, and the principle is to reduce the production of uric acid, promote the excretion of uric acid, and inhibit the reabsorption of uric acid to reduce the uric acid concentration in the body to achieve the treatment purpose. However, the curative effects of these medications are unstable, the individual differences are obvious, and the toxic and side effects of some medications are difficult to avoid, especially the greater impact on liver and kidney functions. These factors limit the clinical treatment.

[0003] Hemoperfusion is a blood purification technology that introduces the patient's blood into a hemoperfusion device filled with solid adsorbents, and through the adsorption effect, removes exogenous or endogenous toxins, drugs, or metabolites that cannot be removed by dialysis in the blood. It is mainly used for rescuing drug and poison poisoning, and can also be combined with hemodialysis to remove macromolecular toxins in the body of maintenance dialysis patients with chronic renal failure. Since the adsorbent materials filled inside are all polystyrene resins or activated carbon, currently most rely on the direct supply of suppliers, and there is less independent research and development by users. The types of substances that the adsorbent can adsorb are limited, and the molecular weight of the adsorbed substances cannot be accurately controlled, so most hemoperfusion devices are non-specific adsorption. During the clinical use of hemoperfusion devices, it often occurs that while effectively adsorbing certain pathogenic substances, other body fluid components with similar molecular weights are also adsorbed together, resulting in the loss of beneficial body fluid components in the human body and causing some potential health risks.

[0004] Currently, some users have made different degrees of modification and reprocessing to the solid adsorbents, but the filler substrate is still limited by the product properties of the resin suppliers themselves, and it is difficult to flexibly select in actual clinical applications. At the same time, the filler substrate batches provided by most existing adsorbent suppliers have large differences, the biocompatibility is unstable, the contact between the filler and harmful substances in the blood is incomplete, and the adsorption efficiency is not high. Moreover, when chemically modifying the resin by the modification or modification methods in the prior art, various chemical reagents will be introduced. Some of the reagents are toxic and harmful or chemically unstable, and the problem of biocompatibility has not been well solved. Summary of the Invention

[0005] In view of this, the present invention provides a modified filler for hemoperfusion and a preparation method thereof to solve the problems of low adsorption efficiency and poor biocompatibility of resin adsorbents in hemoperfusion in the prior art.

[0006] The technical solution of the present invention is realized as follows:

[0007] In the first aspect, the present invention provides a preparation method of a modified filler for hemoperfusion, including the following preparation steps:

[0008] S1. Ultrasonically pretreat the polystyrene resin, place the pretreated polystyrene resin in a plasma coating machine, perform argon plasma coating, and after the coating is completed, react with air for 25 - 35 min to obtain plasma-coated resin;

[0009] S2. Add the plasma-coated resin into an acrylic acid solution and irradiate it with ultraviolet light to obtain a modified plasma-coated resin;

[0010] S3. Disperse 6 - monoamino-β-cyclodextrin in an ethanol aqueous solution, add phenyl isothiocyanate and triethylamine, react at room temperature for 20 - 24 h, after the reaction is completed, perform rotary evaporation under reduced pressure, and separate the obtained solid by a silica gel column with ethyl acetate as the eluent to obtain modified cyclodextrin;

[0011] S4. Mix the modified cyclodextrin, the modified plasma-coated resin and potassium dihydrogen phosphate uniformly in deionized water, heat and react at 130 - 140 °C for 3 - 4 h, and after the reaction is completed, wash and dry to obtain the modified filler for hemoperfusion.

[0012] In the present invention, acrylic acid is grafted and polymerized on the surface of the resin filler by plasma coating and ultraviolet light induction methods to improve the selective adsorption of uric acid. 6 - monoamino-β-cyclodextrin reacts with phenyl isothiocyanate to form a modified cyclodextrin containing a thiourea group, further increasing the affinity for uric acid. The modified cyclodextrin is fixed on the resin surface, and through the synergistic effect among cyclodextrin, thiourea group and polyacrylic acid, the adsorption capacity of the filler for uric acid is greatly improved. The modified filler for hemoperfusion prepared by the present invention significantly enhances the ability of the filler to remove uric acid through multiple mechanisms of physical adsorption and chemical adsorption.

[0013] Based on the above technical solution, preferably, the ultrasonic pretreatment in step S1 includes: ultrasonically cleaning the polystyrene resin with absolute ethanol, and the mass - volume ratio of the polystyrene resin to absolute ethanol is 3 g:3 - 5 mL.

[0014] Based on the above technical solutions, preferably, the polystyrene resin has a particle size of 0.5 - 1.2 mm; a pore diameter of 2 - 6 nm, a specific surface area ≥ 1200 m 2 / g, a pore volume ≥ 0.9 mL / g, and a wet apparent density of 0.7 - 0.8 g / mL.

[0015] Compared with traditional macroporous resins, the polystyrene resin has no macroporous structure and does not rely on the adsorption of the macroporous resin itself. Instead, it achieves affinity for substances such as uric acid through surface modification. This structural feature helps to improve hemodynamics and reduce the risk of thrombus formation.

[0016] Based on the above technical solutions, preferably, in step S1, the argon plasma coating includes the following steps: Place the pretreated polystyrene resin in a plasma coating machine. When the vacuum degree reaches 5×10 -3 Pa, introduce nitrogen into the ion source at a flow rate of 0.7 - 0.8 L / min for 15 - 25 min, heat the temperature to 130 - 170 °C, then stop introducing nitrogen, turn on the plasma power supply, and continuously introduce argon until the vacuum degree reaches 4×10 -2 Pa. Subsequently, adjust the ion current to 70 - 80 A, adjust the voltage to 150 V, and the coating time is 15 - 20 min.

[0017] Based on the above technical solutions, preferably, in step S2, the mass - to - volume ratio of the plasma - coated resin to the acrylic acid solution is 3 g:3 - 5 mL, the concentration of the acrylic acid solution is 0.2 - 0.3 mol / L, the power during the ultraviolet light irradiation is 25 - 35 W, and the wavelength is 365 nm.

[0018] First, use high - energy argon plasma to bombard the resin surface to produce physical sputtering, forming a highly active film. The argon plasma can remove the inert groups on the resin surface, generate free radicals or active sites, providing active groups for subsequent reactions; React with air for 25 - 35 minutes. The active sites on the resin surface react with oxygen to introduce oxygen - containing functional groups, improving the hydrophilicity and reaction activity of the resin surface. Then, graft - polymerize acrylic acid on the resin filler surface by ultraviolet - light - induced method to form a polyacrylic acid layer on the resin surface, increasing the affinity for uric acid; At the same time, form hydrogen bonds between the carboxyl group and the carbonyl group of uric acid to improve the selective adsorption of uric acid.

[0019] Based on the above technical solutions, preferably, in step S3, the mass ratio of 6 - monoamino - β - cyclodextrin, phenyl isothiocyanate, and triethylamine is 1:1.2 - 1.5:1.5 - 2.

[0020] By reacting 6 - monoamino - β - cyclodextrin with phenyl isothiocyanate, a modified cyclodextrin containing thiourea groups is formed. First, cyclodextrin has a tubular cavity structure, and the cavity size matches the size of uric acid molecules, so uric acid molecules can be effectively adsorbed through host - guest inclusion. Second, the thiourea groups can form hydrogen bonds with the hydroxyl groups and nitrogen atoms in uric acid molecules, further increasing the affinity for uric acid.

[0021] Based on the above - mentioned technical solutions, preferably, in step S4, the mass ratio of the modified cyclodextrin, the modified plasma - coated resin, and potassium dihydrogen phosphate is 1.8 - 2.2:1:0.4 - 0.6.

[0022] Based on the above - mentioned technical solutions, preferably, in step S4, the heating temperature is 130 - 140 °C, and the heating reaction time is 3 - 4 h.

[0023] Through the esterification cross - linking of the hydroxyl groups on the outer cavity of cyclodextrin with the carboxyl groups in the modified plasma - coated resin, the modified cyclodextrin is grafted onto the surface of the modified plasma - coated resin. Through the above - mentioned esterification cross - linking, on the one hand, the complete cavity structure of cyclodextrin can be maintained, promoting cyclodextrin to better adsorb uric acid molecules; on the other hand, the cyclodextrin, thiourea groups, and polyacrylic acid can act synergistically, greatly improving the adsorption capacity of the filler for uric acid.

[0024] In the second aspect, the present invention provides a modified filler for hemoperfusion prepared by the preparation method as described above.

[0025] In the third aspect, the present invention provides an application of a modified filler for hemoperfusion, and the modified filler for hemoperfusion is used in a hemoperfusion device.

[0026] The modified filler for hemoperfusion and its preparation method of the present invention have the following

[0027] Beneficial effects:

[0028] (1) The present invention uses a polystyrene resin without a macroporous structure as the substrate, and through multiple modifications on the resin surface, cyclodextrin, thiourea groups, and a polyacrylic acid layer are introduced, forming a unique synergistic adsorption mechanism: the cyclodextrin cavity provides a size - matching inclusion effect, and the carboxyl groups of polyacrylic acid and thiourea groups provide hydrogen - bonding sites. The multiple mechanisms work synergistically to significantly improve the adsorption efficiency; significantly improve the selective adsorption of uric acid, improve blood compatibility, reduce the risk of side effects, and are suitable for hemoperfusion; at the same time, the entire preparation method is mild and controllable, without the use of toxic reagents, and the product has good stability;

[0029] (2) The surface of polystyrene resin is modified by plasma coating technology to form a negatively charged film on the resin surface, effectively improving hydrophilicity. At the same time, it provides groups for grafting, with no pollution in the reaction process and good biocompatibility. Polyacrylic acid is grafted onto the surface of the plasma-coated resin by ultraviolet light induction, introducing a large number of carboxyl functional groups to the filler, endowing it with specific affinity for uric acid molecules, capable of quickly and efficiently binding to the carbonyl group of uric acid in the blood, expanding the indication range of conventional hemoperfusion devices, and having a therapeutic effect on gout or hyperuricemia. Moreover, the matrix resin has no macroporous structure, does not rely on the adsorption of macroporous resin itself, has more stable hemodynamics, reduces thrombus formation, and lowers the thrombus risk for patients.

[0030] (3) By introducing thiourea groups onto cyclodextrin, the adsorption capacity of the filler for uric acid is enhanced. The thiourea groups not only retain the original cavity inclusion effect of cyclodextrin but also further increase the affinity with uric acid molecules through hydrogen bonding, forming a synergistic effect with the polyacrylic acid layer on the resin surface and significantly improving the selective adsorption capacity of the filler for uric acid. Brief Description of the Drawings

[0031] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required in the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0032] Figure 1 It is a flowchart for the preparation of the modified filler for hemoperfusion according to the present invention;

[0033] Figure 2 It is a product diagram of the modified filler for hemoperfusion according to the present invention. Detailed Embodiments

[0034] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in combination with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0035] Unless otherwise specified, the raw materials used in the following examples and comparative examples are all commercially available. Among them:

[0036] The particle size of the polystyrene resin is 0.5 - 1.2 mm, the pore diameter is 2 - 6 nm, and the specific surface area is ≥1200 m 2 / g, pore volume ≥ 0.9 mL / g, wet bulk density 0.7 - 0.8 g / mL; 6 - monoamino - β - cyclodextrin was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0037] Example 1

[0038] This example provides a modified filler for hemoperfusion and its preparation method. As Figure 1 shown, it includes the following steps:

[0039] S1. Take 150 g of polystyrene resin and ultrasonically clean it with 200 mL of absolute ethanol for 20 min. After filtration, ultrasonically clean it with deionized water three times. After filtration, dry it at room temperature to obtain the pretreated polystyrene resin for standby;

[0040] Lay 150 g of the pretreated polystyrene resin evenly on the carrier plate 15 cm away from the radio frequency electrode in the reaction chamber of the plasma coating machine. Close the bell jar reaction chamber and all valves, and turn on the vacuum pump. When the body vacuum reaches 5×10 - 3 Pa, open the inlet pipeline, and introduce nitrogen into the ion source at a flow rate of 0.75 L / min for 20 min to exhaust all the residual air in the resin gaps, reaction chamber, and pipeline. During the whole nitrogen introduction process, heat the polystyrene resin on the carrier plate to 150 °C. After the temperature is constant, close the nitrogen introduction, and turn on the plasma power supply. At the same time, continuously introduce argon until the body vacuum reaches 4×10 -2 Pa. Then adjust the ion current to 75 A and the voltage to 150 V. The coating time is 18 min. After the coating is completed, turn off the plasma power supply, inlet pipeline, and vacuum pump, immediately take out the polystyrene resin sample, place it flat at room temperature, and let it react with air for 30 min to obtain the plasma - coated resin;

[0041] S2. Prepare 200 mL of 0.25 mol / L acrylic acid solution, add all 150 g of the plasma - coated resin into the solution, add 1.5 g of 2,2 - dimethoxy - 2 - phenylacetophenone, and oscillate and mix evenly at a constant temperature of 25 °C at a speed of 120 rpm for 30 min. During the oscillation of the solution, irradiate it fully with ultraviolet light with a power of 30 W and a wavelength of 365 nm throughout the process. After the reaction is completed, filter out the product, wash it several times with phosphate buffer solution (50 mM, pH 7.4), and then dry it under vacuum to obtain the modified plasma - coated resin;

[0042] S3. Disperse 10 g of 6 - monoamino - β - cyclodextrin in 200 mL of ethanol - aqueous solution (ethanol and water ratio 2:1), add 13.5 g of phenyl isothiocyanate and 18 g of triethylamine, react at room temperature for 22 h. After the reaction is completed, perform rotary evaporation under reduced pressure. The obtained solid is separated by silica gel column chromatography, and the eluent is ethyl acetate to obtain the modified cyclodextrin;

[0043] S4. Mix 20 g of modified cyclodextrin, 10 g of modified plasma coating resin, and 5 g of potassium dihydrogen phosphate, add 200 mL of deionized water, and heat and react at 135 °C for 3.5 h. After the reaction is completed, wash the product with deionized water and dry it under vacuum to obtain the modified filler for hemoperfusion (as Figure 2 shown).

[0044] Example 2

[0045] This example provides a modified filler for hemoperfusion and its preparation method, including the following steps:

[0046] S1. Take 150 g of polystyrene resin, ultrasonically clean it with 150 mL of absolute ethanol for 25 min, filter it out, ultrasonically clean it with deionized water 3 times, filter it out, and dry it at room temperature to obtain the pretreated polystyrene resin for standby;

[0047] Lay 150 g of the pretreated polystyrene resin evenly on the carrier plate 15 cm away from the radio frequency electrode in the reaction chamber of the plasma coating machine. Close the bell jar reaction chamber and all valves, turn on the vacuum pump. When the body vacuum reaches 5×10 - 3 Pa, open the inlet pipeline, and introduce nitrogen into the ion source at a flow rate of 0.7 L / min for 25 min to discharge all the residual air in the resin gaps, reaction chamber, and pipeline. During the whole nitrogen introduction process, heat the polystyrene resin on the carrier plate to 140 °C. After the temperature is constant, close the nitrogen introduction, and turn on the plasma power supply. At the same time, continuously introduce argon until the body vacuum reaches 4×10 -2 Pa, then adjust the ion current to 70 A, the voltage to 150 V, and the coating time to 20 min. After the coating is completed, turn off the plasma power supply, inlet pipeline, and vacuum pump, immediately take out the polystyrene resin sample, place it flat at room temperature, and fully contact with air for oxidation reaction for 25 min to obtain the plasma coating resin;

[0048] S2. Prepare 250 mL of 0.2 mol / L acrylic acid solution, add all 150 g of the plasma coating resin to the solution, and oscillate and mix it at a constant temperature of 25 °C at a speed of 100 rpm for 35 min. The solution is fully irradiated with ultraviolet light with a power of 25 W and a wavelength of 365 nm during the oscillation process. After the reaction is completed, filter out the product, wash it several times with phosphate buffer solution (50 mM, pH 7.4), and then dry it under vacuum to obtain the modified plasma coating resin;

[0049] S3. Disperse 10 g of 6 - monoamino - β - cyclodextrin in 200 mL of an ethanol - water solution (ethanol and water in a ratio of 2:1), add 12 g of phenyl isothiocyanate and 15 g of triethylamine, react at room temperature for 20 h. After the reaction, perform rotary evaporation under reduced pressure. The obtained solid is separated by a silica gel column, and the eluent is ethyl acetate to obtain the modified cyclodextrin;

[0050] S4. Mix 18 g of the modified cyclodextrin, 10 g of the modified plasma - coated resin, and 5 g of potassium dihydrogen phosphate, add 200 mL of deionized water, heat and react at 130 °C for 4 h. After the reaction, wash the product with deionized water and dry it under vacuum to obtain the modified filler for hemoperfusion.

[0051] Example 3

[0052] This example provides a modified filler for hemoperfusion and its preparation method, including the following steps:

[0053] S1. Take 150 g of polystyrene resin, ultrasonically clean it with 250 mL of absolute ethanol for 15 min, filter it out, ultrasonically clean it with deionized water 3 times, filter it out, and dry it at room temperature to obtain the pretreated polystyrene resin for standby;

[0054] Lay 150 g of the pretreated polystyrene resin evenly on the carrier plate 15 cm away from the radio - frequency electrode in the reaction chamber of the plasma coating machine. Close the bell - jar reaction chamber and all valves, turn on the vacuum pump. When the body vacuum reaches 5×10 - 3 Pa, open the inlet pipeline, and introduce nitrogen into the ion source at a flow rate of 0.8 L / min for 15 min to discharge all the residual air in the resin gaps, reaction chamber, and pipeline. During the whole nitrogen - introducing process, heat the polystyrene resin on the carrier plate to 160 °C. After the temperature is constant, close the nitrogen introduction, turn on the plasma power supply. At the same time, continuously introduce argon until the body vacuum reaches 4×10 -2 Pa, then adjust the ion current to 80 A, the voltage to 150 V, and the coating time to 15 min. After the coating is completed, turn off the plasma power supply, inlet pipeline, and vacuum pump, immediately take out the polystyrene resin sample, place it flat at room temperature, and let it fully contact with air for an oxidation reaction for 35 min to obtain the plasma - coated resin;

[0055] S2. Prepare 150 mL of 0.3 mol / L acrylic acid solution, add all 150 g of the plasma - coated resin into the solution, and oscillate and mix it at a constant temperature of 25 °C at a speed of 120 rpm for 25 min. During the oscillation of the solution, irradiate it fully with ultraviolet light with a power of 35 W and a wavelength of 365 nm throughout the process. After the reaction is completed, filter out the product, wash it several times with a phosphate - buffered solution (50 mM, pH 7.4), and dry it under vacuum to obtain the modified plasma - coated resin;

[0056] S3. Disperse 10 g of 6 - monoamino - β - cyclodextrin in 200 mL of ethanol - aqueous solution (ethanol and water at a ratio of 2:1), add 15 g of phenyl isothiocyanate and 20 g of triethylamine, react at room temperature for 24 h. After the reaction, perform rotary evaporation under reduced pressure. The obtained solid is separated by a silica gel column, and the eluent is ethyl acetate to obtain modified cyclodextrin;

[0057] S4. Mix 22 g of modified cyclodextrin, 100 g of modified plasma - coated resin and 6 g of potassium dihydrogen phosphate, add 200 mL of deionized water, heat and react at 140 °C for 3 h. After the reaction, wash the product with deionized water and dry it under vacuum to obtain the modified filler for hemoperfusion.

[0058] Example 4

[0059] This example provides a modified filler for hemoperfusion and its preparation method, including the following steps:

[0060] S1. Take 150 g of polystyrene resin, ultrasonically clean it with 180 mL of absolute ethanol for 22 min, filter it out, ultrasonically clean it with deionized water three times, filter it out and dry it at room temperature to obtain the pretreated polystyrene resin for standby;

[0061] Lay 150 g of the pretreated polystyrene resin evenly on the carrier plate 15 cm away from the radio - frequency electrode in the reaction chamber of the plasma coating machine. Close the bell - jar reaction chamber and all valves, turn on the vacuum pump. When the body vacuum reaches 5×10 - 3 Pa, open the inlet pipeline, and introduce nitrogen into the ion source at a flow rate of 0.77 L / min for 18 min to discharge all the residual air in the resin gaps, reaction chamber and pipeline. During the whole nitrogen - introducing process, heat the polystyrene resin on the carrier plate to 145 °C. After the temperature is constant, close the nitrogen introduction, turn on the plasma power supply. At the same time, continuously introduce argon until the body vacuum reaches 4×10 -2 Pa, then adjust the ion current to 75 A, the voltage to 150 V, and the coating time to 16 min. After the coating is completed, turn off the plasma power supply, inlet pipeline and vacuum pump, immediately take out the polystyrene resin sample, lay it flat at room temperature and let it react with air for 28 min to obtain the plasma - coated resin;

[0062] S2. Prepare 220 mL of 0.22 mol / L acrylic acid solution, add all 150 g of the plasma - coated resin into the solution, oscillate and mix it evenly at a speed of 120 rpm at a constant temperature of 25 °C for 24 min. During the oscillation of the solution, irradiate it fully with ultraviolet light with a power of 30 W and a wavelength of 365 nm throughout the process. After the reaction is completed, filter out the product, wash it several times with phosphate buffer solution (50 mM, pH 7.4) and then dry it under vacuum to obtain the modified plasma - coated resin;

[0063] S3. Disperse 10 g of 6 - monoamino - β - cyclodextrin in 200 mL of an ethanol - aqueous solution (ethanol and water at a ratio of 2:1), add 12.5 g of phenyl isothiocyanate and 16 g of triethylamine, react at room temperature for 23 h. After the reaction, perform rotary evaporation under reduced pressure. The obtained solid is separated by a silica gel column, and the eluent is ethyl acetate to obtain the modified cyclodextrin;

[0064] S4. Mix 19 g of the modified cyclodextrin, 10 g of the modified plasma - coated resin, and 5.5 g of potassium dihydrogen phosphate, add 200 mL of deionized water, heat and react at 130 °C for 3.5 h. After the reaction, wash the product with deionized water and dry it under vacuum to obtain the modified filler for hemoperfusion.

[0065] Comparative Example 1

[0066] This example provides a modified filler for hemoperfusion and its preparation method, including the following steps:

[0067] S1. Take 150 g of polystyrene resin, ultrasonically clean it with 200 mL of absolute ethanol for 20 min, filter it out, ultrasonically clean it with deionized water 3 times, filter it out, and dry it at room temperature to obtain the pretreated polystyrene resin for standby;

[0068] Lay 150 g of the pretreated polystyrene resin evenly on the carrier plate 15 cm away from the radio - frequency electrode in the reaction chamber of the plasma coating machine. Close the bell - jar reaction chamber and all valves, turn on the vacuum pump. When the body vacuum reaches 5×10 - 3 Pa, open the inlet pipeline, and introduce nitrogen into the ion source at a flow rate of 0.75 L / min for 20 min to exhaust all the residual air in the resin gaps, reaction chamber, and pipeline. During the whole nitrogen - introducing process, heat the polystyrene resin on the carrier plate to 150 °C. After the temperature is constant, close the nitrogen introduction, turn on the plasma power supply. At the same time, continuously introduce argon until the body vacuum reaches 4×10 -2 Pa, then adjust the ion current to 75 A, the voltage to 150 V, and the coating time to 18 min. After the coating is completed, turn off the plasma power supply, inlet pipeline, and vacuum pump, immediately take out the polystyrene resin sample, lay it flat at room temperature, and let it fully contact with air for an oxidation reaction for 30 min to obtain the plasma - coated resin;

[0069] S2. Prepare 200 mL of 0.25 mol / L acrylic acid solution, add all 150 g of plasma coating resin into the solution, keep the temperature constant at 25 °C and oscillate and mix evenly at a speed of 120 rpm for 30 min. During the oscillation process of the solution, irradiate it fully with ultraviolet light with a power of 30 W and a wavelength of 365 nm. After the reaction is completed, filter out the product, wash it several times with phosphate buffer solution (50 mM, pH 7.4), and then dry it in vacuum to obtain the modified plasma coating resin;

[0070] S3. Mix 20 g of cyclodextrin, 10 g of modified plasma coating resin and 5 g of potassium dihydrogen phosphate, add 200 mL of deionized water, heat and react at 135 °C for 3.5 h. After the reaction is completed, wash the product with deionized water and dry it in vacuum to obtain the modified filler for hemoperfusion.

[0071] Comparative Example 2

[0072] This example provides a modified filler for hemoperfusion and its preparation method, including the following steps:

[0073] S1. Take 150 g of polystyrene resin and ultrasonically clean it with 200 mL of absolute ethanol for 20 min. After filtering, ultrasonically clean it with deionized water 3 times. After filtering, dry it at room temperature to obtain the pretreated polystyrene resin for standby;

[0074] Lay 150 g of the pretreated polystyrene resin evenly on the carrier plate 15 cm away from the radio frequency electrode in the reaction chamber of the plasma coating machine. Close the bell jar reaction chamber and all valves, turn on the vacuum pump. When the body vacuum reaches 5×10 - 3 Pa, open the inlet pipeline, and introduce nitrogen into the ion source at a flow rate of 0.75 L / min for 20 min to discharge all the residual air in the resin gaps, reaction chamber and pipeline. During the whole process of introducing nitrogen, heat the polystyrene resin on the carrier plate to 150 °C. After the temperature is constant, close the nitrogen introduction, and turn on the plasma power supply. At the same time, continuously introduce argon until the body vacuum reaches 4×10 -2 Pa, then adjust the ion current to 75 A and the voltage to 150 V. The coating time is 18 min. After the coating is completed, turn off the plasma power supply, inlet pipeline and vacuum pump, immediately take out the polystyrene resin sample, place it flat at room temperature, and let it react with air fully for 30 min to obtain the plasma coating resin;

[0075] S2. Disperse 10 g of 6-monoamino-β-cyclodextrin in 200 mL of ethanol aqueous solution (ethanol and water 2:1), add 13.5 g of phenyl isothiocyanate and 18 g of triethylamine, and react at room temperature for 22 h. After the reaction is completed, perform rotary evaporation under reduced pressure. The obtained solid is separated by a silica gel column, and the eluent is ethyl acetate to obtain the modified cyclodextrin;

[0076] S3. Mix 20 g of modified cyclodextrin, 10 g of modified plasma coating resin and 5 g of potassium dihydrogen phosphate, add 200 mL of deionized water, and heat and react at 135 °C for 3.5 h. After the reaction, wash the product with deionized water and dry it under vacuum to obtain the modified filler for hemoperfusion.

[0077] Performance detection

[0078] Weigh 50 g of the modified fillers obtained in Examples 1-4 and Comparative Examples 1-2, and apply them to 6 hemoperfusion devices respectively. Connect the upper and lower ends of each hemoperfusion device to two containers through pipes. The container at the upper end contains untreated plasma, and the container at the lower end is used to receive the plasma treated by the hemoperfusion device. A peristaltic pump is installed in the pipe between the container at the upper end and the hemoperfusion device to provide power so that the plasma can flow into the hemoperfusion device. Then, perform the hemoperfusion effect test. Measure the uric acid concentration in the blood before and after perfusion, and use a commercially available uric acid content assay kit (Solarbio Science & Technology Co., Ltd., Beijing, product number E-BC-F018) to detect the uric acid concentration. The test results are shown in Table 1.

[0079] Table 1 Uric acid clearance rate

[0080]

[0081] As can be seen from Table 1, when the modified filler for hemoperfusion prepared by the present invention is applied to a hemoperfusion device, the uric acid clearance rate in the blood can be increased to more than 40%, greatly improving the uric acid clearance rate.

[0082] The above is only the preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a modified filler for blood perfusion, characterized in that: The method comprises the following preparation steps: S1, subjecting a polystyrene resin to ultrasonic pretreatment, placing the pretreated polystyrene resin in a plasma coating machine, and subjecting the polystyrene resin to argon plasma coating. After the coating is completed, the polystyrene resin is exposed to air for a reaction of 25-35 minutes to obtain a plasma coating resin; S2, adding the plasma coating resin to the acrylic acid solution, and irradiating the solution with ultraviolet light to obtain a modified plasma coating resin; S3, dispersing 6-monoamino-β-cyclodextrin in an ethanol aqueous solution, adding phenyl isothiocyanate and triethylamine, reacting at room temperature for 20-24 hours, and performing vacuum rotary evaporation. The obtained solid was separated by a silica gel column with ethyl acetate as the eluent to obtain a modified cyclodextrin; S4, uniformly mixing the modified cyclodextrin, the modified plasma coating resin and potassium dihydrogen phosphate in deionized water, heating for reaction, and after the reaction is completed, washing and drying to obtain the modified filler for blood perfusion; The argon plasma coating in step S1 includes the following steps: placing the pretreated polystyrene resin in a plasma coating machine, and when the vacuum degree reaches 5×10 -3 Pa, nitrogen was introduced into the ion source at a flow rate of 0.7-0.8 L / min for 15-25 min, the temperature was heated to 130-170 °C, and then the nitrogen was stopped, the plasma power was turned on, and argon was continuously introduced until the vacuum degree reached 4 × 10 -2 Pa, then adjust the ion current to 70-80A, the voltage to 150V, and the coating time to 15-20min; In step S2, the power during ultraviolet light irradiation is 25-35W and the wavelength is 365nm.

2. The method for preparing a modified filler for blood perfusion according to claim 1, characterized in that: The ultrasonic pretreatment in step S1 includes: ultrasonically cleaning the polystyrene resin with anhydrous ethanol, the mass volume ratio of the polystyrene resin to the anhydrous ethanol is 3g:3-5mL, and the ultrasonic cleaning time is 15-25min.

3. The method for preparing a modified filler for blood perfusion according to claim 1, characterized in that: In step S2, the mass volume ratio of the plasma coating resin and the acrylic acid solution is 3g:3-5mL, and the concentration of the acrylic acid solution is 0.2-0.3mol / L.

4. The method for preparing a modified filler for blood perfusion according to claim 1, characterized in that: In step S3, the mass ratio of 6-monoamino-β-cyclodextrin, phenyl isothiocyanate and triethylamine is 1:1.2-1.5:1.5-2.

5. The method for preparing a modified filler for blood perfusion according to claim 1, characterized in that: In step S4, the mass ratio of modified cyclodextrin, modified plasma coating resin and potassium dihydrogen phosphate is 1.8-2.2:1:0.4-0.

6.

6. The method for preparing a modified filler for blood perfusion according to claim 1, characterized in that: In step S4, the heating temperature is 130-140° C., and the heating reaction time is 3-4 hours.

7. A modified filler for blood perfusion prepared by the preparation method according to any one of claims 1 to 6.

8. The use of a modified filler for blood perfusion according to claim 7, characterized in that: The modified filler for blood perfusion is filled in a blood perfusion device.

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