Adsorbent with heparin slow release function, preparation method of adsorbent and hemoperfusion device

Abstract

The invention provides an adsorbent with a heparin slow release function, a preparation method of the adsorbent and a hemoperfusion device, and belongs to the technical field of adsorbent resin. The preparation method comprises the following steps: firstly preparing epoxy group-containing cross-linked porous resin, then reacting with an amino acid compound, and carrying out amino acid grafting modification on the surface of the epoxy group-containing cross-linked porous resin by utilizing the reaction between an epoxy group and an amino group, so that the blood compatibility is improved, and the interaction between the adsorbent and blood components is changed; furthermore, the amino acid modified adsorption resin is cross-linked by using an amido-containing micromolecule cross-linking agent, so that on one hand, the cross-linking degree, the pore structure and the surface property of the adsorbent are changed, and the interaction between the adsorbent and heparin is adjusted, and on the other hand, the specific interaction with heparin is increased by introducing an amine group; the adsorbent has the performance of adsorbing heparin and slowly releasing the heparin, the clinical use amount and use frequency of the heparin are reduced, and the clinical treatment safety is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of adsorption resins, and in particular relates to an adsorbent with heparin sustained release, a preparation method thereof and a blood perfusion device. Background Art

[0002] Hemoperfusion adsorption therapy is an extracorporeal blood purification treatment technology, mainly used to treat certain intractable diseases. It is a process of removing harmful substances from the blood by drawing the patient's blood out of the body, filtering it through a special adsorption column, and then returning the purified blood to the patient's body. Common adsorption materials in hemoperfusion adsorption columns include activated carbon, resin, etc. These materials can effectively adsorb and remove harmful substances such as toxins, metabolites, immune complexes, etc. in the blood, and are widely used in the fields of kidney disease, liver disease, immune disease, drug overdose, critical illness, etc.

[0003] In clinical treatment and scientific research experiments, it was found that existing hemoperfusion adsorbents generally have strong hydrophobicity, large protein adsorption, and blood compatibility that needs to be improved. In addition, in clinical hemoperfusion therapy, in order to prevent and deal with blood coagulation problems, the resin of the hemoperfusion device is usually heparinized before the start of hemoperfusion therapy, and heparin is injected intravenously into the patient to ensure that the blood does not coagulate in the pipeline and the perfusion device; at the same time, during the treatment process, in order to maintain an effective anticoagulant state, heparin maintenance doses are usually added regularly to adjust the patient's coagulation state. Heparinization of hemoperfusion resin before treatment and continuous addition of heparin during the treatment process will cause excessive use of heparin. However, the use of heparin in hemoperfusion therapy may have some potential effects on the health of patients, which are mainly related to the dosage of heparin and long-term use of heparin. Excessive and long-term use of heparin may cause bleeding risks, heparin-induced thrombocytopenia (HIT), allergic reactions, electrolyte imbalance, osteoporosis, liver function and kidney function abnormalities, etc.

[0004] In summary, on the one hand, improving the blood compatibility of hemoperfusion adsorption materials; on the other hand, trying to reduce the amount of heparin used, which is of great significance for improving the clinical treatment safety of clinical hemoperfusion. Summary of the invention

[0005] The purpose of the present invention is to provide an adsorbent with heparin sustained release, a preparation method thereof and a blood perfusion device. The adsorbent prepared by the present invention has a heparin sustained release effect, can reduce the amount of heparin used, improve clinical treatment safety, and has excellent blood compatibility.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing an adsorbent with heparin sustained release, comprising the following steps:

[0008] (1) mixing a polymerization monomer, an epoxy monomer, a porogen and an initiator to obtain an oil phase;

[0009] (2) mixing the dispersant and water to obtain an aqueous phase;

[0010] (3) mixing the oil phase obtained in step (1) and the water phase obtained in step (2) to carry out suspension polymerization to obtain a cross-linked porous resin containing epoxy groups;

[0011] (4) mixing the epoxy group-containing cross-linked porous resin obtained in step (3), the first solvent, the amino acid compound and the first catalyst, and performing a ring-opening reaction to obtain an amino acid-modified adsorption resin;

[0012] (5) mixing the amino acid modified adsorption resin obtained in step (4), an amine-containing small molecule cross-linking agent, a second solvent, and a second catalyst, and performing a cross-linking reaction to obtain an adsorbent having heparin sustained release;

[0013] There is no chronological order for steps (1) and (2).

[0014] Preferably, the polymerizable monomer in step (1) comprises at least one of styrene, divinylbenzene, acrylonitrile, methyl methacrylate and ethyl methacrylate.

[0015] Preferably, in step (1), the mass ratio of the polymerizable monomer, epoxy monomer, porogen and initiator is 1: (0.05-0.5): (0.5-2): (0.005-0.05).

[0016] Preferably, in step (2), the mass ratio of water to dispersant is 1:(0.0005-0.06).

[0017] Preferably, in step (3), the mass ratio of the oil phase to the water phase is 1:(1-5).

[0018] Preferably, the suspension polymerization temperature in step (3) is 70 to 90° C., and the suspension polymerization time is 4 to 24 hours.

[0019] Preferably, in step (4), the mass ratio of the epoxy group-containing cross-linked porous resin, the first solvent, the amino acid compound and the first catalyst is 1:(1-10):(0.1-1):(0.001-0.2).

[0020] Preferably, in step (5), the mass ratio of the amino acid modified adsorption resin, the amine-containing small molecule cross-linking agent, the second solvent and the second catalyst is 1:(0.01-2):(1-10):(0.02-2).

[0021] The present invention also provides an adsorbent with sustained release of heparin prepared by the preparation method described in the above technical solution.

[0022] The present invention also provides a blood perfusion device, comprising the adsorbent with heparin sustained release described in the above technical solution.

[0023] The present invention provides a method for preparing an adsorbent with sustained heparin release, comprising the following steps: (1) mixing a polymerization monomer, an epoxy monomer, a porogen and an initiator to obtain an oil phase; (2) mixing a dispersant and water to obtain an aqueous phase; (3) mixing the oil phase obtained in step (1) and the aqueous phase obtained in step (2) to carry out suspension polymerization to obtain a cross-linked porous resin containing epoxy groups; (4) mixing the cross-linked porous resin containing epoxy groups obtained in step (3), a first solvent, an amino acid compound and a first catalyst to carry out a ring-opening reaction to obtain an amino acid-modified adsorbent resin; (5) mixing the amino acid-modified adsorbent resin obtained in step (4), an amine-containing small molecule cross-linking agent, a second solvent and a second catalyst to carry out a cross-linking reaction to obtain an adsorbent with sustained heparin release; steps (1) and (2) are not performed in any chronological order. The present invention first prepares a cross-linked porous resin containing epoxy groups, and then reacts with an amino acid compound. By using the reaction between the epoxy group and the amino group, amino acid grafting modification is performed on the surface of the cross-linked porous resin containing epoxy groups, thereby reducing the possibility that the human immune system recognizes the adsorbent as a "foreign body", improving blood compatibility, and also changing the physical and chemical properties such as hydrophilicity and charge of the adsorbent surface, and changing the interaction between the adsorbent and blood components; further using an amine-containing small molecule cross-linking agent to cross-link the amino acid modified adsorption resin, on the one hand, changing the cross-linking degree, pore structure, and surface properties of the adsorbent, regulating the interaction between the adsorbent and heparin, and on the other hand, introducing amine groups to increase the specific interaction with heparin, so that the adsorbent has the performance of adsorbing heparin and releasing heparin slowly, reducing the amount and frequency of heparin used in clinical practice, and improving clinical treatment safety. The results of the embodiment show that the adsorbent prepared by the present invention has excellent blood compatibility, an adsorption rate of heparin of more than 80%, and a sustained release effect on heparin. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the infrared spectrum of the cross-linked porous resin containing epoxy groups prepared in step (3) of Example 1 of the present invention;

[0025] Figure 2This is a microscopic appearance picture of the amino acid modified adsorption resin prepared in step (4) of Example 1 of the present invention;

[0026] Figure 3 The infrared spectrum of the amino acid modified adsorption resin prepared in step (4) of Example 1 of the present invention;

[0027] Figure 4 This is a microscopic appearance picture of the adsorbent with sustained release of heparin prepared in Example 1 of the present invention;

[0028] Figure 5 The heparin sustained release graphs of the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4, the adsorbent with heparin sustained release prepared in Examples 1 to 6, the cross-linked polystyrene porous resin prepared in Comparative Example 1, the adsorbent prepared in Comparative Examples 2 to 3, and the commercial resin XAD16. DETAILED DESCRIPTION

[0029] The present invention provides a method for preparing an adsorbent with heparin sustained release, comprising the following steps:

[0030] (1) mixing a polymerization monomer, an epoxy monomer, a porogen and an initiator to obtain an oil phase;

[0031] (2) mixing the dispersant and water to obtain an aqueous phase;

[0032] (3) mixing the oil phase obtained in step (1) and the water phase obtained in step (2) to carry out suspension polymerization to obtain a cross-linked porous resin containing epoxy groups;

[0033] (4) mixing the epoxy group-containing cross-linked porous resin obtained in step (3), the first solvent, the amino acid compound and the first catalyst, and performing a ring-opening reaction to obtain an amino acid-modified adsorption resin;

[0034] (5) mixing the amino acid modified adsorption resin obtained in step (4), an amine-containing small molecule cross-linking agent, a second solvent, and a second catalyst, and performing a cross-linking reaction to obtain an adsorbent having heparin sustained release;

[0035] There is no chronological order for steps (1) and (2).

[0036] Unless otherwise specified, the present invention has no particular limitation on the sources of the raw materials, and commercially available products known to those skilled in the art may be used.

[0037] The invention mixes polymerization monomers, epoxy monomers, porogens and initiators to obtain an oil phase.

[0038] In the present invention, the polymerizable monomer preferably includes at least one of styrene, divinylbenzene, acrylonitrile, methyl methacrylate and ethyl methacrylate.

[0039] In the present invention, the epoxy monomer preferably includes at least one of glycidyl methacrylate and glycidyl acrylate.

[0040] In the present invention, the porogen preferably includes at least one of toluene, xylene, ethylbenzene, methyl isobutyl carbinol, diisobutyl carbinol, ethyl acetate, isobutyl alcohol, isooctyl alcohol, cycloalkanes, paraffins, industrial white oil, solvent gasoline, kerosene, polyvinyl alcohol, paraffin and carbon alcohol.

[0041] In the present invention, the initiator preferably includes at least one of benzoyl peroxide, tert-butyl peroxide, acetophenone peroxide and azobisisobutyronitrile.

[0042] In the present invention, the mass ratio of the polymerizable monomer, epoxy monomer, porogen and initiator is preferably 1: (0.05-0.5): (0.5-2): (0.005-0.05). As an embodiment, the mass ratio of the polymerizable monomer, epoxy monomer, porogen and initiator may be 1: (0.1-0.4): (0.5-1.5): (0.01-0.04). The present invention limits the mass ratio of the polymerizable monomer, epoxy monomer, porogen and initiator to the above range, which can further improve the adsorption performance of the adsorbent.

[0043] The present invention has no special limitation on the mixing operation of the polymerizable monomer, epoxy monomer, porogen and initiator. The raw materials can be uniformly mixed using a mixing technical scheme well known to those skilled in the art.

[0044] The present invention mixes the dispersant and water to obtain an aqueous phase.

[0045] In the present invention, the dispersant preferably includes one of gelatin, polyvinyl alcohol, cellulose derivatives, polyvinyl pyrrolidone, gum arabic, sodium alginate, polyoxyethylene stearate and sodium lauryl sulfate; the cellulose derivative preferably includes at least one of methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.

[0046] In the present invention, the mass ratio of water to dispersant is preferably 1:(0.0005-0.06). As an embodiment, the mass ratio of water to dispersant may be 1:(0.001-0.05), or 1:(0.01-0.04). The present invention limits the mass ratio of water to dispersant to the above range, so that the dispersant can be fully dissolved.

[0047] The present invention has no special limitation on the mixing operation of the dispersant and water, and the raw materials can be uniformly mixed using a mixing technical solution well known to those skilled in the art.

[0048] After obtaining the oil phase and the water phase, the present invention mixes the oil phase and the water phase and performs suspension polymerization to obtain a cross-linked porous resin containing epoxy groups.

[0049] In the present invention, the mass ratio of the oil phase to the water phase is preferably 1:(1-5). As an embodiment, the mass ratio of the oil phase to the water phase can be 1:(1-4) or 1:(2-3). The present invention limits the mass ratio of the oil phase to the water phase within the above range, so that the obtained epoxy group-containing cross-linked porous resin has a better particle size.

[0050] In the present invention, the mixing of the oil phase and the water phase is preferably performed by adding the oil phase into the water phase.

[0051] In the present invention, the temperature of the suspension polymerization is preferably 70 to 90° C. As an embodiment, the temperature of the suspension polymerization may be 75 to 85° C., or may be 80° C.

[0052] In the present invention, the suspension polymerization time is preferably 4 to 24 hours. As an embodiment, the suspension polymerization time can be 5 to 20 hours, or 10 to 15 hours. The present invention limits the temperature and time of suspension polymerization within the above ranges, so that the reaction can proceed fully.

[0053] After the suspension polymerization is completed, the present invention preferably purifies and dries the product of the suspension polymerization in sequence to obtain a cross-linked porous resin containing epoxy groups.

[0054] In the present invention, the purification is preferably washing; the detergent during the washing is preferably an ethanol solution; the volume concentration of the ethanol solution is preferably 50-100%; the number of washings is preferably 3-8 times; the time for each washing is preferably 2-4 hours, more preferably 3 hours; and the washing is preferably carried out under stirring conditions.

[0055] In the present invention, the drying temperature is preferably 40 to 80° C. The present invention has no particular limitation on the drying time, as long as the product is sufficiently dried. In the present invention, the drying preferably includes hot air drying or vacuum heating.

[0056] After obtaining the epoxy group-containing cross-linked porous resin, the present invention mixes the epoxy group-containing cross-linked porous resin, a first solvent, an amino acid compound and a first catalyst to perform a ring-opening reaction to obtain an amino acid-modified adsorption resin.

[0057] In the present invention, the first solvent preferably includes at least one of water, ethanol and methanol.

[0058] In the present invention, the amino acid compound preferably includes at least one of lysine, ornithine, histidine and cysteine. Amino acids are the basic units constituting proteins and are widely present in organisms. The present invention can make the resin surface closer to the natural biological interface by grafting amino acid compounds on the surface of the cross-linked porous resin containing epoxy groups, which can reduce the possibility that the human immune system recognizes the adsorbent as a "foreign body" and improve blood compatibility; in addition, the present invention uses amino acids to graft and modify the resin surface, which can change the physical and chemical properties of the adsorbent resin surface such as hydrophilicity and charge, thereby changing the interaction between the adsorbent surface and blood components; by selecting lysine, ornithine, histidine and cysteine, these amino acid compounds carry groups such as amino and carboxyl groups. Since carboxyl and amino groups are protonated or deprotonated under different pH conditions, they exhibit pH response behavior. Lysine, ornithine, histidine and cysteine ​​are grafted on the material surface, which exhibits zwitterionic characteristics near the physiological pH value, so that the surface of the porous adsorbent material has excellent hydrophilicity and anti-biological substance adhesion characteristics, which can effectively improve the blood compatibility and biocompatibility of the porous adsorbent material.

[0059] In the present invention, the first catalyst preferably includes at least one of sodium hydroxide, triethylamine, ethylenediamine, diethylamine, 1-methylimidazole, benzyltriethylammonium chloride, zinc chloride, ferric chloride, benzoic acid and phthalic acid.

[0060] In the present invention, the mass ratio of the epoxy group-containing cross-linked porous resin, the first solvent, the amino acid compound and the first catalyst is preferably 1: (1-10): (0.1-1): (0.001-0.2). As an embodiment, the mass ratio of the epoxy group-containing cross-linked porous resin, the first solvent, the amino acid compound and the first catalyst can be 1: (2-8): (0.1-0.8): (0.005-0.15), or 1: (3-6): (0.3-0.7): (0.005-0.15). The present invention reacts the epoxy group-containing cross-linked porous resin with the amino acid compound, and utilizes the reaction between the epoxy group and the amino group to perform amino acid grafting modification on the surface of the epoxy group-containing cross-linked porous resin, thereby reducing the possibility that the human immune system recognizes the adsorbent as a "foreign body", improving blood compatibility, and also changing the physical and chemical properties of the adsorbent surface such as hydrophilicity and charge, and changing the interaction between the adsorbent and blood components. The present invention limits the mass ratio of the epoxy group-containing cross-linked porous resin, the first solvent, the amino acid compound and the first catalyst within the above range, which can further improve the adsorption performance, blood compatibility and other properties of the adsorbent.

[0061] In the present invention, the temperature of the ring-opening reaction is preferably 30 to 80° C. As an embodiment, the temperature of the ring-opening reaction can be 40 to 70° C., or 50 to 60° C.

[0062] In the present invention, the time of the ring-opening reaction is preferably 1 to 48 hours. As an embodiment, the time of the ring-opening reaction can be 5 to 40 hours, or 10 to 30 hours. The present invention limits the temperature and time of the ring-opening reaction to the above ranges, so that the reaction can proceed fully.

[0063] After the ring-opening reaction is completed, the product of the ring-opening reaction is preferably purified and dried in sequence to obtain an amino acid-modified adsorption resin.

[0064] In the present invention, the purification is preferably washing; the detergent during the washing is preferably an ethanol solution; the volume concentration of the ethanol solution is preferably 50-100%; the number of washings is preferably 3-8 times; the time for each washing is preferably 2-4 hours, more preferably 3 hours; and the washing is preferably carried out under stirring conditions.

[0065] The present invention has no particular limitation on the drying temperature and time. The drying temperature and time well known to those skilled in the art can be used to ensure that the product is fully dried.

[0066] After obtaining the amino acid modified adsorption resin, the present invention mixes the amino acid modified adsorption resin, an amine-containing small molecule cross-linking agent, a second solvent and a second catalyst to perform a cross-linking reaction to obtain an adsorbent with heparin sustained release.

[0067] In the present invention, the amino-containing small molecule cross-linking agent preferably includes at least one of 4-aminobutyraldehyde dimethyl acetal, aminoacetaldehyde dimethyl acetal, aminoacetaldehyde diethyl acetal, 4-aminobutyraldehyde diethyl acetal, 1-amino-3,3-diethoxypropane, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, 4,4-(dimethylamino)butyraldehyde diethyl acetal, (dimethylamino)acetaldehyde dimethyl acetal, dimethylaminoacetaldehyde diethyl acetal, (3,3-diethoxypropyl)dimethylamine, 4,4-diethoxy-N,N-diethyl-1-butylamine, methylaminoacetaldehyde dimethyl acetal, 2,2-diethoxy-N-methylethyl-1-amine and 2,2-diethoxy-N-ethylethylamine. In the clinical practice of hemoperfusion, heparin is usually used as an anticoagulant. Heparin is mainly composed of mucopolysaccharide sulfate composed of glucosamine, L-iduronide, N-acetylglucosamine and D-glucuronic acid. The molecular structure of heparin contains sulfate groups (-OSO3 -), carboxyl (-COOH), hydroxyl (-OH) and other groups, these chemical groups together constitute the unique structure of heparin, which makes it have strong anticoagulant activity and highly negative charge characteristics. In the present invention, the prepared amino acid modified adsorption resin is subjected to Friedel-Crafts post-crosslinking using an amine-containing small molecule crosslinking agent, and the amine-containing small molecule crosslinking agent used has an alkoxy group and an amine group that can be catalyzed for Friedel-Crafts crosslinking in its structure. In the post-crosslinking reaction, as the Friedel-Crafts alkylation post-crosslinking reaction proceeds, on the one hand, the crosslinking degree, pore structure and surface properties of the adsorption resin are all changed, so that the interaction between the adsorption resin and heparin can be controllably adjusted; on the other hand, amine groups, such as primary amino groups, secondary amino groups, tertiary amino groups and other groups, are introduced into the resin through the crosslinking reaction of the amine-containing small molecule crosslinking agent, which can increase the specific interaction with heparin.

[0068] The adsorbent material obtained by constructing an amine-containing small molecule cross-linking agent in the present invention can continue to maintain good hydrophilicity and blood compatibility, and at the same time has the performance of adsorbing heparin and slowly releasing heparin, that is, the adsorbent material can effectively adsorb a certain amount of heparin and show a slow-release behavior in environments such as buffer, plasma, and blood. The slow-release behavior can avoid the presence of large doses of heparin in the patient's blood and maintain a stable anticoagulant effect, thereby balancing the overall impact of heparin on the patient and reducing the risk of bleeding. The heparin slow-release behavior of the adsorbent with heparin slow-release of the present invention helps to reduce the amount and frequency of heparin use in clinical practice and improve clinical treatment safety.

[0069] In the present invention, the second solvent preferably includes at least one of ethylene dichloride and nitrobenzene.

[0070] In the present invention, the second catalyst preferably includes at least one of ferric chloride and aluminum chloride.

[0071] In the present invention, the mass ratio of the amino acid modified adsorption resin, the amine-containing small molecule cross-linking agent, the second solvent and the second catalyst is preferably 1: (0.01-2): (1-10): (0.02-2). As an embodiment, the mass ratio of the amino acid modified adsorption resin, the amine-containing small molecule cross-linking agent, the second solvent and the second catalyst can be 1: (0.05-1.5): (2-8): (0.05-1.5). The present invention limits the mass ratio of the amino acid modified adsorption resin, the amine-containing small molecule cross-linking agent, the second solvent and the second catalyst to the above range, which can further improve the various properties of the adsorbent.

[0072] In the present invention, the temperature of the cross-linking reaction is preferably 50 to 100° C. As an embodiment, the temperature of the cross-linking reaction can be 60 to 90° C., or 70 to 80° C.

[0073] In the present invention, the cross-linking reaction time is preferably 3 to 48 hours. As an embodiment, the cross-linking reaction time can be 5 to 40 hours, or 10 to 30 hours. The present invention limits the temperature and time of the cross-linking reaction to the above range, so that the reaction can proceed fully.

[0074] After the cross-linking reaction is completed, the present invention preferably purifies and dries the product of the cross-linking reaction in sequence to obtain an adsorbent with sustained release of heparin.

[0075] In the present invention, the purification is preferably: first, use a hydrochloric acid solution with a mass concentration of 0.2-8% to stir and wash for 1-24 hours, then use a sodium hydroxide solution with a mass concentration of 0.5-5% to stir and wash for 1-24 hours, then wash with water until neutral, and finally use an ethanol solution with a volume concentration of 50-100% to rinse for 2-10 hours.

[0076] In the present invention, the drying temperature is preferably 40 to 80° C. The present invention has no particular limitation on the drying time, as long as the product is sufficiently dried. In the present invention, the drying preferably includes hot air drying or vacuum heating.

[0077] In the present invention, the suspension polymerization reaction, the ring-opening reaction (amino acid grafting reaction), and the cross-linking reaction conditions have an impact on the surface physicochemical properties of the product, the pore structure (specific surface area, average pore size and pore volume, etc.), the heparin sustained-release behavior, and the adsorption performance of toxins or proteins. The suspension polymerization reaction conditions include the type and content of the added polymerization monomer and epoxy monomer, the degree of cross-linking, the type and amount of the porogen; the ring-opening reaction (amino acid grafting reaction) conditions include the reaction temperature and time, the type and amount of the catalyst, the type and amount of the amino acid, etc.; the cross-linking reaction conditions include the type and content of the catalyst, the type and content of the cross-linking agent, the reaction time and the reaction temperature, etc. By appropriately changing the reaction conditions, the structure and performance of the adsorbent can be effectively regulated to obtain the target product with ideal performance; the preparation process of the present invention is simple and effective, and can be mass-produced and applied; the structure and performance of the adsorbent are controllable, and it has good blood compatibility and target toxin adsorption performance.

[0078] The present invention also provides an adsorbent with sustained release of heparin prepared by the preparation method described in the above technical solution.

[0079] The adsorbent prepared by the present invention has good blood compatibility and special heparin adsorption and sustained-release behavior, which helps to reduce the amount and frequency of heparin use in clinical practice, reduce the adverse reactions of heparin, reduce the risk of bleeding, etc., thereby improving clinical treatment safety.

[0080] The present invention also provides a blood perfusion device, comprising the adsorbent with heparin sustained release described in the above technical solution.

[0081] The blood perfusion device provided by the present invention is used to remove endogenous or exogenous poisons or pathogenic substances in the blood. The adsorbent with heparin slow release prepared by the present invention can be used in the perfusion device to adsorb endogenous or exogenous poisons or pathogenic substances in the human body or animal body during blood perfusion. The adsorbent with heparin slow release described in the present invention can adsorb and remove uremic toxins (urea, creatinine, macromolecular toxins in uremia, uremic protein-bound toxins, etc.), bilirubin and other toxins related to liver failure, bacterial toxins, inflammatory mediators, autoantibodies and immune complexes, high lipoproteins, etc. The perfusion device for removing endogenous or exogenous poisons or pathogenic substances in the blood described in the present invention can be used for the clinical treatment of diseases and conditions such as renal failure, liver failure, acute poisoning, sepsis and sepsis, autoimmune diseases, inflammatory diseases, hyperlipidemia, etc. These applications are all based on the fact that the blood perfusion device of the present invention can effectively remove harmful substances in the body, thereby providing significant therapeutic effects in emergency situations or as an auxiliary treatment method.

[0082] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0083] Example 1

[0084] The preparation method of the adsorbent with sustained release of heparin is as follows:

[0085] (1) 100 g of divinylbenzene (DVB 80), 20 g of glycidyl methacrylate, 150 g of a porogen (100 g of toluene, 50 g of methyl isobutyl carbinol) and 1.2 g of benzoyl peroxide BPO were mixed to obtain an oil phase, wherein the mass ratio of divinylbenzene, glycidyl methacrylate, porogen and benzoyl peroxide was 1:0.2:1.5:0.012;

[0086] (2) mixing 400 g of water and 6 g of gelatin to obtain an aqueous phase, wherein the mass ratio of water to gelatin is 1:0.015;

[0087] (3) adding the oil phase obtained in step (1) to the water phase obtained in step (2), and performing suspension polymerization at 80° C. for 12 h. After the reaction is completed, washing with 95% ethanol solution by stirring for 3 times, each time for 3 h, and then drying at 80° C. to obtain a cross-linked porous resin containing epoxy groups, wherein the mass ratio of the oil phase to the water phase is 1:1.5;

[0088] (4) 50 g of the epoxy group-containing cross-linked porous resin prepared in step (3) was mixed with 400 g of a solvent (300 g of water and 100 g of ethanol), 30 g of lysine and 4 g of sodium hydroxide were added, and a ring-opening reaction was carried out at 80° C. for 24 h. The mixture was stirred and washed with 100% ethanol by volume for 3 times, each time for 3 h, and then dried at 80° C. to obtain an amino acid-modified adsorption resin, wherein the mass ratio of the epoxy group-containing cross-linked porous resin, the solvent, lysine and sodium hydroxide was 1:8:0.6:0.08;

[0089] (5) 50 g of the amino acid modified adsorption resin prepared in step (4) was mixed evenly with 20 g of 4-aminobutyraldehyde dimethyl acetal, 500 g of dichloroethane and 20 g of ferric chloride. After swelling, the mixture was refluxed at 80° C. for a cross-linking reaction for 10 h. The mixture was first washed with a 2% hydrochloric acid solution under stirring for 12 h, then washed with a 2% sodium hydroxide solution under stirring for 12 h, then washed with water until neutral, and finally rinsed with an 80% ethanol solution under a volume concentration of 80 h. After drying at 60° C., an adsorbent with heparin sustained release was obtained, wherein the mass ratio of the amino acid modified adsorption resin, 4-aminobutyraldehyde dimethyl acetal, dichloroethane and ferric chloride was 1:0.4:10:0.4.

[0090] The cross-linked porous resin containing epoxy groups prepared in step (3) of Example 1 is white spherical smooth particles with a particle size between 0.1 and 1 mm.

[0091] The infrared spectrum of the cross-linked porous resin containing epoxy groups prepared in step (3) of Example 1 is as follows: Figure 1 As shown. Figure 1 It can be seen that at 1730cm -1 The characteristic peaks attributable to the ester bond group of glycidyl methacrylate appeared at 1259 cm -1 The infrared characteristic peaks attributed to the epoxy group appeared at 1602, 1510 cm -1 Characteristic peaks belonging to the benzene ring structure appear at the same time; this indicates that divinylbenzene and glycidyl methacrylate are successfully copolymerized to obtain the epoxy group-containing cross-linked porous resin of this embodiment.

[0092] The microscopic appearance of the amino acid modified adsorption resin prepared in step (4) of Example 1 is as follows: Figure 2 As shown. Figure 2 It can be seen that the amino acid modified adsorption resin prepared in step (4) of Example 1 is light yellow spherical smooth particles with a particle size between 0.1 and 1 mm.

[0093] The infrared spectrum of the amino acid modified adsorption resin prepared in step (4) of Example 1 is as follows: Figure 3 As shown. Figure 3It can be seen that at 3000~3500cm -1 The intensity of the infrared characteristic peak is significantly enhanced, which should be attributed to the superposition and enhancement of the characteristic peak of lysine and the characteristic peak of hydroxyl obtained by the ring-opening reaction of epoxy group.

[0094] The microscopic appearance of the adsorbent with sustained release of heparin prepared in Example 1 is as follows: Figure 4 As shown. Figure 4 It can be seen that the adsorbent with sustained release of heparin prepared in Example 1 is brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0095] Example 2

[0096] The preparation method of the adsorbent with sustained release of heparin is as follows:

[0097] (1) to (3) are the same as in Example 1, to obtain a cross-linked porous resin containing epoxy groups;

[0098] (4) 50 g of the epoxy group-containing cross-linked porous resin prepared in step (3) was mixed with 500 g of water, 20 g of ornithine and 10 g of triethylamine were added, and a ring-opening reaction was carried out at 80° C. for 12 h. The mixture was stirred and washed 5 times with a 50% by volume ethanol solution for 3 h each time, and then dried at 40° C. to obtain an amino acid-modified adsorption resin, wherein the mass ratio of the epoxy group-containing cross-linked porous resin, water, ornithine and triethylamine was 1:10:0.4:0.2;

[0099] (5) 50 g of the amino acid modified adsorption resin prepared in step (4) was evenly mixed with 10 g of aminoacetaldehyde dimethyl acetal, 300 g of dichloroethane and 10 g of ferric chloride. After swelling, the mixture was refluxed at 80° C. for a cross-linking reaction for 8 h. The mixture was first washed with a 0.2% hydrochloric acid solution under stirring for 24 h, then washed with a 0.5% sodium hydroxide solution under stirring for 24 h, then washed with water until neutral, and finally rinsed with 100% ethanol by volume for 2 h. After drying at 80° C., an adsorbent with sustained release of heparin was obtained, wherein the mass ratio of the amino acid modified adsorption resin, aminoacetaldehyde dimethyl acetal, dichloroethane and ferric chloride was 1:0.2:6:0.2.

[0100] The amino acid-modified adsorption resin prepared in step (4) of Example 2 is light yellow spherical smooth particles with a particle size between 0.1 and 1 mm.

[0101] The adsorbent with sustained release of heparin prepared in Example 2 is brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0102] Example 3

[0103] The preparation method of the adsorbent with sustained release of heparin is as follows:

[0104] (1) 100 g of divinylbenzene (DVB 80), 30 g of glycidyl methacrylate, 200 g of a porogen (150 g of toluene, 50 g of methyl isobutyl carbinol) and 1.0 g of benzoyl peroxide BPO were mixed to obtain an oil phase, wherein the mass ratio of divinylbenzene, glycidyl methacrylate, porogen and benzoyl peroxide was 1:0.3:2:0.01;

[0105] (2) mixing 500 g of water and 8 g of gelatin to obtain an aqueous phase, wherein the mass ratio of water to gelatin is 1:0.016;

[0106] (3) adding the oil phase obtained in step (1) to the water phase obtained in step (2), and performing suspension polymerization at 80° C. for 24 h. After the reaction is completed, washing with 90% by volume ethanol solution for 5 times, each time for 3 h, and then drying at 80° C. to obtain a cross-linked porous resin containing epoxy groups, wherein the mass ratio of the oil phase to the water phase is 1:1.5;

[0107] (4) 50 g of the epoxy group-containing cross-linked porous resin prepared in step (3) was mixed with 100 g of water, 50 g of histidine and 1 g of sodium hydroxide were added, and a ring-opening reaction was carried out at 60° C. for 48 h. The mixture was stirred and washed three times with a 60% by volume ethanol solution for 3 h each time, and then dried at 80° C. to obtain an amino acid modified adsorption resin, wherein the mass ratio of the epoxy group-containing cross-linked porous resin, water, histidine and sodium hydroxide was 1:2:1:0.02;

[0108] (5) 50 g of the amino acid modified adsorption resin prepared in step (4) was mixed evenly with 30 g of N,N-dimethylformamide dimethyl acetal, 400 g of dichloroethane and 20 g of ferric chloride. After swelling, the mixture was refluxed at 78° C. for a cross-linking reaction for 12 h. The mixture was first washed with 8% hydrochloric acid solution with stirring for 1 h, then washed with 5% sodium hydroxide solution with stirring for 1 h, then washed with water until neutral, and finally rinsed with 95% ethanol solution with volume concentration for 6 h. After drying at 70° C., an adsorbent with heparin sustained release was obtained, wherein the mass ratio of the amino acid modified adsorption resin, N,N-dimethylformamide dimethyl acetal, dichloroethane and ferric chloride was 1:0.6:8:0.4.

[0109] The cross-linked porous resin containing epoxy groups prepared in step (3) of Example 3 is white spherical smooth particles with a particle size between 0.1 and 1 mm.

[0110] The amino acid-modified adsorption resin prepared in step (4) of Example 3 is light yellow spherical smooth particles with a particle size between 0.1 and 1 mm.

[0111] The adsorbent with sustained release of heparin prepared in Example 3 is brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0112] Example 4

[0113] The preparation method of the adsorbent with sustained release of heparin is as follows:

[0114] (1) 100 g of polymerizable monomers (10 g of styrene, 80 g of divinylbenzene (DVB 80), 10 g of methyl methacrylate), 50 g of epoxy monomer (glycidyl acrylate), 50 g of porogen (isooctanol) and 0.75 g of azobisisobutyronitrile were mixed to obtain an oil phase, wherein the mass ratio of the polymerizable monomers, the epoxy monomers, the porogen and the azobisisobutyronitrile was 1:0.5:0.5:0.0075;

[0115] (2) mixing 600 g of water and 0.5 g of hydroxypropyl methylcellulose to obtain an aqueous phase, wherein the mass ratio of water to hydroxypropyl methylcellulose is 1:0.0008;

[0116] (3) adding the oil phase obtained in step (1) to the water phase obtained in step (2), and performing suspension polymerization at 76° C. for 12 h. After the reaction is completed, washing with 95% by volume ethanol solution for 3 times, each time for 3 h, and then drying at 80° C. to obtain a cross-linked porous resin containing epoxy groups, wherein the mass ratio of the oil phase to the water phase is 1:3;

[0117] (4) 50 g of the epoxy group-containing cross-linked porous resin prepared in step (3) was mixed with 500 g of a solvent (400 g of water and 100 g of ethanol), 25 g of cysteine ​​and 5 g of ethylenediamine were added, and a ring-opening reaction was carried out at 80° C. for 48 h. The mixture was stirred and washed four times with a 50% by volume ethanol solution for 3 h each time, and then dried at 60° C. to obtain an amino acid modified adsorption resin, wherein the mass ratio of the epoxy group-containing cross-linked porous resin, the solvent, cysteine ​​and ethylenediamine was 1:10:0.5:0.1;

[0118] (5) 50 g of the amino acid modified adsorption resin prepared in step (4) was mixed evenly with 20 g of N,N-dimethylformamide diethyl acetal, 200 g of dichloroethane and 100 g of ferric chloride. After swelling, the mixture was refluxed at 80° C. for a cross-linking reaction for 3 h. The mixture was first washed with a 1% hydrochloric acid solution with stirring for 8 h, then washed with a 1% sodium hydroxide solution with stirring for 24 h, then washed with water until neutral, and finally rinsed with a 60% ethanol solution with a volume concentration for 8 h. After drying at 60° C., an adsorbent with heparin sustained release was obtained, wherein the mass ratio of the amino acid modified adsorption resin, N,N-dimethylformamide diethyl acetal, dichloroethane and ferric chloride was 1:0.4:4:2.

[0119] The cross-linked porous resin containing epoxy groups prepared in step (3) of Example 4 is white spherical smooth particles with a particle size between 0.1 and 1 mm.

[0120] The amino acid modified adsorption resin prepared in step (4) of Example 4 is white spherical smooth particles with a particle size between 0.1 and 1 mm.

[0121] The adsorbent with sustained release of heparin prepared in Example 4 is dark brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0122] Example 5

[0123] The preparation method of the adsorbent with sustained release of heparin is as follows:

[0124] (1) to (4) are the same as in Example 1, to obtain an amino acid modified adsorption resin;

[0125] (5) 50 g of the amino acid modified adsorption resin prepared in step (4) was mixed evenly with 50 g of (dimethylamino)acetaldehyde dimethyl acetal, 300 g of nitrobenzene and 2 g of aluminum trichloride. After swelling, the mixture was refluxed at 60° C. for a cross-linking reaction for 24 h. The mixture was first washed with a 2% hydrochloric acid solution with stirring for 2 h, then washed with a 3% sodium hydroxide solution with stirring for 3 h, then washed with water until neutral, and finally rinsed with 100% ethanol by volume for 6 h. After drying at 50° C., an adsorbent with sustained release of heparin was obtained, wherein the mass ratio of the amino acid modified adsorption resin, (dimethylamino)acetaldehyde dimethyl acetal, nitrobenzene and aluminum trichloride was 1:1:6:0.04.

[0126] The microscopic appearance of the amino acid modified adsorption resin prepared in step (4) of Example 5 is as follows: Figure 2 As shown. Figure 2 It can be seen that the amino acid modified adsorption resin prepared in step (4) of Example 5 is light yellow spherical smooth particles with a particle size between 0.1 and 1 mm.

[0127] The infrared spectrum of the amino acid modified adsorption resin prepared in step (4) of Example 5 is as follows: Figure 3 As shown. Figure 3 It can be seen that at 3000~3500cm -1 The intensity of the infrared characteristic peak is significantly enhanced, which should be attributed to the superposition and enhancement of the characteristic peak of lysine and the characteristic peak of hydroxyl obtained by the ring-opening reaction of epoxy group.

[0128] The adsorbent with sustained release of heparin prepared in Example 5 is dark brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0129] Example 6

[0130] The preparation method of the adsorbent with sustained release of heparin is as follows:

[0131] (1) to (4) are the same as in Example 1, to obtain an amino acid modified adsorption resin;

[0132] (5) 50 g of the amino acid modified adsorption resin prepared in step (4) was mixed evenly with 25 g of methylaminoacetaldehyde dimethyl acetal, 400 g of nitrobenzene and 5 g of aluminum trichloride. After swelling, the mixture was refluxed at 50° C. for a cross-linking reaction for 48 h. The mixture was first washed with a 5% hydrochloric acid solution with stirring for 3 h, then washed with a 3% sodium hydroxide solution with stirring for 4 h, then washed with water until neutral, and finally rinsed with a 90% ethanol solution with a volume concentration for 6 h. After drying at 75° C., an adsorbent with sustained release of heparin was obtained, wherein the mass ratio of the amino acid modified adsorption resin, methylaminoacetaldehyde dimethyl acetal, nitrobenzene and aluminum trichloride was 1:0.5:8:0.1.

[0133] The adsorbent with sustained release of heparin prepared in Example 6 is light brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0134] Comparative Example 1

[0135] (1) 100 g of divinylbenzene (DVB 80), 150 g of a porogen (including 100 g of toluene and 50 g of methyl isobutyl carbinol) and 1.2 g of benzoyl peroxide BPO were mixed to obtain an oil phase, wherein the mass ratio of divinylbenzene, porogen and benzoyl peroxide was 1:1.5:0.012;

[0136] (2) mixing 400 g of water and 6 g of gelatin to obtain an aqueous phase, wherein the mass ratio of water to gelatin is 1:0.015;

[0137] (3) adding the oil phase obtained in step (1) to the water phase obtained in step (2), and performing suspension polymerization at 80° C. for 12 h. After the reaction is completed, the resin is purified and dried to obtain a cross-linked polystyrene porous resin without any modified groups.

[0138] The cross-linked polystyrene porous resin without any modified groups prepared in Comparative Example 1 is white spherical smooth particles with a particle size between 0.1 and 1 mm.

[0139] Comparative Example 2

[0140] 50 g of the cross-linked polystyrene porous resin prepared in Comparative Example 1 was evenly mixed with 20 g of 4-aminobutyraldehyde dimethyl acetal, 500 g of ethylene dichloride and 20 g of ferric chloride. After swelling, the mixture was refluxed at 80° C. for 10 hours for cross-linking reaction. After purification and drying, an adsorbent was obtained, in which the mass ratio of the cross-linked polystyrene porous resin, 4-aminobutyraldehyde dimethyl acetal, ethylene dichloride and ferric chloride was 1:0.4:10:0.4.

[0141] The adsorbent prepared in Comparative Example 2 is brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0142] Comparative Example 3

[0143] 50 g of the cross-linked polystyrene porous resin prepared in Comparative Example 1 was evenly mixed with 30 g of N,N-dimethylformamide dimethyl acetal, 400 g of dichloroethane and 20 g of ferric chloride. After swelling, the mixture was refluxed at 78° C. for 12 h for cross-linking reaction. After purification and drying, an adsorbent was obtained, in which the mass ratio of the cross-linked polystyrene porous resin, N,N-dimethylformamide dimethyl acetal, dichloroethane and ferric chloride was 1:0.6:8:0.4.

[0144] The adsorbent prepared in Comparative Example 3 is brown spherical smooth particles with a particle size between 0.1 and 1 mm.

[0145] The amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4, the adsorbent with sustained release of heparin prepared in Examples 1 to 6, the cross-linked polystyrene porous resin prepared in Comparative Example 1, the adsorbent prepared in Comparative Examples 2 to 3, and the commercial resin XAD16 were subjected to heparin adsorption and sustained release tests, blood compatibility evaluation, physicochemical parameter evaluation, and adsorption performance evaluation.

[0146] Heparin adsorption and sustained release testing

[0147] Refer to the amount and method of heparin use in clinical perfusion apparatus, that is: use physiological saline (0.9%) to moisten the adsorption resin or adsorbent to be tested, drain it, and obtain wet resin for standby use; mix heparin injection with physiological saline (0.9%) to prepare about 1 mg / mL heparin-physiological saline solution; measure 100 ml of wet resin, mix it with 100 ml of 1 mg / mL heparin-physiological saline solution, shake to mix evenly, and let it stand for 30 minutes.

[0148] By measuring the concentration of heparin in the solution before and after adsorption, the adsorption rate R is calculated from the concentration difference of the solute before and after adsorption, as shown in formula (1):

[0149] Adsorption rate

[0150] Where, R: adsorption rate of heparin, %; C0: initial concentration of heparin; C S : Concentration of heparin after adsorption.

[0151] After the adsorption is completed, the resin adsorbed with heparin is separated from the heparin-physiological saline solution; 50 mL of the resin adsorbed with heparin is taken and loaded into a cylindrical tube (glass chromatography column) with a sand core filter, and at a set time interval (15 min), 100 mL of PBS buffer solution (pH = 7.4) is slowly dripped into the glass chromatography column containing the resin each time, and the percolate is completely collected from the bottom of the glass chromatography column, thereby simulating the release of heparin from the resin, and testing and analyzing the heparin release behavior of the resin.

[0152] The heparin adsorption rates corresponding to the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4, the adsorbent with heparin sustained release prepared in Examples 1 to 6, the cross-linked polystyrene porous resin prepared in Comparative Example 1, the adsorbent prepared in Comparative Examples 2 to 3 and the commercial resin XAD16 are shown in Table 1.

[0153] Table 1 Heparin adsorption rate of the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4, the adsorbent with heparin sustained release prepared in Examples 1 to 6, the cross-linked polystyrene porous resin prepared in Comparative Example 1, the adsorbent prepared in Comparative Examples 2 to 3, and the commercial resin XAD16

[0154]

[0155]

[0156] It can be seen from Table 1 that the adsorbents of Examples 1 to 6 and Comparative Examples 2 to 3 of the present invention have obvious heparin adsorption rates, all greater than 80%; the resin prepared in step (4) of Example 3 has a certain heparin adsorption rate, about 42.5%; while the amino acid modified adsorption resin prepared in step (4) of Example 1, the amino acid modified adsorption resin prepared in step (4) of Example 2, the amino acid modified adsorption resin prepared in step (4) of Example 4, Comparative Example 1, and the XAD16 adsorbent have no obvious heparin adsorption rates, all lower than 10%.

[0157] The heparin sustained release behavior of each resin or adsorbent was further tested and analyzed. Figure 5 As shown. Figure 5It can be seen that under the PBS environment, the adsorbents of Examples 1 to 6 and Comparative Examples 2 to 3 of the present invention have obvious heparin sustained-release behavior; among them, the heparin release effects of the adsorbents of Example 1, Example 2 and Comparative Example 2 are relatively close, showing a release effect of first fast and then slow. After 2 hours, the heparin sustained-release rate reaches 84-89%; the heparin release effects of the adsorbents of Example 3, Example 4, Example 5 and Comparative Example 3 are also relatively close, and they also show a release effect of first fast and then slow. After 2 hours, the heparin sustained-release rate reaches 68-78%; the adsorbent of Example 6 of the present invention, its heparin sustained-release rate is based on the above; the resin of Example 6 of the present invention has certain heparin sustained-release characteristics within the first hour, and can reach a sustained-release rate of 88% within 1 hour. After 2 hours, its heparin sustained-release rate reaches 98%. On the contrary, the amino acid modified adsorption resin prepared in step (4) of Example 1 of the present invention, the amino acid modified adsorption resin prepared in step (4) of Example 2, the amino acid modified adsorption resin prepared in step (4) of Example 4, and the resin of Comparative Example 1, the heparin adsorbed therein will be rapidly desorbed and released within half an hour, and no good sustained-release effect is shown.

[0158] In addition to the heparin sustained release test of the material in PBS buffer solution, the present invention conducted tests in different environments such as plasma and blood, and the results showed that the samples of the embodiments of the present invention and the comparative examples had similar heparin sustained release behaviors as those in PBS buffer solution. It can be seen that the resin adsorbent with heparin sustained release behavior can be obtained by adopting the scheme of the present invention.

[0159] Blood compatibility evaluation

[0160] The present invention evaluates the blood compatibility of the adsorbent material through performance indicators such as protein adsorption rate, hemolysis rate, platelet count test, etc. The values ​​of protein adsorption rate, hemolysis rate, and platelet decrease rate can directly reflect the blood compatibility of the material; lower values ​​reflect better blood compatibility.

[0161] in:

[0162] Protein adsorption rate test: The resin sample was washed with physiological saline for 5 times, and the washed sample was tested at a bath ratio of 1mL / 10mL. The sample was dynamically contacted with plasma at 170r / min for 120min at 37℃, and the content of albumin and total protein before and after adsorption was detected, and the adsorption rate was calculated.

[0163] Hemolysis rate test: The resin sample was washed with physiological saline for 5 times, and the washed sample was tested at a bath ratio of 5g / 10mL. The sample was incubated with diluted rabbit blood at 37°C, and the absorbance of hemoglobin released by red blood cell rupture was detected to calculate the hemolysis rate.

[0164] Platelet count test: The resin sample was washed 5 times with saline, and the washed sample was tested at a bath ratio of 0.2 g / mL. The sample was in dynamic contact with whole blood at 37°C at 30 r / min for 60 minutes, and the number of platelets in the whole blood was detected using a blood cell analyzer, and the platelet decrease rate was calculated.

[0165] The blood compatibility index evaluation test results of the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4, the adsorbent with heparin sustained release prepared in Examples 1 to 6, the cross-linked polystyrene porous resin prepared in Comparative Example 1, the adsorbent prepared in Comparative Examples 2 to 3, and the commercial resin XAD16 are shown in Table 2.

[0166] Table 2 Blood compatibility index evaluation test results of the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4, the adsorbent with heparin sustained release prepared in Examples 1 to 6, the cross-linked polystyrene porous resin prepared in Comparative Example 1, the adsorbent prepared in Comparative Examples 2 to 3, and the commercial resin XAD16

[0167]

[0168]

[0169] As can be seen from Table 2, the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4 of the present invention and the adsorbent with sustained heparin release prepared in Examples 1 to 6 have albumin adsorption rates less than 5%, hemolysis rates less than 1%, and platelet reduction rates less than 10%. Compared with Comparative Examples 1 to 3 and XAD16, the embodiments of the present invention exhibit better blood compatibility. At the same time, the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4 of the present invention and the adsorbent with sustained heparin release prepared in Examples 1 to 6 were tested for biocompatibility such as cytotoxicity, thrombosis, coagulation, complement activation, and immunity, and all showed excellent biocompatibility results or blood compatibility results.

[0170] In summary, by adopting the scheme of the present invention, the resin adsorbents obtained in Examples 1 to 6 can simultaneously have obvious heparin sustained-release behavior and excellent blood compatibility.

[0171] Evaluation of physical and chemical parameters and adsorption performance

[0172] The pore size and specific surface area data of the resin were measured by N2 adsorption-desorption method using a specific surface area and pore analyzer. 10 mL of plasma solution containing parathyroid hormone PTH, β2-microglobulin (β2-MG), and interleukin 6 (IL-6) were taken, 1 mL of the adsorption resin obtained in the above examples and comparative examples was added, and after shaking at 37°C for 2 hours, the changes of the adsorbed substances were measured, and the results are shown in Table 3.

[0173] Table 3 Physical structural parameters of the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4, the adsorbent with heparin sustained release prepared in Examples 1 to 6, the cross-linked polystyrene porous resin prepared in Comparative Example 1, the adsorbent prepared in Comparative Examples 2 to 3, and the commercial resin XAD16 and their macromolecular toxin adsorption performance

[0174]

[0175]

[0176] By comparing the examples in Table 3 with the comparative examples, it can be seen that by changing the preparation process conditions, adsorbents with different pore structures can be obtained. It can also be seen from Table 3 that the amino acid modified adsorption resin prepared in step (4) of Examples 1 to 4 of the present invention and the adsorbent with heparin sustained release prepared in Examples 1 to 6 all maintain a relatively high adsorption rate of parathyroid hormone (PTH), β2-microglobulin (β2-MG), and interleukin IL-6, and are even better than the control sample and the reference sample XAD16. It can be seen that the resin adsorbent obtained by the scheme of the present invention not only has obvious heparin sustained release behavior and excellent blood compatibility, but also does not affect the adsorption effect of the material on medium and macromolecular toxins.

[0177] In addition, experiments have found that the resin of the embodiments of the present invention also has good adsorption performance for uremic protein-bound toxins, bilirubin, bile acid, endotoxin, etc.

[0178] The resin adsorbent prepared in the embodiment of the present invention is further prepared into a hemoperfusion device, which can be used for clinical treatment of diseases and symptoms such as renal failure, liver failure, acute poisoning, sepsis and septicemia, autoimmune diseases, inflammatory diseases, and hyperlipidemia.

[0179] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing an adsorbent having sustained release of heparin, comprising the following steps: (1) mixing a polymerization monomer, an epoxy monomer, a porogen and an initiator to obtain an oil phase; (2) mixing the dispersant and water to obtain an aqueous phase; (3) mixing the oil phase obtained in step (1) and the water phase obtained in step (2) to carry out suspension polymerization to obtain a cross-linked porous resin containing epoxy groups; (4) mixing the epoxy group-containing cross-linked porous resin obtained in step (3), the first solvent, the amino acid compound and the first catalyst, and performing a ring-opening reaction to obtain an amino acid-modified adsorption resin; (5) mixing the amino acid modified adsorption resin obtained in step (4), an amine-containing small molecule cross-linking agent, a second solvent, and a second catalyst, and performing a cross-linking reaction to obtain an adsorbent having heparin sustained release; There is no chronological order for steps (1) and (2).

2. The preparation method according to claim 1, characterized in that: The polymerizable monomer in step (1) includes at least one of styrene, divinylbenzene, acrylonitrile, methyl methacrylate and ethyl methacrylate.

3. The preparation method according to claim 1, characterized in that: In the step (1), the mass ratio of the polymerizable monomer, the epoxy monomer, the porogen and the initiator is 1: (0.05-0.5): (0.5-2): (0.005-0.05).

4. The preparation method according to claim 1, characterized in that: The mass ratio of water to dispersant in the step (2) is 1:(0.0005-0.06).

5. The preparation method according to claim 1, characterized in that: The mass ratio of the oil phase to the water phase in the step (3) is 1:(1-5).

6. The preparation method according to claim 1, characterized in that: The temperature of the suspension polymerization in step (3) is 70 to 90° C., and the time of the suspension polymerization is 4 to 24 hours.

7. The preparation method according to claim 1, characterized in that: In the step (4), the mass ratio of the epoxy group-containing cross-linked porous resin, the first solvent, the amino acid compound and the first catalyst is 1:(1-10):(0.1-1):(0.001-0.2).

8. The preparation method according to claim 1, characterized in that: In the step (5), the mass ratio of the amino acid modified adsorption resin, the amine-containing small molecule cross-linking agent, the second solvent and the second catalyst is 1:(0.01-2):(1-10):(0.02-2).

9. The adsorbent with sustained release of heparin obtained by the preparation method according to any one of claims 1 to 8.

10. A blood perfusion device comprising the adsorbent capable of sustained release of heparin according to claim 9.

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