High cross-linked macroporous resin for adsorbing macromolecular toxin and preparation method thereof

Abstract

The present application relates to a kind of high crosslinking macroporous resin of adsorbing macromolecular toxin and its preparation method, belong to blood perfusion adsorption resin technical field.The preparation method described in the present application includes: (1) the styrene monomer, polyvinyl crosslinking agent, pore-forming agent and initiator are mixed as oil phase, dispersant, surfactant, salt and pure water are mixed as water phase, oil phase is dispersed in water phase under stirring condition to prepare O / W emulsion, suspension polymerization reaction is carried out by heating, polystyrene-based white ball is obtained, washing, extraction, drying;(2) polystyrene-based white ball is swelled, then fatty aldehyde and lewis acid catalyst are added, reaction is carried out, and the product is washed and dried.The high crosslinking macroporous resin described in the present application has larger specific surface area, excellent biocompatibility, can adsorb protein binding class toxin such as macromolecular toxin in blood;The present application simultaneously provides preparation method, green and environmental protection.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of high crosslinking macroporous resin of adsorbing middle macromolecular toxin and preparation method thereof, belong to blood perfusion adsorption resin technical field. BACKGROUND

[0002] Blood perfusion is a kind of medical method widely used in blood purification technology, mainly used for treating acute drug poisoning, uremia, severe hepatitis, hyperlipidemia and immune system diseases, etc., its principle is to lead the blood of patient out of body and pass through the special function adsorbent in blood perfusion device, removes endogenous and exogenous toxin in blood by adsorption, then the purified blood is returned to patient, to achieve the purpose of rapidly improving the environment in patient's body.

[0003] Adsorbent is the core of blood perfusion technology, mainly divided into activated carbon, polysaccharide and synthetic resin according to material source:

[0004] (1) activated carbon adsorbent has large specific surface area, wide source and low cost, has good adsorption effect on small molecules such as creatinine and uric acid, but the main problem is poor blood compatibility, low mechanical strength, carbon particles are easy to fall off during perfusion process, causing thrombosis and white blood cell and platelet decrease.

[0005] (2) polysaccharide adsorbent has good biocompatibility, surface is rich in hydroxyl group and easy to be derived into special function adsorbent, but polysaccharide adsorbent is not only expensive, but also has poor mechanical strength, low specific surface area and unsatisfactory adsorption capacity.

[0006] (3) synthetic resin has three-dimensional network structure, controllable pore structure, large specific surface area, good mechanical strength and chemical stability, and is not easy to fall off, has better adsorption capacity for middle and large molecules toxin, common synthetic resins include polystyrene, polyacrylic acid (ester), polyvinyl alcohol, etc., among which superhigh crosslinking polystyrene resin is a commonly used broad-spectrum macroporous adsorbent with excellent performance in clinic, and plays an important role in the field of treating liver and kidney failure and acute drug poisoning.

[0007] However, there are still some problems in the practical application of the current superhigh crosslinking polystyrene resin:

[0008] 1) Current process includes the preparation of styrene-divinylbenzene white ball, chloromethylation of white ball and post-crosslinking of chloromethylation microspheres, and the chloromethylation process mostly uses the highly toxic and carcinogenic chloromethyl ether for reaction, which can cause great harm to the health of production operators and the environment. Patents (201210540786.7, 202010290146.x) report a method of indirect chloromethylation, i.e. adding methylal and thionyl chloride in the system to generate chloromethyl ether under the action of catalyst, and then reacting with white ball to obtain chloromethylated resin. Although this method avoids the direct use of chloromethyl ether, the reaction raw material thionyl chloride is also a highly irritating toxic solvent, and the generated chloromethyl ether in the reaction process is also a potential hazard;

[0009] 2) The resin prepared by this process will remain a certain amount of chloromethyl, and the hydrolysis of chloromethyl will cause the pH value of the solution to decrease, which exists a potential safety hazard;

[0010] 3) The biocompatibility of super-high cross-linked polystyrene resin is not as good as that of polysaccharide adsorbent, and the surface lacks functional groups, which limits the development of its specific adsorption function.

[0011] In addition to small molecule toxins such as creatinine and urea, uremic patients also have albumin-bound small molecule toxins (indoxyl sulfate, indole acetic acid, etc.) and parathyroid hormone (PTH), β2-microglobulin (β2-MG) and other medium and large molecule toxins. The accumulation of these toxins can cause patients to develop stubborn skin itching, bone and joint lesions and other complications. Lixelle (Japan, Kaneka) adsorption column uses cellulose microspheres loaded with 16-alkyl as adsorbent, and through the synergistic effect of pore size screening and hydrophobic force, the clearance rate of β2-MG in blood can reach more than 90%. In addition, the adsorption column also has good clearance effect on other toxins in blood such as cell inflammatory factors (Therapeutic Apheresis, 1998, 2:13-17; Biochimica et Biophysica Acta, 2005, 1753:141-145), but Lixelle belongs to polysaccharide adsorption column, which is not only expensive but also has low mechanical strength, and the blood perfusion speed is not ideal. Traditional super-high cross-linked polystyrene resin has low cost, but its clearance capacity for the above toxins is very limited due to the limitation of pore structure and lack of functional ligands.

[0012] In summary, the traditional super-high cross-linked polystyrene resin also has problems such as involving toxic chemicals in the preparation process, serious environmental pollution, limited ability to remove protein-bound toxins and macromolecular toxins, etc. It is of great significance to develop a green and environmentally friendly, cost-effective, controllable pore structure and specific surface area, and at the same time, effectively remove the protein-bound toxins and macromolecular toxins accumulated in the patient's body. High cross-linked polystyrene resin for promoting technological innovation in the field of blood purification and improving the health level of the masses. SUMMARY

[0013] The purpose of the present application is to provide a high cross-linked macroporous resin for adsorbing macromolecular toxins, which has a large specific surface area, excellent biocompatibility, and can adsorb macromolecular toxins such as protein-bound toxins, PTH, β2-MG and cell inflammatory factors in blood; the present application also provides a preparation method of the high cross-linked macroporous resin, which is simple in process and realizes the post-crosslinking and functional modification of polystyrene-based white balls by one-pot method, and is green and environmentally friendly.

[0014] The preparation method of the high cross-linked macroporous resin for adsorbing macromolecular toxins provided by the present application mainly comprises the following steps:

[0015] (1) A polystyrene-based macroporous resin is prepared by a suspension polymerization method:

[0016] The styrene monomer, the multi-vinyl crosslinking agent, the pore-forming agent and the initiator are uniformly mixed as an oil phase, the dispersant, the surfactant, the salt and the pure water are uniformly mixed as an aqueous phase, the oil phase is dispersed in the aqueous phase under stirring to prepare an O / W emulsion, nitrogen is passed for 30 min, then the temperature is raised to start polymerization, and after a period of reaction, polystyrene-based white balls with a particle size of 0.1-2 mm are obtained, the white balls are washed with hot water and ethanol for several times, then extracted with acetone or ethanol for 6 h, and vacuum dried;

[0017] (2) One-pot method realizes post-crosslinking and functional modification of polystyrene-based white balls:

[0018] The polystyrene-based white balls obtained in step (1) are swelled with a swelling agent overnight, fatty aldehyde and Lewis acid catalyst are added, and after a period of reaction at a certain temperature, the functional modified high cross-linked polystyrene macroporous resin is obtained, the obtained resin is washed with methanol-pure water-methanol for several times respectively, and then dried in a vacuum oven to obtain the high cross-linked macroporous resin capable of adsorbing macromolecular toxins.

[0019] There are two post-crosslinking reactions in this step, one is the crosslinking of adjacent benzene rings of the resin under the action of an acid catalyst, and the other is the crosslinking of adjacent benzene rings through Friedel-Crafts alkylation reaction under the action of a Lewis acid catalyst; in this step, the fatty aldehyde will also undergo benzene ring hydroxyalkylation under the action of a Lewis acid catalyst to realize the functional modification of the benzene ring; the reaction schematic process is as follows:

[0020]

[0021] wherein R is H(CH2)n, n = 2-20.

[0022] In step (1), the styrene monomer is selected from one or more of styrene, methylstyrene, ethylstyrene, and 4-vinylbiphenyl; the multi-vinyl crosslinking agent is selected from one or more of divinylbenzene (DVB), p,p'-divinyl-1,2-diphenylethane (BVPE), and triallyl isocyanurate (TAIC); the crosslinking degree of the obtained polystyrene-based white ball is 5-90%, preferably 30-80%.

[0023] In step (1), the porogen is selected from any one or a mixture of two to three of toluene, xylene, an alcohol having 3-12 carbon atoms, an alkane having 6-16 carbon atoms, ethyl acetate, butyl acetate, butyl butyrate, gasoline, and liquid paraffin, and the porogen is added in an amount of 30%-300%, preferably 50%-150%, of the total mass of the styrene monomer and the multi-vinyl crosslinking agent.

[0024] In step (1), the initiator is an oil-soluble initiator, which can be an azo initiator such as azobisisobutyronitrile (AIBN) or azobisisoheptyl nitrile (ABVN); a peroxide initiator such as benzoyl peroxide (BPO), tert-butyl peroxy-2-ethylhexanoate, tert-amyl peroxy-2-ethylhexanoate, dodecanoyl peroxide, or alkyl hydroperoxide; or a mixture thereof. The amount of the initiator is 1%-10%, preferably 2%-6%, of the sum of the mass of the styrene monomer and the multi-vinyl crosslinking agent.

[0025] In step (1), the dispersant is a water-soluble polymer such as polyvinyl alcohol, polyvinylpyrrolidone, gelatin, polyethylene glycol, carboxymethyl cellulose, or hydroxyethyl cellulose, and the content is 0.5%-8% of the mass of the water phase; the salt is an inorganic salt such as sodium chloride, sodium sulfate, or magnesium sulfate, and the content is 0.02%-5% of the mass of the water phase; and the surfactant is sodium dodecyl sulfate, sodium dodecyl sulfonate, dodecyltrimethylammonium bromide, or Tween-80, and the content is controlled to be within 5% of the mass of the water phase.

[0026] In step (1), the mass ratio of oil phase to water phase ranges from 1:2 to 1:100, preferably from 1:4 to 1:10; the reaction temperature is 55-95℃, preferably 70-80℃; and the reaction time is 8-36h, preferably 18-24h.

[0027] In step (1), the stirring speed affects the size of the resin particle, and a suitable stirring speed can be selected according to the desired particle size, and the stirring speed ranges from 50 to 1000 rpm, preferably from 100 to 500 rpm.

[0028] In step (2), the swelling agent is at least one of dichloromethane, dichloroethane, dichloropropane, carbon disulfide, chlorobenzene, chloroform, chlorotoluene, and nitrobenzene, and the volume-mass ratio of the swelling agent to the white ball ranges from 5 mL / g to 30 mL / g, preferably from 10 mL / g to 15 mL / g.

[0029] In step (2), the aliphatic aldehyde is anhydrous aliphatic aldehyde containing 2-20 carbon atoms, preferably 6-16 carbon atoms; and the mass ratio of the aliphatic aldehyde to the white ball ranges from 1:1 to 10:1, preferably from 2:1 to 5:1.

[0030] In step (2), the Lewis acid catalyst is one of anhydrous SnCl4, AlCl3, FeCl3, or ZnCl2, or a mixture thereof, and the mass ratio of the catalyst to the white ball ranges from 0.1:1 to 5:1, preferably from 0.5:1 to 3:1.

[0031] In step (2), the reaction temperature is 20-85℃, preferably 55-75℃; and the reaction time is 1-24h, preferably 5-12h.

[0032] The high-crosslinking macroporous resin for adsorbing macromolecular toxins prepared by the present application has a crosslinked polystyrene skeleton, and the benzene rings are also α-hydroxyalkylated. The high-crosslinking macroporous resin for adsorbing macromolecular toxins has a particle size of 0.1-2mm, a pore size of 2-170nm, a porosity of 30-70%, a specific surface area of 100-1000m 2 / g, and a hydroxyalkyl density of 0.5-1.2mmol / g.

[0033] Compared with the prior art, the present application has the following beneficial effects:

[0034] (1) The present application uses a mixed crosslinking agent containing two or three double bonds, cooperates with a porogen, and uses a suspension polymerization method to prepare a macroporous polystyrene-based white ball; further adding aliphatic aldehyde and Lewis acid catalyst, and using one-pot method to realize the post-crosslinking and functional modification of the macroporous polystyrene-based white ball, which increases the specific surface area of the resin and introduces hydroxyalkyl groups on the surface of the resin, thereby improving the biocompatibility of the resin.

[0035] (2)The prepared novel high crosslinking macroporous adsorption resin avoids direct or indirect use of chloromethyl ether, saves reaction steps, and is green and environmentally friendly in process. The coupled hydroxyalkyl can realize high-efficiency adsorption of macromolecular toxins such as protein binding toxins, parathyrin, β2-MG and cell inflammatory factors in blood through the combined action of hydrophobicity and hydrogen bond, and has great application potential in the fields of blood purification, chemical analysis, separation and purification, catalysis and energy. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 Infrared spectrum of polystyrene-based white ball, post-crosslinking and functional modification of microspheres in Example 1;

[0037] In the figure: a line is the infrared spectrum of polystyrene-based white ball; b line is the infrared spectrum of high crosslinking macroporous adsorption resin;

[0038] Figure 2 Scanning electron microscope images (a, × 35; b, × 30000) of the high crosslinking macroporous adsorption resin prepared in Example 1;

[0039] Figure 3 BET pore size distribution graph of high crosslinking macroporous adsorption resin;

[0040] In the figure: a line is the BET pore size distribution graph of high crosslinking macroporous resin in Example 1;

[0041] b line is the BET pore size distribution graph of high crosslinking macroporous resin in Example 2;

[0042] c line is the BET pore size distribution graph of high crosslinking macroporous resin in Example 3. DETAILED DESCRIPTION

[0043] The application will be further described below in combination with examples, but it does not limit the implementation of the application.

[0044] The raw materials used are commercially available.

[0045] Example 1

[0046] (1) Preparation of macroporous polystyrene-based white ball

[0047] Add styrene (9g), triallyl isocyanurate (4.5g), divinylbenzene (1.5g), benzoyl peroxide (0.45g), toluene (10g), and dodecane (5g) to a beaker to prepare an oil phase. Stir until the solids are completely dissolved. Add 50g of an aqueous phase (containing 1% PVA, 0.02% SDS, and 0.1% Na2SO4). Disperse the oil phase in the aqueous phase under stirring at 150 rpm to prepare an O / W emulsion. After purging with nitrogen for 30 min, raise the temperature to 80℃ to begin polymerization. The polymerization reaction lasts for 24 h. The resulting polystyrene microspheres are washed several times with hot water and ethanol in a G3 sintered glass funnel, then extracted with acetone for 6 h to remove oligomers from the microspheres. After vacuum drying for 5 h, the microspheres are ready for use.

[0048] (2) Preparation of highly cross-linked macroporous adsorption resins

[0049] 10g of polystyrene-based white spheres were weighed and placed in 150mL of dichloroethane to swell overnight. Then, 30g of dodecyl aldehyde and 12g of FeCl3 were added with stirring. The reaction was carried out at 80℃ for 10h. The resulting resin was washed several times with methanol-pure water-methanol sequentially, and dried in a vacuum oven to obtain a highly cross-linked macroporous adsorption resin. The obtained macroporous adsorption resin had an average particle size of 635μm, an average pore size of 25.7nm (2-160nm), a porosity of 57.2%, and a specific surface area of ​​845m². 2 / g, hydroxyalkyl density 0.86mmol / g. Infrared spectrum see [reference needed]. Figure 1 Scanning electron microscope showed Figure 2 Aperture distribution is shown in Figure 3 a.

[0050] from Figure 1 As can be seen from the data, the microspheres after post-crosslinking and functional modification have a crosslinking effect at 3440 cm⁻¹. -1 and 1020cm -1 Two new absorption peaks appeared at the point, which correspond to the stretching vibration peaks of -OH and CO coupled on the benzene ring, respectively, indicating that the excess aliphatic aldehydes achieved hydroxyalkylation of the benzene ring while undergoing post-crosslinking.

[0051] Example 2

[0052] (1) Preparation of macroporous polystyrene-based white spheres

[0053] In a beaker, add styrene (6 g), divinylbenzene (9 g), benzoyl peroxide (0.45 g), n-heptane (15 g) to form an oil phase, and stir until the solids are completely dissolved. The water phase is 60 g (containing 1.5% PVA, 0.01% SDS, and 0.5% NaCl). Under stirring, disperse the oil phase in the water phase to form an O / W emulsion, and the stirring speed is 300 rpm. After 30 min of nitrogen blowing, increase the temperature to 70°C to start the polymerization, and the polymerization reaction is carried out for 24 h. The obtained polystyrene-based microspheres are washed with hot water and ethanol several times in a G3 sand core funnel, and then extracted with acetone for 6 h to remove the oligomers in the microspheres. After vacuum drying for 5 h, the product is ready for use.

[0054] (2) Preparation of high-crosslinking macroporous adsorption resin

[0055] Weigh 10 g of polystyrene-based white microspheres, and put them in 150 mL of dichloroethane to swell overnight. Under stirring, add heptanal 25 g and AlCl3 10 g, and react at 65°C for 12 h. The obtained resin is washed with methanol-pure water-methanol several times, and then dried in a vacuum oven to obtain the high-crosslinking macroporous adsorption resin. The average particle size of the obtained macroporous adsorption resin is 450 μm, the average pore size is 15.9 nm (2-110 nm), the porosity is 49.2%, the specific surface area is 665 m 2 / g, and the hydroxyalkyl density is 0.69 mmol / g. The pore size distribution is shown in Figure 3 b.

[0056] Example 3

[0057] (1) Preparation of macroporous polystyrene-based white microspheres

[0058] In a beaker, add styrene (7.5 g), triallyl isocyanurate (3.5 g), divinylbenzene (4 g), azobisisobutyronitrile (0.3 g), and n-heptane (12 g) to form an oil phase, and stir until the solids are completely dissolved. The water phase is 60 g (containing 2% gelatin, 0.01% SDS, and 1% NaCl). Under stirring, disperse the oil phase in the water phase to form an O / W emulsion, and the stirring speed is 200 rpm. After 30 min of nitrogen blowing, increase the temperature to 75°C to start the polymerization, and the polymerization reaction is carried out for 24 h. The obtained polystyrene-based microspheres are washed with hot water and ethanol several times in a G3 sand core funnel, and then extracted with ethanol for 6 h to remove the oligomers in the microspheres. After vacuum drying for 5 h, the product is ready for use.

[0059] (2) Preparation of high-crosslinking macroporous adsorption resin

[0060] Take 10 g of polystyrene-based white ball into 150 mL of carbon disulfide and swell overnight, add valeraldehyde 20 g, FeCl3 15 g under stirring, react at 60 °C for 10 h, the obtained resin is washed with methanol-pure water-methanol several times respectively, and dried in vacuum oven to obtain high crosslinking macroporous adsorption resin. The obtained macroporous adsorption resin has an average particle size of 550 μm, an average pore size of 13.8 nm (2-150 nm), a porosity of 41.3%, a specific surface area of 597 m 2 / g, and a hydroxyalkyl density of 0.78 mmol / g. The pore size distribution is shown in Figure 3 c.

[0061] Example 4

[0062] (1) Preparation of macroporous polystyrene-based white ball

[0063] In a beaker, add styrene (4.5 g), p,p'-divinyl-1,2-diphenylethane (6.5 g), divinylbenzene (4 g), benzoyl peroxide (0.45 g), xylene (9 g), cyclohexane (9 g), and prepare an oil phase by stirring until the solids are completely dissolved. Prepare an aqueous phase of 50 g (containing 1% PVA, 0.02% SDS, and 0.1% Na2SO4). Under stirring, disperse the oil phase in the aqueous phase to prepare an O / W emulsion, and the stirring speed is 150 rpm. After 30 min of nitrogen blowing, increase the temperature to 80 °C to start the polymerization, and the polymerization is carried out for 24 h. The obtained polystyrene-based microspheres are washed with hot water and ethanol several times in a G3 sand core funnel, and then extracted with acetone for 6 h to remove the oligomers in the microspheres, and dried in vacuum for 5 h to obtain the polystyrene-based microspheres.

[0064] (2) Preparation of high crosslinking macroporous adsorption resin

[0065] Take 10 g of polystyrene-based white ball into 150 mL of chlorobenzene and swell overnight, add nonanal 25 g, FeCl3 15 g under stirring, react at 70 °C for 15 h, the obtained resin is washed with methanol-pure water-methanol several times respectively, and dried in vacuum oven to obtain high crosslinking macroporous adsorption resin. The obtained macroporous adsorption resin has an average particle size of 602 μm, an average pore size of 10.5 nm (2-100 nm), a porosity of 60.2%, a specific surface area of 906 m 2 / g, and a hydroxyalkyl density of 0.91 mmol / g.

[0066] Example 5

[0067] (1) Preparation of macroporous polystyrene-based white ball

[0068] In a beaker, styrene (4.5 g), p, p'-divinyl-1,2-diphenylethane (6.5 g), divinylbenzene (4 g), benzoyl peroxide (0.45 g), toluene (10 g), dodecane (5 g) were added to form an oil phase, and stirred until the solids were completely dissolved. The water phase was 50 g (containing 0.5% PVA, 1.5% gelatin, 0.02% SDS, and 0.1% Na2SO4). Under stirring, the oil phase was dispersed in the water phase to form an O / W emulsion, and the stirring speed was 200 rpm. After 30 min of nitrogen blowing, the temperature was raised to 80°C to start the polymerization, and the polymerization reaction was carried out for 24 h. The obtained polystyrene-based microspheres were washed several times with hot water and ethanol in a G3 sand core funnel, and then extracted with acetone for 6 h to remove the oligomers in the microspheres. After vacuum drying for 5 h, the product was ready for use.

[0069] (2) Preparation of high-crosslinking macroporous adsorption resin

[0070] 10 g of polystyrene-based white microspheres were weighed into 150 mL of dichloroethane and swelled overnight. Under stirring, 25 g of nonanal and 15 g of FeCl3 were added, and the reaction was carried out at 70°C for 15 h. The obtained resin was washed several times with methanol-pure water-methanol in sequence, and then dried in a vacuum oven to obtain the high-crosslinking macroporous adsorption resin. The average particle size of the obtained macroporous adsorption resin was 610 μm, the average pore size was 23.5 nm (2-160 nm), the porosity was 59.1%, the specific surface area was 876 m2 / g, and the hydroxyalkyl density was 1.03 mmol / g. 2

[0071] Comparative Example 1

[0072] (1) Preparation of macroporous polystyrene-based white microspheres

[0073] In a beaker, styrene (4.5 g), p, p'-divinyl-1,2-diphenylethane (6.5 g), divinylbenzene (4 g), benzoyl peroxide (0.45 g), toluene (10 g), dodecane (5 g) were added to form an oil phase, and stirred until the solids were completely dissolved. The water phase was 50 g (containing 0.5% PVA, 1.5% gelatin, 0.02% SDS, and 0.1% Na2SO4). Under stirring, the oil phase was dispersed in the water phase to form an O / W emulsion, and the stirring speed was 200 rpm. After 30 min of nitrogen blowing, the temperature was raised to 80°C to start the polymerization, and the polymerization reaction was carried out for 24 h. The obtained polystyrene-based microspheres were washed several times with hot water and ethanol in a G3 sand core funnel, and then extracted with acetone for 6 h to remove the oligomers in the microspheres. After vacuum drying for 5 h, the product was ready for use.

[0074] (2) Preparation of high-crosslinking macroporous adsorption resin

[0075] ​Take 10 g polystyrene-based white ball into 150 mL dichloroethane to swell overnight, add FeCl315 g under stirring, react at 70°C for 15 h, the obtained resin is washed with methanol-pure water-methanol several times respectively, and dried in vacuum oven to obtain high crosslinking macroporous adsorption resin. The average particle size of the obtained macroporous adsorption resin is 610 μm, the average pore size is 24.7 nm (2-160 nm), the porosity is 61.1%, the specific surface area is 895 m 2 / g, and the hydroxyalkyl density is 0.0 mmol / g.

[0076] In order to verify the adsorption performance of the high crosslinking macroporous adsorption resin of the present application on uremic toxins, taking parathyroid hormone (PTH) and β2-microglobulin (β2-MG) as target substances, the adsorption effects of the high crosslinking macroporous adsorption resin of examples 1-5 and the general commercial resin (average particle size 600 μm, average pore size 12.8 nm, porosity 57%, specific surface area 898 m 2 / g) on the plasma solution containing PTH and β2-MG are respectively investigated, the clearance rate of PTH is determined by ELISA method, and the clearance rate of β2-MG is determined by immunoturbidity method, and the results are shown in Table 1.

[0077] Table 1 Influence of examples and comparative examples on adsorption of PTH and β2-MG in plasma

[0078]

[0079]

[0080] As shown in the above table, compared with the general commercial resin, the adsorption rates of the high crosslinking macroporous adsorption resin prepared in examples 1-5 on PTH and β2-MG are greatly improved, which is mainly because the resin prepared in examples is modified and grafted with hydroxyalkyl, and the combined action of hydrophobicity and hydrogen bond increases the adsorption effect on middle and large molecular toxins. Comparative example 1 is compared with example 5, and no nonanal is added in step (2), so there is no hydroxyalkyl on the surface of the resin, and the adsorption rates of the resin on PTH and β2-MG are greatly reduced.

[0081] In addition, the high crosslinking adsorption resins obtained from examples 1-5 and comparative example 1 are used to perform hemolysis and platelet adhesion evaluation, and are compared with the general commercial resin, the evaluation method is tested according to GB / T16886.4-2003 and GB / T16175-1996, and the evaluation results are shown in Table 2.

[0082] Table 2 Hemolysis and platelet adhesion of examples and comparative examples

[0083]

[0084] From the above table, the high crosslinking adsorption resin prepared in Examples 1-5 has obviously improved biocompatibility due to the introduction of hydroxyalkyl, and the hemolysis rate and adsorption rate to platelets are lower than those of the general commercial resin, while the resin in Comparative Example 1 has no hydroxyalkyl on the surface, and the hemolysis rate and adsorption rate to platelets are both high.

[0085] In conclusion, the high crosslinking macroporous adsorption resin prepared by the present application has simple and green preparation process, and has obvious clearance rate to PTH and β2-MG, and has good biocompatibility, and has great application prospect in the field of blood perfusion resin.

[0086] Finally, it should be noted that: the above only for the preferred embodiments of the present application, and not for limiting the present application, although the foregoing embodiments of the present application are described in detail, for those skilled in the art, it still can be modified, equivalent replacement, improvement, etc. recorded in the technical scheme of the foregoing embodiments, any modification, within the spirit and principles of the present application, should be included within the scope of the present application.

Claims

1. A method for preparing a high crosslinked macroporous resin for adsorbing a middle or large molecular toxin, characterized in that, The method comprises the following steps: (1) mixing styrene monomer, multi-vinyl crosslinking agent, porogen and initiator as oil phase, mixing dispersant, surfactant, salt and pure water as water phase, dispersing oil phase in water phase under stirring to prepare O / W emulsion, suspending polymerization at 55-95℃ for 8-36h to obtain polystyrene-based white ball, washing, extracting and drying; the dispersant is water-soluble polymer, such as polyvinyl alcohol, polyvinylpyrrolidone, gelatin, polyethylene glycol, carboxymethyl cellulose or hydroxyethyl cellulose; the salt is sodium chloride, sodium sulfate or magnesium sulfate inorganic salt; the mass ratio of oil phase to water phase is 1:2-1:100; (2) swelling the polystyrene-based white ball obtained in step (1), then adding fatty aldehyde and Lewis acid catalyst, reacting at 20-85℃ for 1-24h, washing the obtained resin with methanol-pure water-methanol in sequence, and drying to obtain the high-crosslinking macroporous resin; The swelling agent is one or more of dichloromethane, dichloroethane, dichloropropane, carbon disulfide, chlorobenzene, chloroform, chlorotoluene or nitrobenzene, and the volume / mass ratio of the swelling agent to the polystyrene-based white ball is 5mL / g-30mL / g; The fatty aldehyde is dodecanal, heptanal, pentanal or nonanal, and the mass ratio of the fatty aldehyde to the polystyrene-based white ball is 1:1-10:1; the Lewis acid catalyst is one or more of anhydrous SnCl4, AlCl3, FeCl3 or ZnCl2.

2. The method for preparing the highly cross-linked macroporous resin for adsorbing macromolecular toxins according to claim 1, characterized in that: The styrene monomer is one or more of styrene, methylstyrene, ethylstyrene or 4-vinylbiphenyl; the multi-vinyl crosslinking agent is one or more of divinylbenzene, p,p'-divinyl-1,2-diphenylethane or triallylisocyanurate; and the crosslinking degree of the polystyrene-based white ball obtained in step (1) is 5-90%.

3. The method for preparing the highly cross-linked macroporous resin for adsorbing macromolecular toxins according to claim 1, characterized in that: The porogen is any one or a mixture of two to three of toluene, xylene, alcohol with 3-12 carbon atoms, alkane with 6-16 carbon atoms, ethyl acetate, butyl acetate, butyl butyrate, gasoline or liquid paraffin, and the amount of the porogen added is 30%-300% of the total mass of the styrene monomer and the multi-vinyl crosslinking agent.

4. The method for preparing the highly cross-linked macroporous resin for adsorbing medium-sized macromolecular toxins according to claim 1, characterized in that: The initiator is one or more of azobisisobutyronitrile, azobisisoheptyl nitrile, benzoyl peroxide, tert-butyl peroxy-2-ethylhexanoate, tert-amyl peroxy-2-ethylhexanoate, dodecanoyl peroxide or alkyl hydroperoxide; and the amount of the initiator is 1%-10% of the sum of the mass of the styrene monomer and the multi-vinyl crosslinking agent.

5. The method for preparing the highly cross-linked macroporous resin for adsorbing medium-sized macromolecular toxins according to claim 1, characterized in that: The content of the dispersant is 0.5%-8% of the mass of the water phase; the surfactant is sodium dodecyl sulfate, sodium dodecyl sulfonate, dodecyltrimethylammonium bromide or Tween-80, and the content is controlled within 5% of the mass of the water phase; and the content of the salt is 0.02%-5% of the mass of the water phase.

6. A high crosslinked macroporous resin for adsorbing a middle or large molecular toxin, characterized in that: The method is prepared by any one of claims 1-5.

Images