CN114106407A - Blood perfusion adsorbent and preparation method thereof - Google Patents

Blood perfusion adsorbent and preparation method thereof Download PDF

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CN114106407A
CN114106407A CN202010896353.XA CN202010896353A CN114106407A CN 114106407 A CN114106407 A CN 114106407A CN 202010896353 A CN202010896353 A CN 202010896353A CN 114106407 A CN114106407 A CN 114106407A
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adsorbent
group structure
hemoperfusion
nitrogen
agent
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CN114106407B (en
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刘云鸿
彭新艳
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Quanzhou Normal University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
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    • C08J9/286—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum the liquid phase being a solvent for the monomers but not for the resulting macromolecular composition, i.e. macroporous or macroreticular polymers
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    • C08J2325/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Derivatives of such polymers
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    • C08J2325/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Derivatives of such polymers
    • C08J2325/02—Homopolymers or copolymers of hydrocarbons
    • C08J2325/04—Homopolymers or copolymers of styrene
    • C08J2325/08—Copolymers of styrene

Abstract

The invention discloses a blood perfusion adsorbent and a preparation method thereof. According to the preparation method, the use of carcinogenic chloromethyl methyl ether is avoided in the preparation process, so that the problem of safety and environmental protection caused by the use of carcinogenic chloromethyl methyl ether in the traditional process is solved; the invention adopts a novel cross-linking agent system, realizes the post-crosslinking and the nitrogen-containing group functionalization of the adsorbent resin by a one-step method on the basis of the polystyrene microsphere, and has simple reaction process; the preparation and development of the novel adsorbent resin are beneficial to improving the broad-spectrum toxin adsorption and removal functions of the adsorbent and reducing the medical cost.

Description

Blood perfusion adsorbent and preparation method thereof
Technical Field
The invention relates to the technical field of production processes of adsorbent resins in functional polymer materials, in particular to a blood perfusion adsorbent and a preparation method thereof.
Background
The blood perfusion technology is widely applied to the fields of first aid of poisoning, kidney disease, liver disease and critical disease, and the principle is that the blood of a patient is led to extracorporeal circulation by means of power and is contacted with an adsorbent with a special adsorption function in a blood perfusion device to remove endogenous or exogenous toxicants or pathogenic substances in the blood of the patient, so that the aim of purifying the blood is fulfilled. China has made more intensive research on the adsorbent for blood perfusion since the end of the last 70 th century and has been widely applied. Particularly, great results have been achieved in the aspects of drug poisoning, liver failure, renal failure, immunoadsorption and the like. Currently, perfusion adsorbents used in clinical applications include coated activated carbon, macroporous adsorption resin, ion exchange resin, carbonized resin, DNA immunoadsorption, protein a immunoadsorption, and the like.
Polystyrene-based cross-linked macroporous adsorbent resins and polystyrene-based ion exchange resins, as two main blood perfusion adsorbents, exhibit excellent blood purification performance in the blood perfusion field. However, polystyrene ion exchange resins and highly crosslinked porous resins still have problems in production and use, such as anion exchange resins prepared by chloromethylation followed by amination of styrene-divinylbenzene crosslinked polymers; crosslinked polystyrene resins, such as ultra-high crosslinked polystyrene resins, are mainly prepared by chloromethylation and Friedel-Crafts postcrosslinking of macroporous low crosslinked polystyrene-divinylbenzene copolymers. At present, chloromethyl ether is widely used as a chloromethylation reagent in the industry, and due to the strong carcinogenicity, low boiling point and volatility, the chloromethyl ether has great threat to the health of production operators, causes great pollution to the environment, has high preparation cost, thereby influencing the continuous development of the whole industry and needing further technical optimization and improvement.
In addition, in the blood perfusion technology, the ultrahigh cross-linked macroporous adsorption resin can adsorb excessive medium-large molecular toxins in blood by utilizing a pore structure, so that the damage and complications of important organs are reduced; the styrene anion exchange resin is used for specifically adsorbing and removing organ injury toxins with negative electricity, such as bilirubin, endotoxin and the like, by virtue of lipophilic binding property and strong electrostatic force. In the field of artificial liver therapy, two adsorbents are commonly combined together for therapy, such as the DPMAS artificial liver system from jianfan corporation. However, in view of the differences in the blood purification function and principle between the ultra-highly crosslinked macroporous adsorbent resin and the ion exchange resin, and the limitation of the adsorption removal effect, a plurality of separation/adsorbers are required in clinical use. Due to the connection of a plurality of devices, the pipeline is complex, the operation is complex, the equipment is complex, and the treatment cost is high. The development of a novel resin with a higher broad-spectrum toxin adsorption and removal function, the reduction of medical cost and the improvement of the treatment rate of patients become urgent clinical requirements.
Therefore, the development of a novel adsorbent which avoids the use of chloromethyl ether as a raw material, has a green and environment-friendly preparation process method, controllable performance and higher broad-spectrum toxin adsorption and removal functions is important for ensuring human health and promoting the development of the blood perfusion adsorbent resin industry.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the blood perfusion adsorbent and the preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a hemoperfusion adsorbent, which is obtained by carrying out post-crosslinking reaction on porous polystyrene microspheres with nitrogen-containing groups mainly in the presence of a swelling agent, a crosslinking agent and a catalyst.
The molecular formula of the cross-linking agent is as follows:
Figure BDA0002658537470000021
Figure BDA0002658537470000022
at least one of (a);
wherein R is1Is: -CH3、*—CH2CH3、*—CH2CH2CH3、*—CH2CH2CH2CH3、*—CH(CH3)2One of (a) and (b); k is an integer of 0 to 18;
R2is hydrogen, -CH3、*—CH2CH3、
Figure BDA0002658537470000023
One of (a) and (b);
R3is hydrogen, -CH3、*—CH2CH3、
Figure BDA0002658537470000024
One of (a) and (b);
wherein denotes a covalently linked dot;
the nitrogen-containing group is at least one of a quaternary ammonium salt group structure, a tertiary amine group structure, a secondary amine group structure, a primary amine group structure, a pyridine group structure, an aromatic amine group structure, a pyrrole group structure and an imidazole group structure;
the blood perfusion adsorbent is spherical particles with the particle size of 0.01-3 mm;
the specific surface area of the blood perfusion adsorbent is 10-3500 m2/g；
The ion exchange capacity of the blood perfusion adsorbent can be controlled to be 0.0001-5.0 mmol/ml.
The preparation method of the blood perfusion adsorbent sequentially comprises the following steps:
(1) an oil phase is composed of a styrene monomer, a nitrogen-containing group monomer, a comonomer, an organic pore-forming agent and an initiator, the oil phase is subjected to suspension polymerization in a water phase composed of a dispersant, a dispersing auxiliary and water, the pore-forming agent in the resin obtained by polymerization is removed, purified and dried to obtain porous polystyrene-based microspheres with nitrogen-containing groups;
in the monomers of suspension polymerization, the styrene monomer is at least one of a polyvinyl aromatic monomer and a monovinyl aromatic monomer;
the polyvinyl aromatic monomer includes a class of compounds consisting of divinylbenzene, a mixture of m-divinylbenzene and p-divinylbenzene, trivinylbenzene, divinyltoluene, divinylxylene, divinylnaphthalene, and derivatives thereof such as halides, for example, chlorodivinylbenzene, and the like. These compounds may be used alone or in a mixture of two or more. The multivinyl aromatic monomer is preferably at least one of m-divinylbenzene and p-divinylbenzene; a particularly preferred mixture of multivinyl aromatic monomers consists of m-divinylbenzene and p-divinylbenzene. In the step (1) of the present invention, in preparing polystyrene-based microspheres by suspension polymerization, the amount of the polyvinyl aromatic monomer is based on the dry weight of the copolymer; said monomers comprising at least 1 wt% of a multivinyl aromatic monomer; the amount of said polyvinyl aromatic monomer is preferably from 1 to 80% by weight based on the dry weight of the copolymer.
Among the monomers for suspension polymerization, the monovinyl aromatic monomers include, but are not limited to, for example, styrene and C1-C4Alkyl-substituted styrenes such as ethylstyrene, m-ethylstyrene and p-ethylstyrene and mixtures thereof, derivatives such as halides, for example chlorostyrene and chloroethylstyrene. These compounds may be used alone or in a mixture of two or more; the monovinyl aromatic monomer is preferably at least one of styrene, m-ethyl styrene and p-ethyl styrene; particularly preferred are mixtures such as mixtures of m-and p-ethylstyrene and mixtures of styrene, m-and p-ethylstyrene. In the step (1) of the present invention, in preparing polystyrene-based microspheres by suspension polymerization, the amount of the monovinyl aromatic monomer is based on the dry weight of the copolymer; the sheetThe body comprises no more than 99 wt% monovinyl aromatic monomer; the amount of the monovinyl aromatic monomer is preferably 20 to 99 wt% based on the dry weight of the copolymer.
The nitrogen-containing group monomer is:
Figure BDA0002658537470000041
Figure BDA0002658537470000042
at least one of (a);
wherein R is4Is one of hydrogen, methyl, ethyl, propyl and isopropyl; r5Alkylene having 0 to 6 carbon atoms;
R6the material is one of a quaternary ammonium salt group structure, a tertiary amine group structure, a secondary amine group structure, a primary amine group structure, a pyridine group structure, an aromatic amine group structure, a pyrrole group structure and an imidazole group structure;
when R is6In the case of a tertiary amine group structure, the nitrogen-containing group monomer is preferably N-methyldiallylamine, dimethylacrylamide, dimethylaminopropyl methacrylamide, N, N, N ', N' -tetramethyldipropylenetriamine, diethylaminoethyl methacrylate, N, N-diethylacrylamide, dimethylaminoethyl methacrylate;
when R is6In the structure of secondary amine group, the monomer containing nitrogen group is preferably hydroxymethyl acrylamide;
when R is6When the monomer is a primary amine group structure, the monomer containing the nitrogen group is preferably allylamine, 2-propylene-1-aminomethyl;
when R is6In the pyridine group structure, the nitrogen-containing group monomer is preferably 4-vinylpyridine, 2-methyl-3-vinylpyridine, 3-methyl-5-vinylpyridine, 5-ethyl-2-vinylpyridine, 2-vinylpyridine or 4-styrylpyridine;
when R is6In the case of aromatic amine group structure, the nitrogen group-containing monomer is preferably acrylanilide, N- (2-aminophenyl) acrylamide;
when R is6In the case of a pyrrole group structure, the nitrogen group-containing monomer is preferably N-vinylpyrrolidone;
when R is6When the monomer is an imidazole group structure, the nitrogen-containing group monomer is preferably 2-vinylimidazole or 1-vinylimidazole;
the comonomer is at least one of methyl methacrylate, methacrylic acid, acrylic acid, butyl acrylate, methyl acrylate, ethyl acrylate, isooctyl acrylate, 2-hydroxyethyl acrylate, ethyl methacrylate, butyl methacrylate, vinyl acetate, N-hydroxymethyl acrylamide, acrylonitrile, acrylamide and 2-hydroxyethyl methacrylate;
the organic pore-foaming agent is at least one of organic chlorine, hydrocarbon and alcohol; the organic chlorine is at least one of methylene dichloride, ethylene dichloride, propylene dichloride, chlorobenzene and chlorotoluene; the hydrocarbon is at least one of cyclohexylamine, methylcyclohexylamine, ethylcyclohexylamine, benzene, toluene, xylene and ethylbenzene; the alcohol is at least one of methyl isobutyl carbinol, diisobutyl carbinol and isooctyl alcohol;
the initiator is at least one of peroxide and azo compound; the peroxide is preferably dibenzoyl peroxide, tert-butyl 2-ethyl peroxyhexanoate or dilauroyl peroxide; the azo compound is preferably azobisisobutyronitrile, 2' -azobis-2-methylbutyronitrile.
The dispersing agent is at least one of polyvinyl alcohol, gelatin, cellulose derivatives or polyacrylamide;
the dispersing auxiliary agent is at least one of sodium pyrophosphate, polyethylene glycol, polydiene dimethyl ammonium chloride, acrylamide, cellulose, isopropanol, n-butanol and isooctanol, and preferably polyethylene glycol and polydiene dimethyl ammonium chloride.
Furthermore, the mass ratio of the styrene monomer, the nitrogen-containing group monomer, the comonomer, the organic pore-forming agent and the initiator is 1 (0.01-1): 0-1): 0.1-10): 0.001-0.1;
the mass ratio of the water to the dispersing agent to the dispersing auxiliary agent is 1 (0.0001-0.1) to 0-0.01;
the mass ratio of the oil phase to the water phase is 1 (0.5-10);
the suspension polymerization reaction temperature is 20-90 ℃, and the reaction time is 1-24 h;
in view of the fact that the monomer containing the nitrogen group has certain solubility in water, in order to reduce the solubility of the monomer containing the nitrogen group in water, salt substances can be added into the water phase, and the salt substances can comprise sodium chloride, magnesium sulfate, sodium carbonate, sodium bicarbonate and the like.
(2) Crosslinking reaction
Mixing the porous polystyrene-based microspheres with the nitrogen-containing groups with a swelling agent and a crosslinking agent, adding a catalyst for post-crosslinking reaction, and purifying to obtain the hemoperfusion adsorbent.
The swelling agent is at least one of dichloromethane, dichloroethane, propylene dichloride, chlorobenzene, chlorotoluene and nitrobenzene;
the catalyst is at least one of ferric trichloride, aluminum chloride and zinc chloride;
the mass ratio of the porous polystyrene-based microspheres with nitrogen-containing groups, the swelling agent, the catalyst and the crosslinking agent is 1 (1-100): 0.1-10): 0-10;
the post-crosslinking reaction condition is reflux reaction at the temperature of 40-130 ℃ for 2-80 h.
In the step (2), porous polystyrene-based microspheres with nitrogen-containing groups are mixed with a swelling agent and are swelled at 10-60 ℃ for 1-12 h; then adding a cross-linking agent and a catalyst to carry out cross-linking reaction.
By adopting the cross-linking method in the step (2), the post-cross-linking reaction can also be carried out on the existing commercial resins, such as ion exchange resins with amine groups, such as strongly basic anion exchange resins with quaternary amine groups and weakly basic anion exchange resins with amino groups, pyridine groups, secondary amine groups, tertiary amine groups and the like, so as to obtain the corresponding blood perfusion adsorbent.
In addition, the suspension polymerization reaction and the crosslinking reaction conditions, which include, for example, the kind and content of the added monomer, the degree of crosslinking, the presence or absence and kind of the porogen, etc., have an influence on the functional group capacity, surface area, pore volume, etc., of the product; the crosslinking reaction conditions include, for example, the amount of catalyst, the kind and content of crosslinking agent, the reaction time and the reaction temperature, and the like. By properly changing the reaction conditions, the structure and the performance of the adsorbent can be effectively regulated and controlled, and a target product with ideal performance is obtained.
On the basis of the obtained blood perfusion adsorbent with the nitrogen-containing groups, the nitrogen-containing groups of the adsorbent can be further subjected to chemical reaction modification, and the structure and the performance of the adsorbent material can be further regulated and controlled. Taking vinyl pyridine as an example of a nitrogen-containing group monomer, the vinyl pyridine is copolymerized with styrene monomers such as styrene and divinylbenzene to obtain porous polystyrene microspheres with pyridine groups, and the porous polystyrene microspheres are further mixed with a swelling agent and a crosslinking agent, added with a catalyst to perform post-crosslinking reaction and purified to obtain the blood perfusion adsorbent. The obtained hemoperfusion adsorbent has pyridine functional groups inside. The invention can further carry out chemical reaction on the pyridine group, such as quaternization, and the pyridine group is further quaternized by adding quaternization reagents, such as alkyl halide, organic acid, benzyl chloride, chlorohydrin, sulfate and the like, so as to change the surface chemical property of the adsorbent and further regulate and control the adsorption performance of the adsorbent on toxin.
The invention also provides a perfusion apparatus for removing endogenous or exogenous toxicant or pathogenic substance in blood, which comprises the blood perfusion adsorbent or the blood perfusion adsorbent prepared by the preparation method. The adsorption resin for blood perfusion or the adsorption resin for blood perfusion prepared by the preparation method can be used for adsorbing endogenous or exogenous toxicants or pathogenic substances in a human body or an animal body in blood perfusion, and can be particularly used in an perfusion device as an adsorbent.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. according to the preparation method, the use of carcinogenic chloromethyl methyl ether is avoided in the preparation process, so that the problem of safety and environmental protection caused by the use of carcinogenic chloromethyl methyl ether in the traditional process is solved;
2. the invention adopts a novel cross-linking agent system, realizes the post-crosslinking and the nitrogen-containing group functionalization of the adsorbent resin by a one-step method on the basis of the polystyrene microsphere, and has simple reaction process;
3. the preparation and development of the novel adsorbent resin are beneficial to improving the broad-spectrum toxin adsorption and removal functions of the adsorbent and reducing the medical cost.
Drawings
FIG. 1 is a schematic diagram of the preparation of the hemoperfusion adsorbent in example 4;
FIG. 2 is a schematic diagram of the preparation of the hemoperfusion adsorbent in example 7;
FIG. 3 is an internal SEM photograph of the hemoperfusion sorbent of example 7;
FIG. 4 is a schematic diagram showing the preparation of the hemoperfusion adsorbent in example 8;
fig. 5 is an internal SEM image of the hemoperfusion sorbent of example 8.
Detailed Description
The following describes in detail embodiments of the present invention with reference to the drawings and examples, but the embodiments of the present invention are not limited thereto.
Example 1
Uniformly stirring 30g of 80% divinylbenzene/20% ethylstyrene, 60g of styrene, 30g N-methyldiallylamine, 150g of toluene, 20g of isooctanol and 1.4g of benzoyl peroxide to form an oil phase; adding the oil phase into the water phase composed of 900g deionized water and 5g polyvinyl alcohol, stirring, heating the mixture to 60-80 deg.C, and holding the temperature for 15 hr. And removing the pore-foaming agent in the resin obtained by polymerization, and purifying to obtain the porous polystyrene-based microspheres containing tertiary amine groups.
Example 2
50g of 63% divinylbenzene/37% ethylstyrene, 50g of styrene, 50g of 4-vinylpyridine, 10g of toluene, 190g of methylcyclohexane and 1.8g of benzoyl peroxide are stirred uniformly to form an oil phase; adding the oil phase into the water phase composed of 600g deionized water and 25g gelatin, stirring, heating the mixture to 60-90 deg.C, and holding the temperature for 9 hr. And removing the pore-foaming agent in the resin obtained by polymerization, and purifying to obtain the porous polystyrene-based microspheres containing pyridine groups.
Example 3
Uniformly stirring 90g of 55% of divinylbenzene/45% of ethyl styrene, 10g of styrene, 100g of 1-vinyl imidazole, 90g of toluene, 90g of ethyl cyclohexylamine and 1.8g of azobisisobutyronitrile to form an oil phase; adding the oil phase into the water phase composed of 1000g deionized water and 5g gelatin, stirring, heating the mixture to 60-75 deg.C, and maintaining the temperature for 12 hr. And removing the pore-foaming agent in the resin obtained by polymerization, and purifying to obtain the porous polystyrene-based microspheres containing imidazole groups.
Example 4
100g of the porous polystyrene-based microspheres containing tertiary amine groups prepared in example 1 are mixed with 500g of dichloroethane, 200g of dimethoxymethane and 400g of ferric chloride, and subjected to reflux reaction for 12 hours at a temperature gradient of 50-80 ℃ and purification to obtain the hemoperfusion adsorbent.
FIG. 1 is a schematic diagram of the preparation principle of the hemoperfusion adsorbent in example 4.
Example 5
100g of the porous polystyrene-based microspheres containing tertiary amine groups prepared in example 1 and 400g of dichloroethane are mixed, swelled at room temperature for 12h, added with 100g of trimethyl orthoformate, 100g of 1,1,3, 3-tetramethoxypropane and 50g of aluminum trichloride, refluxed and reacted at the temperature of 50-80 ℃ for 20h, and purified to obtain the hemoperfusion adsorbent.
Example 6
100g of the porous polystyrene-based microspheres containing pyridine groups prepared in example 2 were mixed with 1000g of methylene dichloride, 200g of 1, 1-dimethoxyacetone, 50g of trimethyl orthoformate and 1000g of ferric chloride, and subjected to reflux reaction for 18 hours at a gradient temperature rise condition of 50-80 ℃, and purified to obtain the hemoperfusion adsorbent.
Example 7
100g of the porous polystyrene-based microspheres containing pyridine groups prepared in the example 2 are mixed with 2000g of dichloroethane, 10g of dimethoxymethane and 300g of ferric chloride, and subjected to reflux reaction for 120 hours under the condition of gradient temperature rise of 50-80 ℃, and purified to obtain the hemoperfusion adsorbent.
FIG. 2 is a schematic diagram of the preparation of the hemoperfusion adsorbent in example 7; fig. 3 is an SEM image of the inside of the hemoperfusion sorbent of example 7, from which it can be seen that the prepared hemoperfusion sorbent has a distinct porous structure inside.
Example 8
100g of the porous polystyrene-based microspheres containing imidazole groups prepared in example 3 are mixed with 800g of dichloroethane, 300g of dimethoxymethane and 600g of ferric chloride, and subjected to reflux reaction for 12 hours at a gradient temperature rise condition of 50-80 ℃, and purified to obtain the hemoperfusion adsorbent.
FIG. 4 is a schematic diagram showing the preparation of the hemoperfusion adsorbent in example 8; FIG. 5 is an internal SEM photograph of a hemoperfusion sorbent of example 8; as can be seen from the figure, the prepared hemoperfusion sorbent has a distinct porous structure inside.
Example 9
100g of a commercially available anion exchange resin (Amberlite-400) with quaternary ammonium groups is mixed with 500g of dichloroethane, 20g of trimethyl orthoformate, 10g of dimethoxymethane and 700g of ferric chloride, reflux reaction is carried out for 1h at the temperature of 80 ℃, and purification is carried out to obtain the hemoperfusion adsorbent.
Example 10
100g of the hemoperfusion adsorbent prepared in example 7 is mixed with 500g of dimethyl sulfoxide, 80g of benzyl chloride is added, the mixture is subjected to reflux reaction at 60 ℃ for 12 hours, and purification is carried out, so as to obtain the ultrahigh cross-linked porous resin containing quaternary amine groups.
The adsorbents obtained in the above examples were subjected to physical and chemical parameter evaluation, adsorption performance evaluation, safety evaluation, and the like in this order, using commercially available resins AMBERLITE XAD16, commercially available cartridge resins HA130, and BS330 as reference samples.
(1) Evaluation of physicochemical parameters
The specific surface area and pore analyzer and the N2 adsorption-desorption method are adopted to determine the pore diameter and specific surface area data of the resin.
Mixing 5ml of adsorbent resin with 15ml of pure water solution, placing the mixture at the temperature of 60 ℃ for 100 hours, and detecting the pH value of the solution, namely the pH value of the preservation solution.
TABLE 1 physicochemical evaluation data of examples and comparative examples
Figure BDA0002658537470000081
Figure BDA0002658537470000091
From the comparison of the examples with the comparative examples, it is understood that adsorbents having different pore structures can be obtained by changing the preparation process conditions.
(2) The operating method for the adsorption performance evaluation is as follows:
10ml of plasma solutions containing Dimethoate, sodium pentobarbital, interleukin 6(IL-6), TNF-alpha, parathyroid hormone PTH, bilirubin, bile acid, paracresol PCS sulfate, indoxyl sulfate IS were added to 1ml of the adsorption resins obtained in the above examples and comparative examples, and after shaking at 37 ℃ for 2 hours, changes in the adsorbed substances were measured, respectively, and the results are shown in tables 2 and 3 below.
TABLE 2 adsorption Performance data of examples and comparative examples
Figure BDA0002658537470000092
As can be seen from the results in Table 2, the adsorbents prepared in examples 4 to 10 all have higher adsorption rates to parathyroid hormone (PTH), dimethoate, sodium pentobarbital, interleukin IL-6 and tumor necrosis factor TNF-a, which are better than those of the control samples.
TABLE 3 adsorption Performance data of protein-bound toxins for examples and controls
Figure BDA0002658537470000101
As can be seen from the results in table 3, the adsorbents prepared in examples 4 to 10 have better adsorption performance on protein-bound toxoids such as total bilirubin, total bile acid, Indoxyl Sulfate (IS), and p-cresol sulfate (PCS), and are better than the control.
(3) Blood compatibility and safety evaluations were as follows:
haemolysis and platelet adhesion are mainly used, i.e. tests for the haemocompatibility and safety of materials carried out according to GB/T16886.4-2003 and GB/T16175-1996. See table 4 below for results.
TABLE 4 evaluation data of hemolysis and platelet adhesion in examples and comparative examples
Figure BDA0002658537470000102
Figure BDA0002658537470000111
As can be seen from the results in Table 4, examples 4 to 10 have low hemolysis rate and platelet adhesion rate and exhibit good blood compatibility. Meanwhile, the adsorbents in the embodiments 4 to 10 of the invention are tested for biocompatibility such as cytotoxicity, thrombosis, blood coagulation, complement activation, immunity and the like, and all show excellent biocompatibility results.
Finally, it should be emphasized that the above-described preferred embodiments of the present invention are merely examples of implementations, not limitations, and various changes and modifications may be made by those skilled in the art, without departing from the spirit and scope of the invention, and any changes, equivalents, improvements, etc. made within the spirit and scope of the present invention are intended to be embraced therein.

Claims (10)

1. A hemoperfusion adsorbent, characterized in that: the hemoperfusion adsorbent is obtained by carrying out post-crosslinking reaction on porous polystyrene microspheres with nitrogen-containing groups in the presence of a swelling agent, a crosslinking agent and a catalyst;
the molecular formula of the cross-linking agent is as follows:
Figure FDA0002658537460000011
Figure FDA0002658537460000012
at least one of (a);
wherein R is1Is: -CH3、*—CH2CH3、*—CH2CH2CH3、*—CH2CH2CH2CH3、*—CH(CH3)2One of (a) and (b); k is an integer of 0 to 18;
R2is hydrogen, -CH3、*—CH2CH3、
Figure FDA0002658537460000013
One of (a) and (b);
R3is hydrogen, -CH3、*—CH2CH3、
Figure FDA0002658537460000014
One of (a) and (b);
wherein denotes a covalently linked dot;
the nitrogen-containing group is at least one of a quaternary ammonium salt group structure, a tertiary amine group structure, a secondary amine group structure, a primary amine group structure, a pyridine group structure, an aromatic amine group structure, a pyrrole group structure and an imidazole group structure.
2. A hemoperfusion sorbent according to claim 1 wherein: the blood perfusion adsorbent is spherical particles with the particle size of 0.01-3 mm; the specific surface area of the blood perfusion adsorbent is 10-3500 m2/g。
3. A hemoperfusion sorbent according to claim 1 wherein: the ion exchange capacity of the blood perfusion adsorbent is 0.0001-5.0 mmol/ml.
4. The method for preparing a hemoperfusion adsorbent according to claim 1, wherein: the method comprises the following steps:
(1) an oil phase is composed of a styrene monomer, a nitrogen-containing group monomer, a comonomer, an organic pore-forming agent and an initiator, the oil phase is subjected to suspension polymerization in a water phase composed of a dispersant, a dispersing auxiliary and water, the pore-forming agent in the resin obtained by polymerization is removed, purified and dried to obtain porous polystyrene-based microspheres with nitrogen-containing groups;
the styrene monomer is at least one of a polyvinyl aromatic monomer and a monovinyl aromatic monomer;
the nitrogen-containing group monomer is:
Figure FDA0002658537460000021
Figure FDA0002658537460000022
at least one of (a);
wherein R is4Is one of hydrogen, methyl, ethyl, propyl and isopropyl; r5Alkylene having 0 to 6 carbon atoms; r6The material is one of a quaternary ammonium salt group structure, a tertiary amine group structure, a secondary amine group structure, a primary amine group structure, a pyridine group structure, an aromatic amine group structure, a pyrrole group structure and an imidazole group structure;
the comonomer is at least one of methyl methacrylate, methacrylic acid, acrylic acid, butyl acrylate, methyl acrylate, ethyl acrylate, isooctyl acrylate, 2-hydroxyethyl acrylate, ethyl methacrylate, butyl methacrylate, vinyl acetate, N-hydroxymethyl acrylamide, acrylonitrile, acrylamide and 2-hydroxyethyl methacrylate;
the organic pore-foaming agent is at least one of organic chlorine, hydrocarbon and alcohol;
the initiator is at least one of peroxide and azo compound;
(2) crosslinking reaction
Mixing the porous polystyrene-based microspheres with nitrogen-containing groups with a swelling agent and a crosslinking agent, adding a catalyst for post-crosslinking reaction, and purifying to obtain a hemoperfusion adsorbent;
the swelling agent is at least one of dichloromethane, dichloroethane, propylene dichloride, chlorobenzene, chlorotoluene and nitrobenzene;
the catalyst is at least one of ferric trichloride, aluminum chloride and zinc chloride.
5. The method for preparing a hemoperfusion adsorbent according to claim 4, wherein: in the step (1), the organic chlorine is at least one of methylene dichloride, ethylene dichloride, propylene dichloride, chlorobenzene and chlorotoluene;
the hydrocarbon is at least one of cyclohexylamine, methylcyclohexylamine, ethylcyclohexylamine, benzene, toluene, xylene, ethylbenzene, cycloalkane and alkane;
the alcohol is at least one of methyl isobutyl carbinol, diisobutyl carbinol and isooctyl alcohol.
6. The method for preparing a hemoperfusion adsorbent according to claim 4, wherein: in the step (1), the mass ratio of the styrene monomer, the nitrogen-containing group monomer, the comonomer, the organic pore-forming agent and the initiator is 1 (0.01-1): 0-1): 0.1-10): 0.001-0.1;
the mass ratio of the water to the dispersing agent to the dispersing auxiliary agent is 1 (0.0001-0.1) to 0-0.01;
the mass ratio of the oil phase to the water phase is 1 (0.5-10).
7. The method for preparing a hemoperfusion adsorbent according to claim 4, wherein: in the step (1), the suspension polymerization reaction temperature is 20-90 ℃, and the reaction time is 1-24 h.
8. The method for preparing a hemoperfusion adsorbent according to claim 4, wherein: in the step (2), the mass ratio of the porous polystyrene-based microspheres with the nitrogen-containing groups to the swelling agent to the catalyst to the crosslinking agent is 1 (1-100): (0.1-10) and (0-10).
9. The method for preparing a hemoperfusion adsorbent according to claim 4, wherein: in the step (2), the crosslinking reaction condition is reflux reaction at 40-130 ℃ for 2-80 h.
10. A hemoperfusion ware which characterized in that: the cartridge comprises the blood perfusion adsorbent according to any one of claims 1 to 3 or the blood perfusion adsorbent produced by the production method according to any one of claims 4 to 9.
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