Biological polyphenol macroporous adsorption resin as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of blood purification, and particularly relates to biological polyphenol macroporous adsorption resin as well as a preparation method and application thereof. The biological polyphenol macroporous adsorption resin provided by the invention has multiple effects of adsorbing toxin molecules, keeping the capability of adsorbing the toxin molecules at a high blood flow rate, inhibiting bacteria, resisting oxidation and the like; the specific biological polyphenol monomer curcumin and the cross-linking agent divinyl benzene are selected in the preparation method, so that the yield and the mechanical strength of the biological polyphenol macroporous adsorption resin can be greatly improved, and the high-performance biological polyphenol macroporous adsorption resin is developed; the technical problem of lack of high-performance biological polyphenol macroporous adsorption resin in the prior art is solved.

Description

Technical Field

[0001] The present application belongs to the technical field of blood purification, and in particular relates to a biopolyphenol macroporous adsorption resin and a preparation method and application thereof. Background Art

[0002] Clinically, hemoperfusion is a type of blood purification technology that can be used to rescue patients with drug and toxin poisoning. For patients with chronic renal failure, hemoperfusion and hemodialysis can also be used together to remove large molecular toxins in the body.

[0003] Hemoperfusion technology requires the use of blood lines, injection fluids, and hemoperfusion devices filled with solid adsorbents. The core component of the hemoperfusion device is the solid adsorbent. The solid adsorbent currently filled in the hemoperfusion device is mainly polystyrene-based adsorption resins. The preparation of polystyrene-based adsorption resins requires the use of styrene as a polymerization monomer. Styrene is potentially toxic to the human body and may endanger human health. In addition, the polystyrene-based adsorption resins themselves are highly non-polar and non-selective, and have poor blood compatibility. There are also modification methods on the market to improve the compatibility of polystyrene-based adsorption resins, such as depositing heparin, hydroxyethyl cellulose, polyvinyl pyrrolidone and other substances with good blood compatibility on the surface of styrene-based adsorption resins to improve the compatibility of polystyrene-based adsorption resins. However, this type of modification method is physical adsorption, and there is a risk of shedding during clinical application. The modification process by chemically grafting hydrophilic substances is complicated, the reaction process is uncontrollable, and it is easy to have an adverse effect on the pore structure parameters such as the pore size of the polystyrene-based adsorption resin.

[0004] Biopolyphenols are usually extracted from plants, have good safety, contain more hydroxyl groups in the molecular chain, and have good biocompatibility. They are a potential solid adsorbent raw material for hemoperfusion devices, and can be used to prepare biopolyphenol macroporous adsorption resins for use in hemoperfusion devices. Biopolyphenols include magnolol, resveratrol, eugenol, curcumin, etc. Different biopolyphenols have different properties. Curcumin in biopolyphenols has multiple biological activities and has been used in the fields of edible pigments, food additives and medicine. It is an ideal biopolyphenol raw material. However, compared with biopolyphenols such as magnolol, curcumin has more side chains, longer molecular chains and greater steric hindrance, making it difficult to prepare curcumin-based macroporous adsorption resin microspheres. Moreover, when the hemoperfusion device is used for blood purification, when the blood flow rate is too high, it will cause greater pressure on the solid adsorbent in the hemoperfusion device, and the pore structure of ordinary biopolyphenol macroporous adsorption resins will be compressed, which will have an adverse effect on the blood purification effect.

[0005] Therefore, it is necessary to develop new biopolyphenol macroporous adsorption resins to provide high-performance biopolyphenol macroporous adsorption resins. Summary of the invention

[0006] In view of this, the present application provides a biopolyphenol macroporous adsorption resin and a preparation method and application thereof, which are used to solve the technical problem of the lack of high-performance biopolyphenol macroporous adsorption resin in the prior art.

[0007] In a first aspect, the present application provides a biopolyphenol macroporous adsorption resin, wherein the structure of the biopolyphenol macroporous adsorption resin is a three-dimensional network structure formed by cross-linking of curcumin molecular chains.

[0008] The second aspect of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, which can be used to prepare the biopolyphenol macroporous adsorption resin described in the first aspect. The preparation method comprises the following steps:

[0009] The biopolyphenol monomer, the cross-linking agent, the porogen and the initiator are uniformly mixed to obtain an oil phase as a dispersed phase;

[0010] Mixing the dispersant and water uniformly to obtain an aqueous phase as a continuous phase;

[0011] Under nitrogen atmosphere, the oil phase as the dispersed phase is added dropwise to the water phase as the continuous phase to carry out polymerization reaction, thereby obtaining a suspension of the dispersed biopolyphenol macroporous adsorption resin;

[0012] The biopolyphenol macroporous adsorption resin is separated from the suspension in which the biopolyphenol macroporous adsorption resin is dispersed to obtain the biopolyphenol macroporous adsorption resin.

[0013] Preferably, the biopolyphenol monomer is selected from at least one of curcumin, magnolol, resveratrol and eugenol.

[0014] Preferably, the crosslinking agent is selected from divinylbenzene and / or triallyl isocyanurate.

[0015] Preferably, the biopolyphenol monomer is curcumin, and the cross-linking agent is divinylbenzene.

[0016] Preferably, the porogen is selected from at least one of toluene, isobutyl alcohol, glycerol, polyethylene glycol, white oil, and methyl isobutyl carbinol;

[0017] The initiator is selected from at least one of benzoyl peroxide, tert-butyl peroxide 2-ethylhexanoate, and azobisisobutyronitrile;

[0018] The dispersant is selected from at least one of gelatin, polyvinyl alcohol and hydroxyethyl cellulose.

[0019] Preferably, calculated by parts by mass, the oil phase as the dispersed phase comprises: 100 parts by mass of biopolyphenol, 1 to 100 parts by mass of a cross-linking agent, 50 to 120 parts by mass of a porogen, and 0.3 to 1 part by mass of an initiator.

[0020] Preferably, calculated by parts by mass, the aqueous phase as the continuous phase comprises 0.5 to 1.5 parts by mass of a dispersant and 98.5 to 99.5 parts by mass of water.

[0021] Preferably, in the polymerization reaction, the volume ratio of the oil phase as the dispersed phase to the water phase as the continuous phase is 1:1-3, the reaction temperature is 80-95° C., and the reaction time is 4-12 h.

[0022] Preferably, the separation process includes: filtering the suspension of dispersed biopolyphenol macroporous adsorption resin in turn, separating solid and liquid by centrifugation or gravity sedimentation, washing the biopolyphenol macroporous adsorption resin with ethanol and water, and removing impurities by Soxhlet extraction to obtain the biopolyphenol macroporous adsorption resin.

[0023] The third aspect of the present application provides the use of the biopolyphenol macroporous adsorption resin described in the first aspect in blood purification.

[0024] The fourth aspect of the present application provides a blood perfusion device, the interior of which is filled with the biological polyphenol macroporous adsorption resin described in the first aspect.

[0025] Compared with the prior art, the biopolyphenol macroporous adsorption resin provided in the present application includes at least the following beneficial effects.

[0026] 1. The biopolyphenol macroporous adsorption resin provided in the present application has excellent hydrophilicity and blood compatibility, has good clearance ability for toxin molecules such as β2-microglobulin and IL-6, has a low hemolysis rate, and can meet the requirements of blood perfusion.

[0027] 2. The biopolyphenol macroporous adsorption resin provided in the present application has multiple functions such as adsorbing toxin molecules, maintaining the ability to adsorb toxin molecules at high blood flow rates, and inhibiting bacteria and antioxidants, and is a high-performance biopolyphenol macroporous adsorption resin for blood perfusion.

[0028] 3. The method for preparing the biopolyphenol macroporous adsorption resin provided in the present application has a high ball formation rate (yield), and the preparation cost of the biopolyphenol macroporous adsorption resin is low, which is conducive to the large-scale promotion and application of the biopolyphenol macroporous adsorption resin. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 This is a schematic diagram of the biopolyphenol macroporous adsorption resin provided in Example 1 of the present application;

[0031] Figure 1 In the figure, 1 is curcumin, and 2 is divinylbenzene, a cross-linking agent. DETAILED DESCRIPTION

[0032] The present application provides a biopolyphenol macroporous adsorption resin and a preparation method and application thereof, which are used to solve the technical problem of the lack of high-performance biopolyphenol macroporous adsorption resin in the prior art.

[0033] The technical solution of the present application will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

[0034] In view of the current lack of high-performance bio-polyphenol macroporous adsorption resins, the present application provides a bio-polyphenol macroporous adsorption resin; the present application provides a bio-polyphenol macroporous adsorption resin, the structure of which is a three-dimensional network structure formed by cross-linking of curcumin molecular chains; and micropores, mesopores or macropores are distributed in the bio-polyphenol macroporous adsorption resin.

[0035] In the bio-polyphenol macroporous adsorption resin provided by the present application, the pore size of the macropores in the adsorption resin is in accordance with the provisions of the International Union of Pure and Applied Chemistry, and the pore size less than 2nm is micropore, the pore size of 2-50nm is mesopore, and the pore size greater than 50nm is macropore; that is, the macropores with a pore size greater than 50nm distributed in the bio-polyphenol macroporous adsorption resin provided by the present application are used to adsorb toxin molecules such as exogenous or endogenous toxins, drugs or metabolic wastes, and the structure is that the curcumin molecular chain forms a three-dimensional network structure through cross-linking. The active groups in the curcumin molecular chain can give the bio-polyphenol macroporous adsorption resin multiple high efficiencies such as antibacterial, antioxidant, antiviral, liver protection, choleretic, anti-cancer, lipid-lowering, and anti-HIV, so that the bio-polyphenol macroporous adsorption resin provided by the present application has both antibacterial and antioxidant properties and adsorption of exogenous or endogenous toxins. , drugs or metabolic wastes, and the curcumin molecular chains are further cross-linked to form a three-dimensional network structure. The three-dimensional network structure improves the mechanical strength of the bio-polyphenol macroporous adsorption resin. In critical situations, when blood purification or blood perfusion is required at a high blood flow rate, the high mechanical strength can avoid the unfavorable situation that the pore structure of the bio-polyphenol macroporous adsorption resin is compressed and the efficacy of adsorbing toxin molecules is affected, thereby improving the therapeutic effect of blood purification or blood perfusion; therefore, the bio-polyphenol macroporous adsorption resin provided in the present application has multiple functions such as adsorbing toxin molecules, maintaining the ability to adsorb toxin molecules at a high blood flow rate, and inhibiting bacteria and antioxidants, and is a high-performance bio-polyphenol macroporous adsorption resin, thereby overcoming the current lack of high-performance bio-polyphenol macroporous adsorption resins.

[0036] At the same time, the present application provides a method for preparing a biopolyphenol macroporous adsorption resin. When the biopolyphenol is curcumin, the above-mentioned biopolyphenol macroporous adsorption resin can be prepared; the preparation method comprises: firstly configuring biopolyphenol monomers such as curcumin, a cross-linking agent, a porogen and an initiator as an oil phase, and configuring a dispersant and water as an aqueous phase; then adding the oil phase as a dispersed phase to the aqueous phase as a continuous phase to carry out a polymerization reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin, and then separating the biopolyphenol macroporous adsorption resin to obtain the biopolyphenol macroporous adsorption resin.

[0037] In the preparation method of the biopolyphenol macroporous adsorption resin provided in the present application, different biopolyphenols have different preparation difficulties. Compared with biopolyphenols such as magnolol, the molecules of curcumin have more side chains, longer molecular chains, and greater steric hindrance. Therefore, in the process of using curcumin as a biopolyphenol monomer to prepare the biopolyphenol macroporous adsorption resin, the yield of the biopolyphenol macroporous adsorption resin is low, which makes the preparation cost of the biopolyphenol macroporous adsorption resin too high, which is not conducive to the large-scale application of the biopolyphenol macroporous adsorption resin in the field of blood purification or blood perfusion. In the process of using curcumin as a biopolyphenol monomer to prepare the biopolyphenol macroporous adsorption resin in the present application, the added cross-linking agent can effectively reduce the steric hindrance, improve the balling rate of the biopolyphenol macroporous adsorption resin, so that the yield of the biopolyphenol macroporous adsorption resin is improved and the preparation cost of the biopolyphenol macroporous adsorption resin is reduced.

[0038] As a preferred technical solution, the preparation method of biopolyphenol macroporous adsorption resin provided in the present application uses a cross-linking agent, and different cross-linking agents have different effects on improving the yield of biopolyphenol macroporous adsorption resin; divinylbenzene has a better effect on improving the sphering rate and yield of biopolyphenol macroporous adsorption resin.

[0039] As a preferred technical solution, the preparation method of the biopolyphenol macroporous adsorption resin provided in the present application needs to control the reaction temperature to 80-95°C and the reaction time to 4-12h during the polymerization reaction; and the amount of the oil phase as the dispersed phase should be lower than the water phase as the continuous phase, and the volume ratio of the two is 1:1-3.

[0040] As a preferred technical solution, the preparation method of biopolyphenol macroporous adsorption resin provided in the present application, when separating the biopolyphenol macroporous adsorption resin from a suspension, the separation process includes: filtering the suspension in which the biopolyphenol macroporous adsorption resin is dispersed, separating the solid and liquid by centrifugation or gravity sedimentation, washing the biopolyphenol macroporous adsorption resin with ethanol and water, and removing impurities by Soxhlet extraction to obtain the biopolyphenol macroporous adsorption resin; wherein the ethanol and water washing is to remove the oil phase and the water phase as much as possible, and the Soxhlet extraction can effectively remove impurities such as porogens in the pores of the adsorption resin.

[0041] Correspondingly, the present application also provides the application of biopolyphenol macroporous adsorption resin in blood purification, and the specific application is the application of biopolyphenol macroporous adsorption resin in blood perfusion technology. On the other hand, it can also be used to adsorb toxin molecules in the body of uremic patients when blood perfusion and hemodialysis are used together to purify the blood of uremic patients.

[0042] Correspondingly, the present application also provides a blood perfusion device, the interior of which is filled with the biological polyphenol macroporous adsorption resin described in the present application.

[0043] The biopolyphenol macroporous adsorption resin provided in the present application will be specifically described below in conjunction with embodiments and experimental examples.

[0044] Example 1

[0045] Example 1 of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, the preparation method comprising: a step of configuring an oil phase and an aqueous phase, a step of polymerization reaction, and a step of separating the biopolyphenol macroporous adsorption resin.

[0046] The steps of preparing the oil phase and the water phase include: mixing 40g of curcumin, 20g of divinylbenzene, 0.2g of benzoyl peroxide and 40g of toluene to obtain the oil phase, adding 210g of water and 1.08g of hydroxyethyl cellulose into a 500mL three-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and heating until the hydroxyethyl cellulose is dissolved to obtain the water phase.

[0047] The steps of the polymerization reaction include: starting mechanical stirring, introducing nitrogen protective gas, adding the oil phase as the dispersed phase dropwise into the water phase as the continuous phase, the dripping is completed within 10 minutes, then heating to 85°C to carry out the polymerization reaction for 8 hours, and ending the reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin.

[0048] The steps of separating the bio-polyphenol macroporous adsorption resin include: separating the suspension solid and liquid by filtering, centrifuging or gravity sedimentation, washing the dispersed bio-polyphenol macroporous adsorption resin with ethanol and water respectively, and the washing times are 2 to 6 times; then removing the porogen of the dispersed bio-polyphenol macroporous adsorption resin and impurities remaining in the resin pores by Soxhlet extraction to obtain the bio-based macroporous adsorption resin. The structure of the bio-based macroporous adsorption resin is a three-dimensional network structure formed by the curcumin molecular chain through the cross-linking agent divinylbenzene, as shown in the schematic diagram Figure 1 shown.

[0049] Example 2

[0050] Example 2 of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, the preparation method comprising: a step of configuring an oil phase and an aqueous phase, a step of polymerization reaction, and a step of separating the biopolyphenol macroporous adsorption resin.

[0051] The steps of preparing the oil phase and the water phase include: mixing 40g of curcumin, 20g of divinylbenzene, 0.2g of benzoyl peroxide and 50g of isobutyl alcohol to obtain the oil phase, adding 300g of water and 4.5g of gelatin into a 500mL three-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and heating until the gelatin is dissolved to obtain the water phase.

[0052] The steps of the polymerization reaction include: starting mechanical stirring, introducing nitrogen protective gas, adding the oil phase as the dispersed phase dropwise into the water phase as the continuous phase, the dripping is completed within 10 minutes, then heating to 95°C for polymerization reaction for 8 hours, and ending the reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin.

[0053] The steps of separating the bio-polyphenol macroporous adsorption resin include: separating the suspension solid-liquid by filtering, centrifuging or gravity sedimentation, washing the dispersed bio-polyphenol macroporous adsorption resin with ethanol and water respectively, and the washing times are 2 to 6 times; then removing the porogen of the dispersed bio-polyphenol macroporous adsorption resin and impurities remaining in the resin pores by Soxhlet extraction to obtain the bio-based macroporous adsorption resin.

[0054] Example 3

[0055] Example 3 of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, the preparation method comprising: a step of configuring an oil phase and an aqueous phase, a step of polymerization reaction, and a step of separating the biopolyphenol macroporous adsorption resin.

[0056] The steps of preparing the oil phase and the water phase include: mixing 40g of curcumin, 10g of divinylbenzene, 0.12g of benzoyl peroxide and 20g of polyethylene glycol to obtain the oil phase, adding 100g of water and 1g of polyvinyl alcohol into a 500mL three-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and heating until the polyvinyl alcohol is dissolved to obtain the water phase.

[0057] The steps of the polymerization reaction include: starting mechanical stirring, introducing nitrogen protective gas, adding the oil phase as the dispersed phase dropwise into the water phase as the continuous phase, the dripping is completed within 10 minutes, then heating to 80°C for polymerization reaction for 8 hours, and ending the reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin.

[0058] The steps of separating the bio-polyphenol macroporous adsorption resin include: separating the suspension solid-liquid by filtering, centrifuging or gravity sedimentation, washing the dispersed bio-polyphenol macroporous adsorption resin with ethanol and water respectively, and the washing times are 2 to 6 times; then removing the porogen of the dispersed bio-polyphenol macroporous adsorption resin and impurities remaining in the resin pores by Soxhlet extraction to obtain the bio-based macroporous adsorption resin.

[0059] Example 4

[0060] Example 4 of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, the preparation method comprising: a step of configuring an oil phase and an aqueous phase, a step of polymerization reaction, and a step of separating the biopolyphenol macroporous adsorption resin.

[0061] The steps of preparing the oil phase and the water phase include: mixing 40g of curcumin, 20g of triallyl isocyanurate, 0.2g of benzoyl peroxide and 40g of toluene to obtain an oil phase, adding 210g of water and 1.08g of hydroxyethyl cellulose into a 500mL three-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and heating until the hydroxyethyl cellulose is dissolved to obtain a water phase.

[0062] The steps of the polymerization reaction include: starting mechanical stirring, introducing nitrogen protective gas, adding the oil phase as the dispersed phase dropwise into the water phase as the continuous phase, the dripping is completed within 10 minutes, then heating to 85°C to carry out the polymerization reaction for 8 hours, and ending the reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin.

[0063] The steps of separating the bio-polyphenol macroporous adsorption resin include: separating the suspension solid-liquid by filtering, centrifuging or gravity sedimentation, washing the dispersed bio-polyphenol macroporous adsorption resin with ethanol and water respectively, and the washing times are 2 to 6 times; then removing the porogen of the dispersed bio-polyphenol macroporous adsorption resin and impurities remaining in the resin pores by Soxhlet extraction to obtain the bio-based macroporous adsorption resin.

[0064] Example 5

[0065] Example 5 of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, the preparation method comprising: a step of configuring an oil phase and an aqueous phase, a step of polymerization reaction, and a step of separating the biopolyphenol macroporous adsorption resin.

[0066] The steps of preparing the oil phase and the water phase include: mixing 40g of magnolol, 20g of divinylbenzene, 0.2g of benzoyl peroxide and 40g of toluene to obtain the oil phase, adding 210g of water and 1.08g of hydroxyethyl cellulose into a 500mL three-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and heating until the hydroxyethyl cellulose is dissolved to obtain the water phase.

[0067] The steps of the polymerization reaction include: starting mechanical stirring, introducing nitrogen protective gas, adding the oil phase as the dispersed phase dropwise into the water phase as the continuous phase, the dripping is completed within 10 minutes, then heating to 85°C to carry out the polymerization reaction for 8 hours, and ending the reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin.

[0068] The steps of separating the bio-polyphenol macroporous adsorption resin include: separating the suspension solid-liquid by filtering, centrifuging or gravity sedimentation, washing the dispersed bio-polyphenol macroporous adsorption resin with ethanol and water respectively, and the washing times are 2 to 6 times; then removing the porogen of the dispersed bio-polyphenol macroporous adsorption resin and impurities remaining in the resin pores by Soxhlet extraction to obtain the bio-based macroporous adsorption resin.

[0069] Example 6

[0070] Example 6 of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, the preparation method comprising: a step of configuring an oil phase and an aqueous phase, a step of polymerization reaction, and a step of separating the biopolyphenol macroporous adsorption resin.

[0071] The steps of preparing the oil phase and the water phase include: mixing 40g of curcumin, 0.2g of benzoyl peroxide and 40g of toluene to obtain the oil phase, adding 210g of water and 1.08g of hydroxyethyl cellulose into a 500mL three-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and heating until the hydroxyethyl cellulose is dissolved to obtain the water phase.

[0072] The steps of the polymerization reaction include: starting mechanical stirring, introducing nitrogen protective gas, adding the oil phase as the dispersed phase dropwise into the water phase as the continuous phase, the dripping is completed within 10 minutes, then heating to 85°C to carry out the polymerization reaction for 8 hours, and ending the reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin.

[0073] The steps of separating the bio-polyphenol macroporous adsorption resin include: separating the suspension solid-liquid by filtering, centrifuging or gravity sedimentation, washing the dispersed bio-polyphenol macroporous adsorption resin with ethanol and water respectively, and the washing times are 2 to 6 times; then removing the porogen of the dispersed bio-polyphenol macroporous adsorption resin and impurities remaining in the resin pores by Soxhlet extraction to obtain the bio-based macroporous adsorption resin.

[0074] Example 7

[0075] Example 7 of the present application provides a method for preparing a biopolyphenol macroporous adsorption resin, the preparation method comprising: a step of configuring an oil phase and an aqueous phase, a step of polymerization reaction, and a step of separating the biopolyphenol macroporous adsorption resin.

[0076] The steps of preparing the oil phase and the water phase include: mixing 40g of magnolol, 0.2g of benzoyl peroxide and 40g of toluene to obtain the oil phase, adding 210g of water and 1.08g of hydroxyethyl cellulose into a 500mL three-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, and heating until the hydroxyethyl cellulose is dissolved to obtain the water phase.

[0077] The steps of the polymerization reaction include: starting mechanical stirring, introducing nitrogen protective gas, adding the oil phase as the dispersed phase dropwise into the water phase as the continuous phase, the dripping is completed within 10 minutes, then heating to 85°C to carry out the polymerization reaction for 8 hours, and ending the reaction to obtain a suspension of dispersed biopolyphenol macroporous adsorption resin.

[0078] The steps of separating the bio-polyphenol macroporous adsorption resin include: separating the suspension solid-liquid by filtering, centrifuging or gravity sedimentation, washing the dispersed bio-polyphenol macroporous adsorption resin with ethanol and water respectively, and the washing times are 2 to 6 times; then removing the porogen of the dispersed bio-polyphenol macroporous adsorption resin and impurities remaining in the resin pores by Soxhlet extraction to obtain the bio-based macroporous adsorption resin.

[0079] Experimental Example 1

[0080] Experimental Example 1 of the present application performed performance tests on the bio-based macroporous adsorption resin prepared in Examples 1-7 and the disposable blood perfusion device KCM-350 resin (hydrophilic modified polystyrene resin) as a comparative example. The performance tests included: hydrophilicity test, toxin molecule clearance rate test, hemolysis rate test, dynamic adsorption performance test and sphering rate (yield) test; the results of the performance tests are shown in Table 1.

[0081] The process of the hydrophilicity test includes: taking the bio-based macroporous adsorption resin and KCM-350 resin prepared in Examples 1-7, drying them at 105°C for 4 hours respectively to remove moisture from the resin; after drying, grinding the resin, and then using a hydraulic tablet press to prepare it into a sheet sample with a diameter of 13 mm and a thickness of 1 mm, and then performing a contact angle test.

[0082] Toxin molecule clearance tests include β2-microglobulin clearance test and IL-6 clearance test;

[0083] The process of the β2-microglobulin clearance test includes: preparing a phosphate buffer solution (PBS, pH=7.4) containing 0.1% bovine serum albumin (BSA), and adding β2-microglobulin to the above buffer to prepare a β2-microglobulin solution with a concentration of 10 mg / L; taking 10 mL of the above-prepared β2-microglobulin solution and placing it in a conical flask, weighing 0.2 g of the bio-based macroporous adsorption resin and KCM-350 resin prepared in Examples 1-7 and putting them into the conical flask, and placing it in a constant temperature oscillator at a temperature of 37±1°C and oscillating at a rate of 180±10 times / min for 2 hours. After the adsorption is completed, the concentration of the β2-microglobulin solution is measured using a biochemical analyzer, and the formula Cr4=100%*(C0-C t ) / C0 to calculate the clearance rate of β2-microglobulin; where Cr4 is the clearance rate of β2-microglobulin (%), C0 is the concentration of β2-microglobulin solution before adsorption (mg / L), C t is the concentration of β2-microglobulin solution after adsorption (mg / L).

[0084] The process of IL-6 clearance test includes: preparing phosphate buffered saline (PBS, pH = 7.4) containing 0.1% bovine serum albumin (BSA), and adding IL-6 to the above buffer to prepare an IL-6 solution with a concentration of 600 pg / mL; taking 10mL of the above prepared IL-6 solution and placing it in a conical flask, and then weighing 0.5g of the bio-based macroporous adsorption resin and KCM-350 resin prepared in Examples 1-7 and putting them into the bottle, and placing it in a constant temperature oscillator at a temperature of 37 ± 1 ° C and oscillating at a speed of 180 ± 10r / min for 2 hours. After the adsorption, the ELISA method (ELISA kit: purchased from BD Company, USA) was used to measure the concentration of IL-6 before and after adsorption, and the IL-6 clearance rate was calculated according to the formula A = 100% * (C1-C2) / C1; wherein A is the β2-microglobulin clearance rate (%), C1 is the concentration of IL-6 solution before adsorption (mg / L), and C2 is the concentration of IL-6 solution after adsorption (mg / L).

[0085] The process of the hemolysis rate test includes: weighing 5 g of the bio-based macroporous adsorption resin and KCM-350 resin prepared in Examples 1-7 in a test tube, and injecting 10 mL of normal saline as a test tube; placing the test tube, the negative tube (only 10 mL of normal saline) and the positive tube (only 10 mL of distilled water) in a 37°C water bath for 30 minutes; after the insulation, adding 0.2 mL of diluted anticoagulated rabbit blood to the test tube, the negative tube and the positive tube, respectively, and gently shaking. Mix well, place the test tube, negative tube and positive tube in a constant temperature water bath at 37°C for 60 minutes. After the insulation, pour out the liquid in the tube, centrifuge at 800N for 5 minutes, take the supernatant in the tube and place it in an ultraviolet spectrophotometer, measure the absorbance at 545nm, and calculate the hemolysis rate according to the formula: hemolysis rate = 100% * (AB) / (CB); where A is the absorbance of the test solution; B is the absorbance of the negative control solution; C is the absorbance of the positive control solution.

[0086] The process of dynamic adsorption performance test includes: weighing 2 g of the bio-based macroporous adsorption resin and KCM-350 resin prepared in Examples 1-7 and placing them in a chromatography column, taking 80 mL of a bovine whole blood solution with a concentration of 10 mg / L of β2-microglobulin for a dynamic adsorption test, and the adsorption time is 240 min; the blood flow rates are 200 ml / min and 400 ml / min respectively; after the adsorption is completed, the β2-microglobulin content of the bovine whole blood solution before and after the test is detected.

[0087] The process of the ball formation rate (yield) test is: compare the mass of the bio-based macroporous adsorption resin prepared in Example 1-7 after drying and the mass of the synthetic monomer + cross-linking agent; the ratio of the two is the ball formation rate (yield).

[0088] Table 1: Test results of hydrophilicity, toxin molecule clearance rate, hemolysis rate, dynamic adsorption performance and pelleting rate (yield)

[0089]

[0090] As can be seen from Table 1, the water contact angle of the biopolyphenol macroporous adsorption resin provided in Examples 1-7 of the present application is lower than that of the disposable blood perfusion device KCM-350 resin (hydrophilic modified polystyrene resin) as a comparative example, which indicates that the biopolyphenol macroporous adsorption resin provided in Examples 1-7 has better hydrophilicity; and the removal effect on β2-microglobulin and IL-6, and the hemolysis rate are also similar to those of the commercial disposable blood perfusion device KCM-350 resin (hydrophilic modified polystyrene resin), indicating that the biopolyphenol macroporous adsorption resin provided in the present application has good safety, meets the needs of blood perfusion to remove toxin molecules, and has commercial potential.

[0091] It can be further seen from Table 1 that there are differences in the dynamic adsorption performance of the biopolyphenol macroporous adsorption resins provided in Examples 1-7. After the blood flow rate is increased from 200 ml / min to 400 ml / min, the biopolyphenol macroporous adsorption resins provided in Examples 6-7 have low mechanical strength due to the lack of a cross-linking agent. The excessively high blood flow rate (400 ml / min) causes greater pressure on the biopolyphenol macroporous adsorption resin, and the pore structure of the biopolyphenol macroporous adsorption resin is compressed, thereby reducing the adsorption effect. However, the adsorption performance of the biopolyphenol macroporous adsorption resin provided in Examples 1-5 is basically unchanged, which can improve the therapeutic effect during blood perfusion at a high blood flow rate.

[0092] It can also be seen from Table 1 that the monomers used in the biopolyphenol macroporous adsorption resins provided in Examples 5 and 7 are all magnolol. Although the use of a cross-linking agent improves the dynamic adsorption performance, the improvement in the ball formation rate is not significant. Compared with Examples 1-5, the biopolyphenol macroporous adsorption resin provided in Example 6, without the use of a cross-linking agent, not only improves the dynamic adsorption performance, but also greatly improves the ball formation rate, from 71.5% to 78.3% to 85.3%. It can also be seen from Table 1 that in the biopolyphenol macroporous adsorption resin provided in Example 4, since the cross-linking agent used is triallyl isocyanurate, its ball formation rate is relatively low, at 78.3%, while after using divinylbenzene in the preparation method of Examples 1-3, its ball formation rate can reach 85.3%.

[0093] Experimental Example 2

[0094] Experimental Example 2 of the present application performs performance tests on the biopolyphenol macroporous adsorption resins provided in Examples 1 and 5-7 and the disposable blood perfusion device KCM-350 resin (hydrophilic modified polystyrene resin) as a comparative example. The performance test is an adsorption column pressure test, and the test results are shown in Table 2.

[0095] The process of the adsorption column pressure test includes: running the biopolyphenol macroporous adsorption resin provided in Example 1 and Examples 5-7 and the disposable blood perfusion device KCM-350 resin (hydrophilic modified polystyrene resin) as a comparative example on the blood purification device at a flow rate of 400 ml / min for 2 hours, and testing the pressure at the liquid inlet and outlet ends of the perfusion device.

[0096] Table 2: Adsorption column pressure test results

[0097] Example 1 Example 5 Example 6 Example 7 Comparative Example Liquid inlet pressure (mmHg) 115.9 122.5 138.6 132.9 112.8 Liquid outlet pressure (mmHg) 60.3 62.8 70.2 67.4 61.2 Pressure difference (mmHg) 55.6 59.7 68.4 65.5 51.6

[0098] It can be seen from Table 2 that the pressures at the liquid inlet and outlet ends of the biopolyphenol macroporous adsorption resin adsorption column provided in Examples 6-7 are relatively large, indicating that at high flow rates (400 ml / min), the pressure increases due to compression due to low mechanical strength. The biopolyphenol macroporous adsorption resin provided in Examples 1 and 5 uses a cross-linking agent divinylbenzene or triallyl isocyanurate to form a three-dimensional network structure with the curcumin or polymagnolia bark phenol molecular chain, thereby increasing the mechanical strength and making it less likely to be compressed.

[0099] The above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some or all of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A biopolyphenol macroporous adsorption resin, characterized in that: The structure of the biopolyphenol macroporous adsorption resin is a three-dimensional network structure formed by cross-linking of curcumin molecular chains.

2. A method for preparing a biopolyphenol macroporous adsorption resin, characterized in that: The preparation method comprises the following steps: The biopolyphenol monomer, the cross-linking agent, the porogen and the initiator are uniformly mixed to obtain an oil phase as a dispersed phase; Mixing the dispersant and water uniformly to obtain an aqueous phase as a continuous phase; Under nitrogen atmosphere, the oil phase as the dispersed phase is added dropwise to the water phase as the continuous phase to carry out polymerization reaction, thereby obtaining a suspension of the dispersed biopolyphenol macroporous adsorption resin; The biopolyphenol macroporous adsorption resin is separated from the suspension in which the biopolyphenol macroporous adsorption resin is dispersed to obtain the biopolyphenol macroporous adsorption resin.

3. The method for preparing a biopolyphenol macroporous adsorption resin according to claim 2, characterized in that: The biopolyphenol monomer is selected from at least one of curcumin, magnolol, resveratrol and eugenol.

4. The method for preparing a biopolyphenol macroporous adsorption resin according to claim 2, characterized in that: The crosslinking agent is selected from divinylbenzene and / or triallyl isocyanurate.

5. The method for preparing a biopolyphenol macroporous adsorption resin according to claim 2, characterized in that: The biological polyphenol monomer is curcumin, and the cross-linking agent is divinylbenzene.

6. The method for preparing a biopolyphenol macroporous adsorption resin according to claim 2, characterized in that: The porogen is selected from at least one of toluene, isobutyl alcohol, glycerol, polyethylene glycol, white oil, and methyl isobutyl carbinol; The initiator is selected from at least one of benzoyl peroxide, tert-butyl peroxide 2-ethylhexanoate, and azobisisobutyronitrile; The dispersant is selected from at least one of gelatin, polyvinyl alcohol and hydroxyethyl cellulose.

7. The method for preparing a biopolyphenol macroporous adsorption resin according to claim 2, characterized in that: In the polymerization reaction, the reaction temperature is 80-95° C. and the reaction time is 4-12 hours.

8. The method for preparing a biopolyphenol macroporous adsorption resin according to claim 2, characterized in that: The separation process includes: filtering the suspension of dispersed biopolyphenol macroporous adsorption resin in sequence, separating solid and liquid by centrifugation or gravity sedimentation, washing the biopolyphenol macroporous adsorption resin with ethanol and water respectively, and removing impurities by Soxhlet extraction to obtain the biopolyphenol macroporous adsorption resin.

9. Use of the biopolyphenol macroporous adsorption resin according to claim 1 in blood purification.

10. A blood perfusion device, characterized in that: The interior of the blood perfusion device is filled with the biological polyphenol macroporous adsorption resin described in claim 1.

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