Anticoagulant adsorption resin material and preparation method thereof

Abstract

The invention discloses an anticoagulant adsorption resin material and a preparation method thereof, styrene-divinylbenzene macroporous adsorption resin is used as a substrate material, carboxylation modification is carried out at normal temperature, then carboxyl is activated, and grafting reaction with heparin is carried out to obtain the anticoagulant adsorption resin material. Carboxyl is introduced to a benzene ring of the resin through carboxymethylation, and heparin is grafted after carboxyl activation. After carboxymethylation modification, the biocompatibility of the resin material can be improved, and the grafted heparin can effectively reduce the blood coagulation phenomenon in the use process of a perfusion device. The synthesis method is simple, efficient, mild in reaction condition and free of high-temperature and high-pressure conditions. And the product resin has excellent anticoagulation performance and biocompatibility performance.

Description

Technical Field

[0001] The invention relates to the technical field of blood purification, and in particular to an anticoagulant blood adsorption resin material and a preparation method thereof. Background Art

[0002] Hemoperfusion is a blood purification technology that uses an extracorporeal circulation system and adsorbents to remove poisons, drugs and metabolic wastes from the blood. The principle is to draw the patient's blood out of the body, pass through a perfusion device filled with solid adsorbents, remove harmful substances in the blood through adsorption, and then re-infuse the purified blood into the body. As an efficient blood purification technology, hemoperfusion can quickly remove drugs or poisons from the blood, reduce their damage to the body, and improve the success rate of rescue. It has important clinical value in the fields of acute poisoning, uremia, immune diseases and severe infections. The core of hemoperfusion is solid adsorbent. The commonly used adsorbent is polystyrene-divinylbenzene macroporous adsorption resin, which has high mechanical strength, stable chemical properties, and high adsorption performance for harmful substances in the blood. However, due to the direct contact between the adsorbent resin and the blood during the blood purification process, plasma proteins are easily adsorbed to the resin surface and bind to the glycoprotein receptors on the platelets, resulting in platelet activation, coagulation cascade and complement activation, and ultimately the formation of thrombus, affecting the safety of the product. Based on this, selecting resins with good biocompatibility, anticoagulant properties and adsorption properties has become a new development direction for hemoperfusion resins and has received widespread attention.

[0003] Chinese patent CN105126787B discloses a method for improving the anticoagulant property of an adsorbent. The anticoagulant heparin is cross-linked with the adsorbent resin to form an interpenetrating network polymer, which improves the stability of the anticoagulant. However, this method is difficult to process and produce on a large scale, and the post-processing is complicated. In addition, the interpenetrating network structure easily wraps unreacted monomers and initiators, which is harmful to the human body.

[0004] Chinese patent CN111468079A discloses a method for preparing a blood perfusion adsorption material with high anticoagulant properties. First, a polyvinyl pyrrolidone-polymethacrylate-polyacrylic acid triblock copolymer is prepared, and then the copolymer is blended with polyethersulfone to prepare a coating liquid, the resin is coated, and finally the carboxyl group on the membrane is amidated with heparin to graft heparin to improve the anticoagulant property. However, the coating preparation process is complicated, and the coating is not resistant to aging and is easy to fall off.

[0005] Chinese patent CN116003662A discloses a method for preparing an anticoagulant adsorption resin, which first copolymerizes monomers to form a cross-linked resin, and then aminates the resin, and the activated amine groups can be grafted with anticoagulant heparin. However, the amination reaction conditions of the resin are relatively harsh, and the grafting efficiency of heparin is a major problem. Summary of the invention

[0006] The purpose of the present invention is to provide an anticoagulant adsorption resin material and a preparation method thereof, so as to solve the problems of difficulty in large-scale production, complex preparation and low grafting efficiency of heparin in the prior art of anticoagulant adsorption resin materials. The present invention provides a new and efficient method for modifying grafted heparin on the surface of a resin to enhance the anticoagulant performance of the resin. The method has mild reaction conditions, a simple process and excellent anticoagulant performance.

[0007] To achieve the above object, the present invention provides the following technical solutions: The present invention provides an anticoagulant adsorption resin material, which uses styrene-divinylbenzene macroporous adsorption resin as a base material, undergoes carboxylation modification at room temperature, activates the carboxyl group, and undergoes a grafting reaction with heparin to obtain the anticoagulant adsorption resin material.

[0008] Furthermore, the carboxylation agent in the carboxylation modification process is phthalic anhydride, and the solvent is a mixed solvent of dichloromethane and nitrobenzene.

[0009] Furthermore, a unique substance is used when activating the carboxyl group: a water-soluble carbodiimide solvent 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) solution. The EDC reaction conditions are mild and there are fewer by-products.

[0010] The present invention also provides a method for preparing an anticoagulant adsorption resin material, comprising the following steps: S1. Add styrene-divinylbenzene adsorption resin microspheres and dichloromethane into a reaction vessel, stir thoroughly to swell the resin, add nitrobenzene and phthalic anhydride after 2 hours, add anhydrous AlCl3 while stirring, and react at room temperature for a certain period of time; S2, the resin after the reaction was washed with anhydrous ethanol, 3% glacial hydrochloric acid, and distilled water in sequence. When the filtrate was determined to be free of chloride ions by silver nitrate solution, it was washed with methanol five times and vacuum dried to constant weight to obtain carboxylated resin microspheres; S3, grafted with heparin S31, soak the carboxylated resin microspheres in S2 in 1-ethyl-(3-dimethylaminopropyl)carbodiimide solution to ensure that they are completely immersed, take them out after soaking for 1 hour, and rinse the microspheres with pure water; S32, soaking the resin microspheres in a heparin solution and reacting at room temperature for 12 h to complete the heparin grafting; S33. The resin microspheres are rinsed with pure water to remove a small amount of ungrafted heparin and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), and then vacuum dried to obtain the resin microspheres grafted with heparin.

[0011] Furthermore, in the S1, the volume ratio of dichloromethane to the mass ratio of styrene-divinylbenzene adsorption resin microspheres is 10:1, and the volume ratio of dichloromethane to nitrobenzene is 10:1.

[0012] Furthermore, in the S1, the ratio of the amount of the carboxylating agent phthalic anhydride to the styrene-divinylbenzene adsorption resin microspheres is 1 mol:1 mol, and the ratio of the catalyst AlCl3 to the styrene-divinylbenzene adsorption resin microspheres is 2 mol:1 mol.

[0013] Furthermore, the concentration of the 1-ethyl-(3-dimethylaminopropyl)carbodiimide solution in S31 is 0.1 g / mL, and the concentration of the heparin solution in S32 is 0.01 g / mL.

[0014] Furthermore, the dosage ratio of the resin microspheres to the heparin solution in S32 is 1 g:0.1 g.

[0015] Based on the above technical solution, the embodiments of the present invention can at least produce the following technical effects: (1) The present invention provides an anticoagulant adsorption resin material and a preparation method thereof. The synthesis method is simple and efficient, the reaction conditions are mild, and high temperature and high pressure conditions are not required. The product resin has excellent anticoagulant properties and biocompatibility properties.

[0016] (2) The present invention provides an anticoagulant adsorption resin material and a preparation method thereof, wherein a carboxyl group is introduced into the resin benzene ring by carboxyl methylation, and heparin is grafted after the carboxyl group is activated. The biocompatibility of the resin material can be improved after carboxyl methylation modification, and the grafted heparin can effectively reduce the coagulation phenomenon during the use of the perfusion device. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.

[0018] Figure 1 is a bar graph of the adsorption performance of the embodiments of the present invention and the comparative examples; Figure 2 It is a bar graph of the anticoagulant performance of the embodiments of the present invention and the comparative examples. DETAILED DESCRIPTION

[0019] The following will combine the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work belong to the scope of protection of the present invention.

[0020] Example 1 Add 15 g of styrene-divinylbenzene adsorption resin microspheres and 150 mL of dichloromethane into a flask and stir thoroughly to swell the resin. After 2 h, add an appropriate amount of 15 mL of nitrobenzene and 0.111 g of phthalic anhydride. Add 0.2 g of anhydrous AlCl3 while stirring and react at room temperature for 2 h.

[0021] After the reaction, the resin was washed with anhydrous ethanol, 3% glacial hydrochloric acid, and distilled water in turn. When the filtrate was determined to be free of chloride ions by silver nitrate solution, it was washed with methanol five times and vacuum dried to constant weight to obtain carboxylated resin microspheres (14.27 g). Accurately weigh 14 g of the above resin microspheres and soak them in 0.1 g / mL EDC solution to ensure that they are completely immersed. After soaking for 1 h, take them out and rinse the microspheres with pure water.

[0022] Then the resin microspheres were immersed in 28 mL of heparin solution with a concentration of 0.05 g / mL and reacted at room temperature for 12 h to complete the heparin grafting. Finally, the resin microspheres were rinsed with pure water to remove a small amount of ungrafted heparin and EDC, and the heparin-grafted resin microspheres were obtained after vacuum drying.

[0023] Example 2 Add 20 g of styrene-divinylbenzene adsorption resin microspheres and 200 mL of dichloromethane into a flask and stir thoroughly to swell the resin. After 2 h, add an appropriate amount of 20 mL of nitrobenzene and 0.148 g of phthalic anhydride. Add 0.266 g of anhydrous AlCl3 while stirring and react at room temperature for 2 h.

[0024] After the reaction, the resin was washed with anhydrous ethanol, 3% glacial hydrochloric acid, and distilled water in turn. When the filtrate was determined to be free of chloride ions by silver nitrate solution, it was washed with methanol five times and vacuum dried to constant weight to obtain carboxylated resin microspheres (18.12 g). Accurately weigh 18 g of the above resin microspheres and soak them in 0.1 g / mL EDC solution to ensure that they are completely immersed. After soaking for 1 h, take them out and rinse the microspheres with pure water.

[0025] Then the resin microspheres were immersed in 18 mL of heparin solution with a concentration of 0.05 g / mL and reacted at room temperature for 12 h to complete the heparin grafting. Finally, the resin microspheres were rinsed with pure water to remove a small amount of ungrafted heparin and EDC, and the heparin-grafted resin microspheres were obtained after vacuum drying.

[0026] Example 3 Add 25 g of styrene-divinylbenzene adsorption resin microspheres and 250 mL of dichloromethane into a flask and stir thoroughly to swell the resin. After 2 h, add an appropriate amount of 25 mL of nitrobenzene and 0.185 g of phthalic anhydride. Add 0.333 g of anhydrous AlCl3 while stirring and react at room temperature for 2 h.

[0027] After the reaction, the resin was washed with anhydrous ethanol, 3% glacial hydrochloric acid, and distilled water in turn. When the filtrate was determined to be free of chloride ions by silver nitrate solution, it was washed with methanol five times and vacuum dried to constant weight to obtain carboxylated resin microspheres (23.29 g). Accurately weigh 23 g of the above resin microspheres and soak them in 0.1 g / mL EDC solution to ensure that they are completely immersed. After soaking for 1 h, take them out and rinse the microspheres with pure water.

[0028] Then the resin microspheres were immersed in 23 mL of heparin solution with a concentration of 0.05 g / mL and reacted at room temperature for 12 h to complete the heparin grafting. Finally, the resin microspheres were rinsed with pure water to remove a small amount of ungrafted heparin and EDC, and the heparin-grafted resin microspheres were obtained after vacuum drying.

[0029] Comparative Example 1: Unmodified resin microspheres Resin performance test method: The resin microspheres prepared in Examples 1-3 and the comparative example resin microspheres were subjected to adsorption performance test and anticoagulation test. The adsorption performance test was carried out according to the reference standard "YY / T 0464-2019 Disposable Blood Perfusion Device", and the anticoagulation performance test was carried out according to the partial thromboplastin time (PTT) experiment of the reference standard "YY / T 1911-2023 Medical Device Coagulation Test Method".

[0030] The results are as follows Figure 1-2 As shown, the resin prepared by the present invention has better adsorption performance and anticoagulant performance than the unmodified resin.

[0031] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. An anticoagulant adsorption resin material, characterized in that: The styrene-divinylbenzene macroporous adsorption resin is used as the base material, and is carboxylated at room temperature, and then the carboxyl group is activated and grafted with heparin to obtain an anticoagulant adsorption resin material.

2. The anticoagulant adsorption resin material according to claim 1, characterized in that: The carboxylation agent in the carboxylation modification process is phthalic anhydride, and the solvent is a mixed solvent of dichloromethane and nitrobenzene.

3. The anticoagulant adsorption resin material according to claim 1, characterized in that: The carboxyl group is activated by using a water-soluble carbodiimide solvent 1-ethyl-(3-dimethylaminopropyl)carbodiimide solution.

4. The method for preparing the anticoagulant adsorption resin material according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. Add styrene-divinylbenzene adsorption resin microspheres and dichloromethane into a reaction vessel, stir thoroughly to swell the resin, add nitrobenzene and phthalic anhydride after 2 hours, add anhydrous AlCl3 while stirring, and react at room temperature for a certain period of time; S2, washing the reacted resin with anhydrous ethanol, 3% glacial hydrochloric acid, and distilled water in sequence, and when the filtrate is determined to be free of chloride ions by silver nitrate solution, washing it with methanol five times, and vacuum drying it to constant weight to obtain carboxylated resin microspheres; S3, grafted with heparin S31, soak the carboxylated resin microspheres in S2 in 1-ethyl-(3-dimethylaminopropyl)carbodiimide solution to ensure that they are completely immersed, take them out after soaking for 1 hour, and rinse the microspheres with pure water; S32, soaking the resin microspheres in a heparin solution and reacting at room temperature for 12 h to complete the heparin grafting; S33, washing the resin microspheres with pure water to remove a small amount of ungrafted heparin and 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and vacuum drying to obtain the resin microspheres grafted with heparin.

5. The method for preparing the anticoagulant adsorption resin material according to claim 4, characterized in that: The volume ratio of dichloromethane to styrene-divinylbenzene adsorption resin microspheres in S1 is 10:1, and the volume ratio of dichloromethane to nitrobenzene is 10:

1.

6. The method for preparing the anticoagulant adsorption resin material according to claim 4, characterized in that: The ratio of the amount of the carboxylating agent phthalic anhydride to the styrene-divinylbenzene adsorption resin microspheres in S1 is 1 mol:1 mol, and the ratio of the catalyst AlCl3 to the styrene-divinylbenzene adsorption resin microspheres is 2 mol:1 mol.

7. The method for preparing the anticoagulant adsorption resin material according to claim 4, characterized in that: The concentration of the 1-ethyl-(3-dimethylaminopropyl)carbodiimide solution in S31 is 0.1 g / mL, and the concentration of the heparin solution in S32 is 0.01 g / mL.

8. The method for preparing the anticoagulant adsorption resin material according to claim 4, characterized in that: The usage ratio of the resin microspheres to the heparin solution in the S32 is 1 g:0.1 g.

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