CN114106407B - Blood perfusion adsorbent and preparation method thereof - Google Patents
Blood perfusion adsorbent and preparation method thereof Download PDFInfo
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- CN114106407B CN114106407B CN202010896353.XA CN202010896353A CN114106407B CN 114106407 B CN114106407 B CN 114106407B CN 202010896353 A CN202010896353 A CN 202010896353A CN 114106407 B CN114106407 B CN 114106407B
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- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/36—After-treatment
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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
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
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- B01J20/28057—Surface area, e.g. B.E.T specific surface area
- B01J20/28061—Surface area, e.g. B.E.T specific surface area being in the range 100-500 m2/g
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
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- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
- B01J20/28057—Surface area, e.g. B.E.T specific surface area
- B01J20/28064—Surface area, e.g. B.E.T specific surface area being in the range 500-1000 m2/g
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- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
- B01J20/28057—Surface area, e.g. B.E.T specific surface area
- B01J20/28066—Surface area, e.g. B.E.T specific surface area being more than 1000 m2/g
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F212/00—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
- C08F212/02—Monomers containing only one unsaturated aliphatic radical
- C08F212/04—Monomers containing only one unsaturated aliphatic radical containing one ring
- C08F212/06—Hydrocarbons
- C08F212/08—Styrene
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- C08F212/00—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
- C08F212/34—Monomers containing two or more unsaturated aliphatic radicals
- C08F212/36—Divinylbenzene
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- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/28—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
- 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
- C08J2325/02—Homopolymers or copolymers of hydrocarbons
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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 safety and environmental protection problems caused by the use of carcinogenic chloromethyl methyl ether in the traditional process are solved; the invention adopts a novel cross-linking agent system, realizes the post-crosslinking of the adsorbent resin and the functionalization of the nitrogen-containing group by a one-step method on the basis of polystyrene microspheres, 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
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 poisoning first aid, kidney disease, liver disease and critical diseases, and the principle is that the blood of a patient is led to extracorporeal circulation by means of power and contacted with an adsorbent with special adsorption function in a blood perfusion device to remove endogenous or exogenous poison or pathogenic substances in the blood of the patient, so that the aim of purifying the blood is achieved. Since the last 70 th century, our country has conducted intensive studies on adsorbents for blood perfusion and has been widely used. Particularly, great achievements are obtained in aspects of drug poisoning, liver failure, renal failure, immunoadsorption and the like. At present, the adsorbent is applied to clinical perfusion adsorbents such as enveloped active carbon, macroporous adsorption resin, ion exchange resin, carbonized resin, DNA immunoadsorption, protein A immunoadsorption and the like.
Polystyrene-based cross-linked macroporous adsorption resin and polystyrene-based ion exchange resin are used as two main blood perfusion adsorbents, and show 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 made from a styrene-divinylbenzene crosslinked polymer by chloromethylation followed by amination; the crosslinked polystyrene resin, such as ultra-high crosslinked polystyrene resin, is mainly prepared by chloromethylation and Friedel-Crafts post-crosslinking of macroporous low crosslinked polystyrene-divinylbenzene copolymer. At present, chloromethyl ether is widely used in industry as chloromethylation reagent, and has strong carcinogenicity and low boiling point and volatility, thus causing great threat to the health of production operators, causing great pollution to the environment, and high preparation cost, thereby influencing the sustainable development of the whole industry and needing further technical optimization and improvement.
In addition, in the blood perfusion technology, the ultra-high cross-linked macroporous adsorption resin can adsorb excessive middle-macromolecule toxins in blood by utilizing a pore structure, so that damage and complications of important organs are reduced; styrene anion exchange resins rely on lipophilic binding and strong electrostatic forces to specifically adsorb and remove organ injury toxins such as bilirubin and endotoxins with negative electrical properties. In the field of artificial liver treatment, two adsorbents are often combined for treatment, such as the DPMAS artificial liver system of the healthy sail company. However, in view of the differences in the respective blood purification functions and principles of the ultra-high cross-linked macroporous adsorbent resin and the ion exchange resin, and the limited adsorption removal effect, a plurality of separation/adsorbers are required in clinical use. Because of 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 novel resin with higher broad-spectrum toxin adsorption and removal functions, the reduction of medical cost and the improvement of the treatment rate of patients become urgent clinical demands.
Therefore, the development of a novel adsorbent which avoids using chloromethyl ether as a raw material, has the advantages of green and environment-friendly preparation process, controllable performance and higher broad-spectrum toxin adsorption and removal function, and is important for guaranteeing human health and promoting the development of the blood perfusion adsorbent resin industry.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention aims to provide the blood perfusion adsorbent and the preparation method thereof, wherein chloromethyl ether is not used as a raw material of the adsorbent, and the preparation process is environment-friendly and has controllable structure and performance.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a hemoperfusion adsorbent which is obtained by performing post-crosslinking reaction on porous polystyrene-based 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:
at least one of (2);
wherein R is 1 Is of the type-CH 3 、*—CH 2 CH 3 、*—CH 2 CH 2 CH 3 、*—CH 2 CH 2 CH 2 CH 3 、*—CH(CH 3 ) 2 One of (2) is provided; k is an integer of 0 to 18;
R 2 is hydrogen, -CH 3 、*—CH 2 CH 3 、One of (2) is provided;
R 3 is hydrogen, -CH 3 、*—CH 2 CH 3 、One of (2) is provided;
wherein, represents the point of covalent attachment;
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 m 2 /g；
The ion exchange capacity of the hemoperfusion adsorbent can be controlled to be 0.0001-5.0 mmol/ml.
The preparation method of the hemoperfusion adsorbent provided by the invention sequentially comprises the following steps:
(1) The preparation method comprises the steps of (1) forming an oil phase by a styrene monomer, a nitrogen group-containing monomer, a comonomer, an organic pore-forming agent and an initiator, performing suspension polymerization on the oil phase in a water phase consisting of a dispersing agent, a dispersing aid and water, removing the pore-forming agent in the polymerized resin, purifying and drying to obtain the porous polystyrene microsphere with a nitrogen group;
in the monomers of suspension polymerization, the styrene monomer is at least one of a multi-vinyl aromatic monomer and a single-vinyl aromatic monomer;
the polyvinyl aromatic monomers include a class of compounds consisting of divinylbenzene, mixtures of m-divinylbenzene and p-divinylbenzene, trivinylbenzene, divinylbenzene, divinylxylene, divinylnaphthalene, and derivatives thereof, for example, halides such as chlorodivinylbenzene, and the like. These compounds may be used singly or as a mixture of two or more. The polyvinyl aromatic monomer is preferably at least one of m-divinylbenzene and p-divinylbenzene; particularly preferred polyvinyl aromatic monomer mixtures consist of m-divinylbenzene and p-divinylbenzene. In the preparation of polystyrene-based microspheres by suspension polymerization in the step (1) of the invention, the amount of the polyvinyl aromatic monomer is calculated by dry weight of the copolymer; the monomer comprises at least 1wt% of a polyvinyl aromatic monomer; the amount of the polyvinyl aromatic monomer is preferably 1 to 80% by weight based on the dry weight of the copolymer.
In the suspension polymerization monomers, the monovinylaromatic monomers include, but are not limited to, for example, styrene and C 1 -C 4 Alkyl substituted styrenes such as ethyl styrene, m-ethyl styrene and p-ethyl styrene and mixtures thereof, derivatives, e.g. halides, such as chlorostyrene and chloroethyl styrene. These compounds may be used singly or in a mixture of two or more kinds; the monovinyl aromatic monomer is preferably at least one of styrene, m-ethyl styrene and p-ethyl styrene; particularly preferred mixtures are, for example, mixtures of m-and p-ethylstyrene and mixtures of styrene, m-and p-ethylstyrene. In the preparation of polystyrene-based microspheres by suspension polymerization in the step (1) of the invention, the amount of the monovinyl aromatic monomer is calculated by dry weight of the copolymer; the monomer comprises no more than 99wt% of a monovinylaromatic monomer; the amount of the monovinylaromatic monomer is preferably 20 to 99% by weight, based on the dry weight of the copolymer.
The monomer containing nitrogen groups is as follows:
at least one of (2);
wherein R is 4 Is one of hydrogen, methyl, ethyl, propyl and isopropyl; r is R 5 Alkylene groups of 0 to 6 carbon atoms;
R 6 is of quaternary ammonium salt group structure and tertiary amine group structureOne of secondary amine group structure, primary amine group structure, pyridine group structure, aromatic amine group structure, pyrrole group structure and imidazole group structure;
when R is 6 In the case of tertiary amine group structure, the nitrogen group-containing monomer is preferably N-methyldiallylamine, dimethylacrylamide, dimethylaminopropyl methacrylamide, N, N, N ', N' -tetramethylbisacryltriamine, diethylaminoethyl methacrylate, N, N-diethylacrylamide, dimethylaminoethyl methacrylate;
when R is 6 In the case of a secondary amine group structure, the nitrogen group-containing monomer is preferably methylolacrylamide;
when R is 6 In the case of primary amine group structure, the monomer containing nitrogen group is preferably acrylamide, 2-propylene-1-aminomethyl or the like;
when R is 6 In the case of a pyridine group structure, the nitrogen group-containing monomer is preferably 4-vinylpyridine, 2-methyl-3-vinylpyridine, 3-methyl-5-vinylpyridine, 5-ethyl-2-vinylpyridine, or 4-styrylpyridine;
when R is 6 In the case of an aromatic amine group structure, the monomer containing nitrogen groups is preferably acrylamide or N- (2-aminophenyl) acrylamide;
when R is 6 In the case of pyrrole group structure, the monomer containing nitrogen group is preferably N-vinyl pyrrolidone;
when R is 6 In the case of imidazole group structure, the monomer containing nitrogen group 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-methylolacrylamide, acrylonitrile, acrylamide and 2-hydroxyethyl methacrylate;
the organic pore-forming 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 cyclohexane, methyl cyclohexane, ethyl cyclohexane, 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 peroxy caproate and dilauryl peroxide; the azo compound is preferably azobisisobutyronitrile, 2' -azobis-2-methylbutyronitrile.
The dispersing agent is at least one of polyvinyl alcohol, gelatin, cellulose derivative or polyacrylamide;
the dispersing aid is at least one of sodium pyrophosphate, polyethylene glycol, polydiene dimethyl ammonium chloride, acrylamide, cellulose, isopropanol, n-butanol and isooctyl alcohol, and polyethylene glycol and polydiene dimethyl ammonium chloride are preferred.
Further, the mass ratio of the styrene monomer to the monomer containing nitrogen groups to the comonomer to the organic pore-forming agent to the initiator is 1 (0.01-1) (0.1-10) (0.001-0.1);
the mass ratio of the water to the dispersing agent to the dispersing auxiliary is 1 (0.0001-0.1) (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 nitrogen-containing group monomer has a certain solubility in water, in order to reduce the solubility of the nitrogen-containing group monomer 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 porous polystyrene microsphere with nitrogen-containing group with swelling agent and crosslinking agent, adding catalyst to make post-crosslinking reaction, purifying so as to obtain the invented 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 chloride, aluminum chloride and zinc chloride;
the mass ratio of the porous polystyrene-based microsphere with the nitrogen-containing group to the swelling agent to the catalyst to the cross-linking agent is 1 (1-100): 0.1-10): 0-10;
the post-crosslinking reaction condition is that reflux reaction is carried out for 2-80 h at the temperature of 40-130 ℃.
In the step (2), porous polystyrene-based microspheres with nitrogen-containing groups can be mixed with a swelling agent and swelled for 1-12 h at the temperature of 10-60 ℃; and adding a cross-linking agent and a catalyst to carry out a cross-linking reaction.
The crosslinking method in the step (2) can also be used for carrying out post-crosslinking reaction on the existing commercial resin, such as ion exchange resin with amine groups, such as strong alkaline anion exchange resin with quaternary amine groups and weak alkaline anion exchange resin 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 have influence on the performances of the product, such as the capacity, the surface area, the pore volume and the like of the functional groups, and the suspension polymerization reaction conditions comprise, for example, the type and the content of added monomers, the degree of crosslinking, the existence or non-existence of a pore-forming agent, the type and the like; the crosslinking reaction conditions include, for example, the amount of catalyst, the kind and content of crosslinking agent, the reaction time and 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 the target product with ideal performance can be obtained.
Based on the obtained hemoperfusion adsorbent with nitrogen-containing groups, the nitrogen-containing groups of the adsorbent can be subjected to further chemical reaction modification, so that the structure and the performance of the adsorbent material can be further regulated and controlled. Taking vinyl pyridine as an example of a monomer containing nitrogen groups, copolymerizing the vinyl pyridine with styrene monomers such as styrene and divinylbenzene to obtain porous polystyrene microspheres with pyridine groups, further mixing the porous polystyrene microspheres with a swelling agent and a crosslinking agent, adding a catalyst for post-crosslinking reaction, and purifying to obtain the hemoperfusion adsorbent. The obtained hemoperfusion adsorbent is internally provided with pyridine functional groups. The invention can further carry out chemical reaction, such as quaternization reaction, on the pyridine group, and the surface chemical property of the adsorbent is changed by adding a quaternizing reagent, such as haloalkane, organic acid, benzyl chloride, chlorohydrin, sulfate and the like, and further quaternizing the pyridine group, so as to regulate and control the adsorption performance of the adsorbent on toxin.
The invention also provides a perfusion device for removing endogenous or exogenous poison or pathogenic substances in blood, which comprises the blood perfusion adsorbent or the blood perfusion adsorbent prepared by the preparation method. The adsorption resin for blood perfusion of the present invention or the adsorption resin for blood perfusion prepared by the preparation method of the present invention can be used for adsorbing endogenous or exogenous poison or pathogenic substances in a human body or an animal body in blood perfusion, and in particular, can be used in a perfusion apparatus 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 safety and environmental protection problems caused by the use of carcinogenic chloromethyl methyl ether in the traditional process are solved;
2. the invention adopts a novel cross-linking agent system, realizes the post-crosslinking of the adsorbent resin and the functionalization of the nitrogen-containing group by a one-step method on the basis of polystyrene microspheres, 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 principle of the hemoperfusion adsorbent in example 4;
FIG. 2 is a schematic diagram showing the preparation principle of the hemoperfusion adsorbent in example 7;
FIG. 3 is an internal SEM image of a blood perfusion adsorbent of example 7;
FIG. 4 is a schematic diagram showing the preparation principle of the hemoperfusion adsorbent in example 8;
FIG. 5 is an internal SEM image of a hemodynamic adsorbent of example 8.
Detailed Description
Specific embodiments of the present invention will be described in further detail below 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 a pre-dissolved and uniform water phase consisting of 900g of deionized water and 5g of polyvinyl alcohol, starting stirring, heating the mixture to 60-80 ℃ in a gradient way, and keeping the temperature for 15 hours. And removing the pore-forming agent in the polymerized resin, and purifying to obtain the porous polystyrene-based microsphere with 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 uniformly stirred to form an oil phase; adding the oil phase into a pre-dissolved and uniform water phase consisting of 600g of deionized water and 25g of gelatin, stirring, and heating the mixture to 60-90 ℃ in a gradient way for 9 hours. And removing the pore-forming agent in the polymerized resin, and purifying to obtain the porous polystyrene-based microsphere with pyridine groups.
Example 3
90g of 55% divinylbenzene/45% ethylstyrene, 10g of styrene, 100g of 1-vinylimidazole, 90g of toluene, 90g of ethylcyclohexylamine and 1.8g of azobisisobutyronitrile are uniformly stirred to form an oil phase; adding the oil phase into a pre-dissolved and uniform water phase consisting of 1000g of deionized water and 5g of gelatin, stirring, heating the mixture to 60-75 ℃ in a gradient way, and keeping the temperature for 12 hours. And removing the pore-forming agent in the polymerized resin, and purifying to obtain the porous polystyrene-based microsphere with imidazole groups.
Example 4
100g of porous polystyrene-based microspheres with tertiary amine groups prepared in example 1 are mixed with 500g of dichloroethane, 200g of dimethoxymethane and 400g of ferric trichloride, and reflux reaction is carried out for 12h under the gradient temperature rise condition of 50-80 ℃ and purification is carried out, thus obtaining the hemoperfusion adsorbent.
FIG. 1 is a schematic diagram of the preparation principle of the hemoperfusion adsorbent in example 4.
Example 5
100g of porous polystyrene-based microspheres with tertiary amine groups prepared in example 1 are taken and mixed with 400g of dichloroethane, after swelling for 12 hours at room temperature, 100g of trimethyl orthoformate, 100g of 1, 3-tetramethoxypropane and 50g of aluminum trichloride are added, reflux reaction is carried out for 20 hours under the gradient heating condition of 50-80 ℃, and the blood perfusion adsorbent is obtained after purification.
Example 6
100g of porous polystyrene-based microspheres with pyridine groups prepared in example 2 are mixed with 1000g of methylene dichloride, 200g of 1, 1-dimethoxy acetone, 50g of trimethyl orthoformate and 1000g of ferric trichloride, and reflux reaction is carried out for 18h under the gradient heating condition of 50-80 ℃ and purification is carried out, thus obtaining the hemoperfusion adsorbent.
Example 7
100g of porous polystyrene-based microspheres with pyridine groups prepared in example 2 are mixed with 2000g of dichloroethane, 10g of dimethoxymethane and 300g of ferric trichloride, and reflux reaction is carried out for 120h under the gradient temperature rise condition of 50-80 ℃ for purification, thus obtaining the hemoperfusion adsorbent.
FIG. 2 is a schematic diagram showing the preparation principle of the hemoperfusion adsorbent in example 7; fig. 3 is an internal SEM image of the hemodynamic adsorbent of example 7, from which it can be seen that the interior of the prepared hemodynamic adsorbent has a distinct porous structure.
Example 8
100g of porous polystyrene microsphere with imidazole group prepared in example 3 is taken and mixed with 800g of dichloroethane, 300g of dimethoxymethane and 600g of ferric trichloride, and the mixture is subjected to reflux reaction for 12 hours under the gradient temperature rise condition of 50-80 ℃ and purified, so as to obtain the hemoperfusion adsorbent.
FIG. 4 is a schematic diagram showing the preparation principle of the hemoperfusion adsorbent in example 8; FIG. 5 is an internal SEM image of a blood perfusion adsorbent of example 8; from the figure, it can be seen that the prepared hemoperfusion adsorbent has a significant porous structure inside.
Example 9
100g of commercial 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 trichloride, and the mixture is subjected to reflux reaction for 1h at 80 ℃ and purified to obtain the hemoperfusion adsorbent.
Example 10
100g of the hemoperfusion adsorbent prepared in example 7 is taken and mixed with 500g of dimethyl sulfoxide, 80g of benzyl chloride is added, and the mixture is subjected to reflux reaction for 12 hours at 60 ℃ and purified to obtain the ultra-high crosslinking polyporous resin containing quaternary amine groups.
The adsorbents obtained in the above examples were subjected to evaluation of physical and chemical parameters, evaluation of adsorption performance, evaluation of safety, and the like in this order, using the commercial resin AMBERLITE XAD16, and the commercial emitter resins HA130 and BS330 as reference samples.
(1) Evaluation of physicochemical parameters
And measuring the pore diameter and specific surface area data of the resin by adopting a specific surface area and pore space analyzer and an N2 adsorption-desorption method.
Mixing 5ml of adsorbent resin with 15ml of pure water solution, placing at 60 ℃ for 100 hours, and detecting the pH value of the solution to obtain the pH value of the preservation solution.
Table 1 physical and chemical evaluation data of examples and comparative examples
By comparing the examples with the comparative examples, it is known that by changing the production process conditions, adsorbents having different pore structures can be obtained.
(2) The operation method for evaluating the adsorption performance is as follows:
10ml of a plasma solution containing Dimethoate, sodium pentobarbital, interleukin 6 (IL-6), tumor necrosis factor TNF-alpha, parathyroid hormone PTH, bilirubin, bile acid, p-cresol PCS sulfate, indoxylIS sulfate was added to 1ml of the adsorption resin obtained in the above examples and comparative examples, and after shaking at 37℃for 2 hours, the change of the adsorbed substances was measured, and the results are shown in tables 2 and 3 below.
Table 2 adsorption performance data for examples and comparative examples
As can be seen from the results in Table 2, the adsorbents prepared in examples 4 to 10 all have higher adsorption rates for parathyroid hormone (PTH), dimethoate, sodium pentobarbital, interleukin IL-6 and tumor necrosis factor TNF-a than the control sample.
TABLE 3 protein-bound toxin adsorption performance data for examples and comparative examples
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), paracresol sulfate (PCS) and the like, and are superior to the control sample.
(3) The blood compatibility and safety were evaluated as follows:
the haemolysis and platelet adhesion were mainly used, i.e. the tests were carried out according to GB/T16886.4-2003 and GB/T16175-1996 for blood compatibility and safety tests of the materials. The results are shown in Table 4 below.
Table 4 hemolysis and platelet adhesion evaluation data of examples and comparative examples
As can be seen from the results in Table 4, examples 4 to 10 have lower hemolysis rate and platelet adhesion rate, showing better blood compatibility. Meanwhile, the adsorbents of examples 4 to 10 of the present invention showed excellent biocompatibility results by performing the tests of cytotoxicity, thrombosis, coagulation, complement activation, immunity and other biocompatibility.
Finally, it should be emphasized that the foregoing is merely a preferred embodiment of the present invention, and is not intended to limit the invention, but rather that various changes and modifications can be made by those skilled in the art without departing from the spirit and principles of the invention, and any modifications, equivalent substitutions, improvements, etc. are intended to be included within the scope of the present invention.
Claims (9)
1. A preparation method of a blood perfusion adsorbent is characterized by comprising the following steps: the method comprises the following steps:
(1) The preparation method comprises the steps of (1) forming an oil phase by a styrene monomer, a nitrogen group-containing monomer, a comonomer, an organic pore-forming agent and an initiator, performing suspension polymerization on the oil phase in a water phase consisting of a dispersing agent, a dispersing aid and water, removing the pore-forming agent in the polymerized resin, purifying and drying to obtain the porous polystyrene microsphere with a nitrogen group;
the styrene monomer is at least one of a multi-vinyl aromatic monomer and a single-vinyl aromatic monomer;
the monomer containing nitrogen groups is as follows:
at least one of (2);
wherein R is 4 Is hydrogen, methylOne of a group, ethyl, propyl, isopropyl; r is R 5 Alkylene groups of 0 to 6 carbon atoms; r is R 6 Is one of quaternary ammonium salt group structure, tertiary amine group structure, secondary amine group structure, primary amine group structure, pyridine group structure, aromatic amine group structure, pyrrole group structure and 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-methylolacrylamide, acrylonitrile, acrylamide and 2-hydroxyethyl methacrylate;
the organic pore-forming 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 porous polystyrene-based microspheres with nitrogen-containing groups with a swelling agent and a crosslinking agent, adding a catalyst to perform post-crosslinking reaction, and purifying to obtain a blood perfusion 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 chloride, aluminum chloride and zinc chloride;
the hemoperfusion adsorbent is obtained by performing post-crosslinking reaction on porous polystyrene-based 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:
at least one of (2)；
Wherein R is 1 Is of the type-CH 3 、*—CH 2 CH 3 、*—CH 2 CH 2 CH 3 、*—CH 2 CH 2 CH 2 CH 3 、*—CH(CH 3 ) 2 One of (2) is provided; k is an integer of 0 to 18;
R 2 is hydrogen, -CH 3 、*—CH 2 CH 3 、One of (2) is provided;
R 3 is hydrogen, -CH 3 、*—CH 2 CH 3 、One of (2) is provided;
wherein, represents the point of covalent attachment;
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. The method for preparing the hemoperfusion adsorbent as set forth in 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 m 2 /g。
3. The method for preparing the hemoperfusion adsorbent as set forth in claim 1, wherein: the ion exchange capacity of the hemoperfusion adsorbent is 0.0001-5.0 mmol/ml.
4. The method for preparing the hemoperfusion adsorbent as set forth in claim 1, 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 cyclohexane, methyl cyclohexane, ethyl cyclohexane, benzene, toluene, xylene, ethylbenzene, naphthene and alkane;
the alcohol is at least one of methyl isobutyl carbinol, diisobutyl carbinol and isooctyl alcohol.
5. The method for preparing the hemoperfusion adsorbent as set forth in claim 1, wherein: in the step (1), the mass ratio of the styrene monomer to the monomer containing nitrogen groups to the comonomer to the organic pore-forming agent to the initiator is 1 (0.01-1): 0.1-10): 0.001-0.1;
the mass ratio of the water to the dispersing agent to the dispersing auxiliary is 1 (0.0001-0.1) (0-0.01);
the mass ratio of the oil phase to the water phase is 1 (0.5-10).
6. The method for preparing the hemoperfusion adsorbent as set forth in claim 1, wherein: in the step (1), the suspension polymerization reaction temperature is 20-90 ℃ and the reaction time is 1-24 h.
7. The method for preparing the hemoperfusion adsorbent as set forth in claim 1, wherein: in the step (2), the mass ratio of the porous polystyrene microsphere with nitrogen-containing groups, the swelling agent, the catalyst and the crosslinking agent is 1 (1-100): (0.1-10), and (0-10).
8. The method for preparing the hemoperfusion adsorbent as set forth in claim 1, wherein: in the step (2), the crosslinking reaction condition is reflux reaction for 2-80 h at the temperature of 40-130 ℃.
9. A blood perfusion apparatus, characterized in that: the perfusion apparatus comprises the hemoperfusion adsorbent produced by the production method according to any one of claims 1 to 8.
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