CN114011389A - Blood purification material for sepsis and preparation method thereof - Google Patents

Blood purification material for sepsis and preparation method thereof Download PDF

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CN114011389A
CN114011389A CN202111488489.8A CN202111488489A CN114011389A CN 114011389 A CN114011389 A CN 114011389A CN 202111488489 A CN202111488489 A CN 202111488489A CN 114011389 A CN114011389 A CN 114011389A
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reaction
acetylation
hollow fiber
blood
blood purification
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CN114011389B (en
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李永桂
杨正根
邓杰文
胡家亮
林振南
陈校园
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Guangzhou Kangsheng Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
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    • 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
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Abstract

The invention belongs to the field of medical instruments, and discloses a blood purification material for sepsis, and a preparation method and application thereof. The carrier of the blood purifying material is hollow fiber, and the surface of the hollow fiber is covalently coupled and modified with cation ligand, anticoagulant containing amino and polysaccharide. In some examples of the blood purification material, the matrix (carrier), the coupling group and the ligand are matched with each other to synergistically improve the adsorption effect, and compared with the traditional adsorption material, the finally obtained adsorption material has the advantages that the adsorption effect on pathogenic components is obviously enhanced and is more comprehensive.

Description

Blood purification material for sepsis and preparation method thereof
Technical Field
The invention relates to the field of medical instruments, in particular to a blood purification material for sepsis and a preparation method and application thereof.
Background
Blood purification technology is an effective treatment technology suitable for various difficult and complicated diseases, such as acute drug or toxicosis, sepsis, end-stage renal diseases, acute and chronic liver failure, and the like. This is because such diseases result in excessive accumulation of harmful substances in the blood, and patients cannot detoxify, remove or neutralize the harmful substances by means of self-protective systems (e.g., liver detoxification system, autoimmune system, excretory system, etc.). Therefore, the treatment of the diseases needs to artificially and efficiently remove harmful substances in blood so as to achieve the purposes of quickly adjusting the stability of the environment in the organism and relieving the disease conditions. Due to the outstanding curative effect of the blood purification technology, the traditional Chinese medicine composition is a main treatment method for patients suffering from acute poisoning, severe hepatorenal diseases and critically ill patients. The currently clinically applied blood purification methods mainly include hemodialysis, hemofiltration, hemoperfusion, plasma adsorption, plasma exchange, and the like.
Sepsis refers to life-threatening multiple organ failure secondary to infection, which is the leading cause of acute kidney injury in patients in intensive care units, with a worldwide incidence of 3150 thousands and a annual death of 530 thousands. Traditional treatment modalities for sepsis include the use of broad spectrum antibiotics, timely fluid resuscitation, and the use of vascular pressors if necessary. However, timely broad-spectrum antibiotics have been widely used in the treatment of patients with sepsis, and the mortality rate of patients with sepsis still reaches 20-50%. In sepsis, high endotoxin concentrations and bacterial loads in the blood are closely related to the severity of multi-organ failure and the mortality of the patient. Previous studies have demonstrated that a number of blood purification techniques, including endotoxin adsorption, are important adjunctive treatments in critical situations (progression to severe sepsis and septic shock) in patients with sepsis. Current commercial blood purification products for sepsis include Toraymyxin (endotoxin-only adsorption), hundreds of oXiris (endotoxin and inflammatory factor adsorption) and Cytosorb (inflammatory factor adsorption only) in the united states of japan, which have not been reported to have positive results for a long time, and may be due to the fact that they do not achieve effective clearance of pathogen-associated molecular patterns (PAMPS), such as bacteria, fungi, viruses and parasites, and damage-associated molecular patterns (DAMPS), such as exotoxin, endotoxin and inflammatory factor, and the like, simultaneously during treatment, and that single or incomplete adsorption treatment may seriously affect their therapeutic effect on sepsis.
The breakthrough in solving the difficulties of blood purification in sepsis may be in developing a blood purification material that can effectively remove both DAMPS and PAMPS pathogenic substances from the blood. This heterozygous mode of treatment can minimize two key causative agents in the onset and progression of sepsis through blood purification: endotoxins and pathogenic bacteria. Meanwhile, in the traditional blood purification treatment process, heparin needs to be injected to prevent blood anticoagulation, which not only increases the treatment cost, but also more importantly increases the risk of severe hemorrhage of patients caused by systemic anticoagulation; considering the special clinical problem that the patients with sepsis often have coagulation dysfunction in the course of disease, the blood purification material with self-anticoagulation has better blood compatibility, can affect the function of the coagulation system of the patients to a smaller extent, and better prevents serious hemorrhage during or after blood purification.
Therefore, the research and development of the blood purification material and the product which can simultaneously remove DAMPS and PAMPS pathogenic substances and have anticoagulation property have important clinical significance and great economic and social values for the treatment of sepsis.
The traditional hemodialysis or hemodiafiltration can only remove medium and small molecules, cannot effectively remove macromolecular pathogenic substances, and needs to perform hemoperfusion. And the coupling reagents used in the traditional blood perfusion technical research are cyanogen bromide, trichlorotriazine, carbonyl diimidazole, sodium periodate, epichlorohydrin and the like generally, wherein the cyanogen bromide is a highly toxic substance, the synthetic process has great harm to human bodies and environment, and the cyanogen bromide method is used for coupling ligands which are easy to fall off and enter the human bodies, so that great side effects are generated on patients. In addition, epichlorohydrin and carbonyldiimidazole are used as coupling reagents to activate carriers to couple PMB in the traditional method, although the use of virulent cyanogen bromide is avoided, the reaction steps in the preparation process are more, the adsorption material can be synthesized only by five chemical reactions, and the method is complex, so that the obtained adsorption material product has large batch difference and unstable performance. The endotoxin adsorption material is prepared by a traditional method, is a polystyrene woven fiber with polymyxin B on the surface, is easy to cause the residue of a strong irritant chemical substance chloromethyl ether in a technical route, and has great potential safety hazard because the chloromethyl ether is a strong carcinogen. Therefore, the development of a blood purification adsorbing material which can comprehensively adsorb pathogenic factors of sepsis, has a simple process route, and is safe and efficient is urgently needed.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides a blood purification material for sepsis and a preparation method and application thereof.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
a blood purification material, the carrier of which is hollow fiber, the surface of which is covalently coupled and modified with 3 functional ligands as follows:
A) cationic ligand: selected from positively charged amino acid polymers, or polymers containing tertiary/quaternary amine groups;
B) an anticoagulant containing an amino group;
C) at least one of hyaluronic acid, salicylic acid, or a polysaccharide having a mannose sequence.
In some examples, the amino acid monomer in the amino acid polymer is selected from at least one of lysine, arginine, and histidine.
In some examples, the tertiary/quaternary amine group-containing polymer is selected from at least one of polyethyleneimine and polymyxin sulfate.
In some examples, the amino group-containing anticoagulant is selected from at least one of nafamostat mesylate, heparin, heparan sulfate, and argatroban.
In some examples, the polysaccharide having a mannose sequence is selected from the group consisting of amino mannose.
In some examples, the hollow fiber is selected from a hollow fiber membrane, a flat sheet membrane, a tubular membrane or a woven material of these hollow fiber membranes made of polyamide, polysulfone, polyethersulfone, polyethylene, polypropylene, cellulose, modified cellulose, polystyrene, polyvinyl alcohol, or derivatives and/or mixtures of these polymers.
In some examples, the hollow fiber surface is covalently coupled and modified with 3 functional ligands:
A) polymyxin sulfate;
B) nafamostat mesylate;
C) amino mannose.
In some examples, the hollow fibers have a pore size of 0.01 μm to 0.699 μm.
In a second aspect of the present invention, there is provided:
a blood purifier for sepsis and/or septic shock, which comprises the blood purifying material according to the first aspect of the present invention.
In some examples, the blood purifier is selected from a dialyzer, hemofilter, hemodiafiltration, plasma separator, adsorption column, cartridge, or a combination of these products.
In some examples, the blood purification material binds gram-negative bacilli and endotoxins released therefrom, gram-positive bacilli and exotoxins released therefrom, fungi, viruses, and inflammatory factors.
In a third aspect of the present invention, there is provided:
the preparation method of the blood purification material of the first aspect of the invention comprises the following steps:
preparing a carboxyl modified carrier by sequentially carrying out acetylation reaction and oxidation reaction on the carrier, and further preparing the carrier into hollow fibers;
covalently coupling functional ligands on the hollow fibers through acylation reaction and/or esterification reaction, and performing post-treatment to obtain the blood purification material.
In some examples, the acetylating agent is selected from at least one of acetyl chloride, acetyl bromide, acetyl iodide or, alternatively, at least one of acetic anhydride, glacial acetic acid.
In some examples, the temperature of the acetylation reaction is between 25 ℃ and 100 DEG C
In some examples, the time for the acetylation reaction is 1h to 5h
In some examples, the solvent employed in the acetylation reaction is an organic solvent selected from the group consisting of dimethyl sulfoxide, and mixtures thereof,N-methylpyrrolidone andN,Nat least one of-dimethylacetamide
In some examples, the acetylation reaction catalyst is selected from the group consisting of aluminum chloride, ferrous chloride, cuprous chloride, [ MORBSA [ ]][HSO4]At least one of ionic liquids
In some examples, the temperature of the oxidation reaction is from 70 ℃ to 100 ℃
In some examples, the time of the oxidation reaction is 4h to 10h
In some examples, the oxidizing agent in the oxidation reaction is selected from permanganate
In some examples, the solvent employed in the oxidation reaction is an organic solvent selected from the group consisting of dimethyl sulfoxide, and mixtures thereof,N-methylpyrrolidone andN,Nat least one of-dimethylacetamide
In some examples, the oxidation catalyst is selected from alkali metal hydroxides.
In some examples, the functional ligand compound is added in the form of a buffer solution in the reaction for covalently coupling the functional ligand.
In some examples, the functional ligand compound consists of nafamostat mesylate, polymyxin B sulfate, and an amino mannose.
In some examples, the functional ligand compound is added in the form of a buffer solution, the functional ligand compound is composed of nafamostat mesylate, polymyxin B sulfate and amino mannose, the concentration of the nafamostat mesylate, the concentration of the polymyxin B sulfate and the concentration of the amino mannose in the buffer solution are respectively 50-100 mg/mL, 25-150 mg/mL and 25-100 mg/mL.
In some examples, the temperature of the covalent coupling reaction is from 20 ℃ to 30 ℃.
In some examples, the pH of the covalent coupling reaction is from 4.5 to 9.5
In some examples, the time for the covalent coupling reaction is 8h to 24 h.
The invention has the beneficial effects that:
in some examples of the blood purification material, the matrix (carrier), the coupling group and the ligand are matched with each other to synergistically improve the adsorption effect, and compared with the traditional adsorption material, the finally obtained adsorption material has the advantages that the adsorption effect on pathogenic components is obviously enhanced and is more comprehensive.
In some embodiments of the blood purification material of the present invention, the functional ligand binds to at least one pathogenic component of blood or plasma. More specifically, the pathogenic components include pathogen-associated molecular patterns (PAMPS), such as bacteria, fungi, viruses and parasites, and damage-associated molecular patterns (DAMPS), such as exotoxins, endotoxins and inflammatory factors, and have self-anticoagulation properties.
According to the blood purification material disclosed by the invention, polyether sulfone is taken as a specific matrix, an acetylation reagent and an oxidant are simultaneously screened to activate the blood purification material, a specific carboxyl group and an amino compound ligand are introduced for coupling, the matrix, the coupling group and the ligand are matched with each other, the adsorption effect is synergistically improved, and the finally obtained adsorption material has a remarkably enhanced and more comprehensive adsorption effect on pathogenic components compared with the traditional adsorption material.
Drawings
FIG. 1 is a schematic view showing the principle of the method for preparing a blood purifying material of the present invention, in which NH is contained2-R represents a ligand, -CONH-R1、-CONH -R2and-CONH-R3Each representing three different ligands.
Detailed Description
The invention provides a blood purification material, wherein a carrier of the blood purification material is a hollow fiber, and the surface of the hollow fiber is covalently coupled and modified with the following 3 functional ligands:
A) cationic ligand: selected from positively charged amino acid polymers, or polymers containing tertiary/quaternary amine groups;
B) an anticoagulant containing an amino group; and
C) at least one of hyaluronic acid, salicylic acid, or a polysaccharide having a mannose sequence.
In a specific example, the amino acid monomer in the amino acid polymer is selected from at least one of lysine, arginine, and histidine.
In a specific example, the polymer containing tertiary/quaternary amine groups is selected from at least one of polyethyleneimine and polymyxin sulfate.
In a specific example, the amino group-containing anticoagulant is selected from at least one of nafamostat mesylate, heparin, heparan sulfate, and argatroban.
In a specific example, the polysaccharide having a mannose sequence is selected from the group consisting of amino mannose.
In a specific example, the hollow fiber surface is covalently coupled and modified with 3 functional ligands as follows:
A) polymyxin sulfate;
B) nafamostat mesylate;
C) amino mannose.
In a particular example, the hollow fiber is selected from a hollow fiber membrane, a flat sheet membrane, a tubular membrane or a woven material of these hollow fiber membranes made of polyamide, polysulfone, polyethersulfone, polyethylene, polypropylene, cellulose, modified cellulose, polystyrene, polyvinyl alcohol, or derivatives and/or mixtures of these polymers.
In a specific example, the polyethersulfone hollow fiber matrix is a woven tube of hollow fibers, a woven mesh of hollow fibers, or a tubular nonwoven material of hollow fibers.
The hollow fiber woven tube is a tubular material formed by weaving hollow fibers, the hollow fiber woven mesh is a net-shaped material formed by weaving hollow fibers, and the hollow fiber tubular non-woven material is a tubular material formed by cutting long hollow fibers into short hollow fibers without any weaving.
In a specific example, the hollow fiber has a pore size of 0.01 μm to 0.699 μm.
In a specific example, the pore diameter of the polyether sulfone hollow fiber membrane is 0.01-0.699 μm. It is understood that the pore size of the polyethersulfone hollow fiber membrane in the present invention includes but is not limited to 0.01 μm, 0.02 μm, 0.03 μm, 0.1 μm, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.699 μm.
The invention also provides a preparation method of the material for purifying blood, which comprises the following steps:
respectively carrying out activation reaction on the polyether sulfone hollow fiber matrix with an acetylation reagent and an oxidation reagent, mixing with a functional ligand, and carrying out covalent coupling reaction. The reaction principle is shown in FIG. 1.
In the invention, active group carboxyl group is introduced on the surface of the polyether sulfone substrate through activation of an acetylation reagent and an oxidation reagent, and during covalent coupling after membrane preparation, amidation reaction is carried out on the nucleophilic group amino and carboxyl of a functional ligand.
In a specific example, the acetylating agent is selected from at least one of acetyl chloride, acetyl bromide, acetyl iodide or at least one of acetic anhydride, glacial acetic acid as a substitute.
In a specific example, the temperature of the acetylation reaction is between 25 ℃ and 100 ℃. It is understood that in the present invention, the temperature of the acetylation reaction includes, but is not limited to, 25 deg.C, 35 deg.C, 45 deg.C, 55 deg.C, 65 deg.C, 75 deg.C, 85 deg.C, 95 deg.C, 100 deg.C.
In a specific example, the time of the acetylation reaction is 1h to 5 h. It is understood that in the present invention, the time of acetylation reaction includes, but is not limited to, 1h, 2 h, 3h, 4h, 5 h.
In a specific example, the solvent employed in the acetylation reaction is an organic solvent. More specifically, the solvent used in the acetylation reaction is dimethyl sulfoxide,N-methylpyrrolidone andN,N-at least one of dimethylacetamide. The catalyst for acetylation reaction is aluminum chloride, ferrous chloride, cuprous chloride, [ MORBSA [ ] -MORBA ] -][HSO4]At least one of ionic liquids.
In one specific example, the polyethersulfone is mixed with an acetylating agent and an acetylating catalyst prior to being mixed with the acetylating agent and the acetylating catalystN-methyl pyrrolidone mixing; the mass ratio of the polyether sulfone to the acetylation reagent and the acetylation reaction catalyst is 1: (0.8-1.5) and (0.2-0.6); the dosage ratio of the polyether sulfone to the organic solvent is 1 g: (5-15) mL.
It is understood that in the present invention, the mass ratio of polyethersulfone, acetylating agent to acetylating reaction catalyst includes, but is not limited to: 1:0.8:0.2, 1:0.8:0.3, 1:0.8:0.4, 1:0.8:0.5, 1:0.8:0.6, 1:1:0.2, 1:1:0.3, 1:1:0.4, 1:1:0.5, 1:1:0.6, 1:1.2:0.2, 1:1.2:0.3, 1:1.2:0.4, 1:1.2:0.5, 1:1.2:0.6, 1:1.5:0.2, 1:1.5:0.3, 1:1.5:0.4, 1:1.5:0.5, 1:1.5: 0.6. The amount ratio of polyethersulfone to organic solvent includes, but is not limited to, 1 g: 5mL, 1 g: 6mL, 1 g: 7mL, 1 g: 8mL, 1 g: 9mL, 1 g: 10mL, 1 g: 11mL, 1 g: 12mL, 1 g: 13mL, 1 g: 14mL, 1 g: 15 mL.
In one specific example, the temperature of the oxidation reaction is 70 ℃ to 100 ℃. It is understood that, in the present invention, the temperature of the acetylation reaction includes, but is not limited to, 70 deg.C, 75 deg.C, 80 deg.C, 85 deg.C, 90 deg.C, 95 deg.C, 100 deg.C.
In a specific example, the time of the oxidation reaction is 4 to 10 hours. It is understood that in the present invention, the time of acetylation reaction includes, but is not limited to, 4h, 5h, 6h, 7 h, 8h, 9 h, 10 h.
In one particular example, the oxidizing agent in the oxidation reaction is a permanganate; the solvent used in the oxidation reaction is an organic solvent. More specifically, the solvent used in the oxidation reaction is dimethyl sulfoxide,N-methylpyrrolidone andN,N-at least one of dimethylacetamide. The oxidation reaction catalyst is alkali metal hydroxide.
In one particular example, the acetylated polyethersulfone is mixed with an oxidizing agent and an oxidation catalyst prior to mixing with the oxidizing agent and the oxidation catalystN-methyl pyrrolidone mixing; the mass ratio of the acetylated polyether sulfone to the oxidizing reagent and the oxidation reaction catalyst is 1: (0.05-0.15): (0.1-0.4); the dosage ratio of the acetylated polyether sulfone to the organic solvent is 1 g: (10-15) mL.
It is to be understood that in the present invention, the mass ratio of acetylated polyethersulfone, oxidizing agent to oxidation catalyst includes, but is not limited to: 1:0.05:0.1, 1:0.05:0.2, 1:0.05:0.3, 1:0.05:0.4, 1:0.05:0.1, 1:0.1:0.2, 1:0.1:0.3, 1:0.1:0.4, 1:0.15:0.1, 1:0.15:0.2, 1:0.15:0.3, 1:0.15: 0.4. The amount ratio of acetylated polyethersulfone to organic solvent includes, but is not limited to: 1 g: 10mL, 1 g: 11mL, 1 g: 12mL, 1 g: 13mL, 1 g: 14mL, 1 g: 15 mL.
Preparing the carboxylated polyether sulfone into a film to obtain a carboxylated polyether sulfone hollow fiber, processing the obtained hollow fiber film, isolating two ends of the hollow fiber film from each other by polyurethane glue, cutting off the end part of the bundle and reopening the fiber at the end part of the package to obtain a hollow fiber film device,
in a specific example, the functional ligand compound is added in the form of a buffer solution, the concentration range of the nafamostat mesylate in the buffer solution is 50 mg/mL-100 mg/mL, the concentration range of the polymyxin B sulfate is 25 mg/mL-150 mg/mL, and the concentration range of the mannose is 25 mg/mL-100 mg/mL. It is understood that in the present invention, the concentration of nafamostat mesylate includes, but is not limited to, 50mg/mL, 60mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL; concentrations of polymyxin B sulfate include, but are not limited to, 25mg/mL, 50mg/mL, 75 mg/mL, 100mg/mL, 125mg/mL, 150 mg/mL; the concentration range of mannose includes, but is not limited to, 25mg/mL, 50mg/mL, 75 mg/mL, 100mg/mL, 125mg/mL, 150 mg/mL. The mass ratio of the carboxylated polyethersulfone to the naproxen mesylate, polymyxin B sulfate, and mannose includes, but is not limited to, 1:0.05: 0.025: 0.025, 1:0.05: 0.025: 0.05, 1:0.05: 0.025: 0.075, 1:0.05: 0.025: 0.1, 1:0.05: 0.05: 0.025, 1:0.05: 0.075: 0.025, 1:0.05: 0.1: 0.025, 1:0.05: 0.15: 0.025, 1: 0.06: 0.025: 1:0.05: 0.025: 0.025, 1: 0.06: 0.025: 0.05, 1: 0.07: 0.025: 0.075, 1: 0.08: 0.025: 0.1, 1: 0.09: 0.025: 0.075, 1:0.1: 0.025: 0.1.
in one specific example, the temperature of the covalent coupling reaction is 20 ℃ to 30 ℃. It is understood that, in the present invention, the temperature of the covalent coupling reaction includes, but is not limited to, 20 deg.C, 22 deg.C, 25 deg.C, 27 deg.C, 30 deg.C.
In a specific example, the time of the covalent coupling reaction is 8h to 24 h. It is understood that in the present invention, the time of the covalent coupling reaction includes, but is not limited to, 8h, 9 h, 10h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h.
In a specific example, the pH of the covalent coupling reaction is 4.5 to 9.5. It is understood that in the present invention, the pH of the covalent coupling reaction includes, but is not limited to, 4.5, 5.5, 6.5, 7.5, 8.5, 9.5.
The following will explain the preparation method and application of the modified fiber membrane blood purification material of the present invention in detail with reference to the specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
This example provides an acetylation, carboxylation and processing treatment hollow fiber membrane device, which specifically comprises:
30g of anhydrous aluminum chloride, 400mL of N-methylpyrrolidone and 40g of acetyl chloride are added into a three-necked flask, and after the mixture is uniformly stirred in a low-temperature water bath, 50g of polyether sulfone dissolved in 250mL of N-methylpyrrolidone is added, the temperature of a reaction system is adjusted to 90 ℃, and the reaction is carried out for 3 hours. After the reaction was complete, the residual solvent was removed by washing several times with water for injection to give the acetylated polyethersulfone designated a 1.
240mL of N-methylpyrrolidone was added to the acetylated polyethersulfone, and after stirring the mixture uniformly, 2.4g of KMnO4, 7.4g of NaOH, and 18g of water for injection were added in this order to react at 80 ℃ for 6 hours. And (3) settling by using dilute hydrochloric acid with the pH value of 1, and performing suction filtration and cleaning to obtain the carboxylated polyether sulfone, which is marked as A2.
And (3) preparing a membrane from the carboxylated polyether sulfone to obtain a carboxylated polyether sulfone hollow fiber, processing the obtained hollow fiber membrane, mutually isolating two ends of the hollow fiber membrane by using polyurethane glue, cutting off the end part of the bundle, and reopening the fiber at the end part of the package to obtain a hollow fiber membrane device, wherein the mark is A3.
Example 2
The embodiment provides a blood purification material using nafamostat mesylate, polymyxin B sulfate and amino mannose as a combined functional ligand, which comprises the following specific steps:
50g of A3 prepared above was placed in 100mL of a solution containing 50mg/mL of nafamostat mesylate, 25mg/mL of PMB solution, and 25mg/mL of aminommannose (dissolved in PBS (pH7.4)), 10g of EDC and 1.5g of NHS were added, and the mixture was subjected to a ring-closure cycling reaction at 25 ℃ for 24 hours, and then washed with 20-fold volume of water for injection to obtain a modified fiber membrane material labeled A4.
Example 3
The embodiment provides a blood purification material using nafamostat mesylate as a functional ligand, which comprises the following specific steps:
50g of A3 prepared above is placed in 100mL of nafamostat mesylate containing 50mg/mL, 10g of EDC and 1.5g of NHS are added for ring closure and circulation reaction at 25 ℃ for 24h, and then the solution is washed by 20 times of volume of water for injection to obtain a modified fiber membrane material, which is marked as B4.
Example 4
The embodiment provides a blood purification material using polymyxin sulfate B as a functional ligand, which specifically comprises the following steps:
50g of A3 prepared above was placed in 100mL of PMB solution containing 25mg/mL, 10g of EDC and 1.5g of NHS were added for ring-closing cycle reaction at 25 ℃ for 24h, and then washed with 20 volumes of water for injection to obtain a modified fibrous membrane material, labeled C4.
Example 5
The embodiment provides a blood purification material using amino mannose as a functional ligand, which specifically comprises the following components:
50g of A3 prepared above was placed in 100mL of a solution containing 25mg/mL of aminommannose (dissolved in PBS pH 7.4), 10g of EDC and 1.5g of NHS were added, and the mixture was subjected to a ring-closure cycling reaction at 25 ℃ for 24 hours, and then washed with 20-fold volume of water for injection to obtain a modified fiber membrane material labeled D4.
Example 6
The embodiment provides a blood purification material with nafamostat mesylate, polymyxin B sulfate and hyaluronic acid as combined functional ligands, which comprises the following specific components:
50g of A3 prepared above was placed in 100mL of a solution containing 50mg/mL of nafamostat mesylate, 25mg/mL of PMB solution, and 25mg/mL of hyaluronic acid (dissolved in PBS pH 7.4), 10g of EDC and 1.5g of NHS were added, and the solution was subjected to a ring-closure cycling reaction at 25 ℃ for 24 hours, and then washed with 20-fold volume of water for injection to obtain a modified fiber membrane material labeled as E4.
Example 7
The embodiment provides a blood purification material with heparan, polymyxin B sulfate and hyaluronic acid as combined functional ligands, which specifically comprises the following components:
50g of A3 prepared above was placed in 100mL of a solution containing 50mg/mL of heparan, 25mg/mL of PMB and 25mg/mL of hyaluronic acid (dissolved in PBS pH 7.4), 10g of EDC and 1.5g of NHS were added, and the mixture was subjected to a loop-closing cycle reaction at 25 ℃ for 24 hours, and then washed with 20-fold volume of water for injection to obtain a modified fibrous membrane material labeled F4.
Example 8
The embodiment provides a blood purification material using nafamostat mesylate, polylysine and amino mannose as a combined functional ligand, which comprises the following specific components:
50G of A3 prepared above was placed in 100mL of a solution containing 50mg/mL of nafamostat mesylate, 25mg/mL of polylysine and 25mg/mL of aminommannose (dissolved in PBS (pH7.4)), 10G of EDC and 1.5G of NHS were added for a ring-closure cycling reaction at 25 ℃ for 24 hours, and then the mixture was washed with 20-fold volume of water for injection to obtain a modified fiber membrane material labeled G4.
First effect verification test: adsorption Performance test
The blood purification materials A4-D4 prepared in the above examples 2-8 were tested for their performance, and the following operations were performed:
fixing the fiber membrane device on a vertical bracket, respectively adding 5 × 10 fiber membrane devices with the volume of 500mL by using a peristaltic pump7CFU Staphylococcus aureus, 5X 107CFU Pseudomonas aeruginosa, 1EU/mL endotoxin and 10000pg/mL IL-6 in bovine plasma solution were circulated at a flow rate of 200mL/min for 2 hours, the experiment was stopped, and the residual concentrations of Staphylococcus aureus, Pseudomonas aeruginosa, endotoxin and IL-6 in plasma were measured by blood culture using TSA growth medium, respectively. The percentage of bacteria, endotoxin and IL-6 adsorbed on the membrane of the module was calculated from the residual concentration. The results are summarized in table 1.
TABLE 1 modified fiber membranes for the removal of pathogenic agents
Figure 541302DEST_PATH_IMAGE001
Effect verification test two: blood compatibility test
Blood compatibility tests were performed on the blood purification materials a4 to G4 prepared in examples 2 to 8, specifically as follows:
hemolysis experiment: hemolysis experiments are carried out according to the experimental selection of interaction with blood in GB/T16886.4-2003 section 4 of medical device biology evaluation and the experimental method of GB/T16175-2008 of biological evaluation of medical organosilicon materials. Respectively adding 4-G41G of the blood purification materials prepared in the embodiments 2-8 into a sample group tube, and then adding 10ml of sodium chloride injection; adding 10ml of sodium chloride injection into each tube of the negative control group; 10ml of distilled water was added to each tube of the positive control group. Each set operated 3 tubes in parallel. Placing all test tubes in constant temperature water bath (37 + -1) deg.C, keeping the temperature for 30min, adding 0.2ml diluted rabbit blood into each test tube, mixing, and placing in water bath (37 + -1) deg.C for keeping the temperature for 60 min. The liquid in the pouring tube was centrifuged at 800g for 5 min. The supernatant was pipetted into a cuvette and the absorbance was measured with a spectrophotometer at 545nm wavelength. The absorbance of the sample combination control group was averaged over 3 tubes. The absorbance of the negative control tube should not be greater than 0.03, the absorbance of the positive control tube should be 0.8 + -0.3, otherwise, the test should be repeated. Hemolysis rate = (a-B)/(C-B) × 100%, where a is the sample set absorbance; b is the absorbance of the negative control group; and C is the absorbance of the positive control group.
Blood compatibility test: the blood purification materials A4 to G41G prepared in examples 2 to 8 were soaked in physiological saline for 10 hours and then placed in a column, 10mL of rabbit whole blood anticoagulated with heparin sodium was injected with a syringe, and the rabbit whole blood was adsorbed at a flow rate of 20mL/min for 2 hours while an empty column was added for a control experiment. The change of each component of the blood before and after adsorption is measured by a Beckman LH750 blood cell analyzer.
The results show that:
(1) the hemolysis rates of the blood purification materials A4-G4 prepared in examples 2-8 are less than 1%, and less than 5% of the national standard requirement.
(2) The blood purifying materials A4, B4, E4 and G4 prepared in example 2, example 3, example 6 and example 8 have little change of main components in blood before and after adsorption, and the reduction percentage is less than 2%; the percentage of the change reduction of each main component in blood before and after adsorption of the blood purification material F4 prepared in example 7 was 4.5%; however, the blood purification materials C4 and D4 prepared in examples 4 and 5 were adsorbed to cause severe blood coagulation, and the percentage of the change in each main component in blood before and after adsorption was decreased by far more than 5%. The results show that the self-anticoagulation blood purification material prepared by the invention has good blood compatibility.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The foregoing is a more detailed description of the invention and is not to be taken in a limiting sense. It will be apparent to those skilled in the art that simple deductions or substitutions without departing from the spirit of the invention are within the scope of the invention.

Claims (10)

1. The blood purifying material has hollow fiber as carrier and features that: the hollow fiber surface is covalently coupled and modified with 3 functional ligands as follows:
A) cationic ligand: selected from positively charged amino acid polymers, or polymers containing tertiary/quaternary amine groups;
B) an anticoagulant containing an amino group; and
C) at least one of hyaluronic acid, salicylic acid, or a polysaccharide having a mannose sequence.
2. A blood purification material according to claim 1, wherein: the amino acid monomer in the amino acid polymer is selected from at least one of lysine, arginine and histidine;
the polymer containing tertiary/quaternary amine groups is selected from at least one of polyethyleneimine and polymyxin sulfate;
the anticoagulant containing amino is selected from at least one of nafamostat mesylate, heparin, heparan sulfate and argatroban;
the polysaccharide having a mannose sequence is selected from amino mannose;
the hollow fiber is selected from hollow fiber membranes, flat plate membranes, tubular membranes or woven materials of the hollow fiber membranes, which are made of polyamide, polysulfone, polyethersulfone, polyethylene, polypropylene, cellulose, modified cellulose, polystyrene and polyvinyl alcohol, or derivatives and/or mixtures of the polymers;
preferably, the hollow fiber surface is covalently coupled and modified with 3 functional ligands as follows:
A) polymyxin sulfate;
B) nafamostat mesylate;
C) amino mannose.
3. A blood purification material according to claim 1 or 2, wherein: the aperture of the hollow fiber is 0.01-0.699 μm.
4. A blood purifier for sepsis and/or septic shock, characterized by: the blood purifier contains the blood purifying material according to any one of claims 1 to 3.
5. The blood purifier according to claim 4, wherein: the blood purifier is selected from a dialyzer, hemofilter, hemodiafiltration, plasmapheresis, adsorption column, perfusion device, or a combination of these products.
6. Use according to claim 4 or 5, characterized in that: the blood purification material binds gram-negative bacilli and endotoxins released by the bacilli, gram-positive bacilli and exotoxins released by the bacilli, fungi, viruses and inflammatory factors.
7. A preparation method of a blood purification material is characterized by comprising the following steps: the blood purification material according to any one of claims 1 to 3, comprising the steps of:
preparing a carboxyl modified carrier by sequentially carrying out acetylation reaction and oxidation reaction on the carrier, and further preparing the carrier into hollow fibers;
covalently coupling functional ligands on the hollow fibers through acylation reaction and/or esterification reaction, and performing post-treatment to obtain a blood purification material; wherein:
the acetylation reaction has at least one of the following characteristics:
the acetylation reagent is selected from at least one of acetyl chloride, acetyl bromide and acetyl iodide or at least one of substitute acetic anhydride and glacial acetic acid;
the temperature of acetylation reaction is 25-100 ℃;
the acetylation reaction time is 1-5 h;
the solvent adopted in the acetylation reaction is an organic solvent, and the organic solvent is selected from dimethyl sulfoxide,N-methylpyrrolidone andN,N-at least one of dimethylacetamide;
the catalyst for acetylation is selected from aluminum chloride, ferrous chloride, cuprous chloride, [ MORBSA [ ] -MORBA ] -][HSO4]At least one of ionic liquids;
the oxidation reaction has at least one of the following characteristics:
the temperature of the oxidation reaction is 70-100 ℃;
the time of the oxidation reaction is 4-10 h;
the oxidant in the oxidation reaction is selected from permanganate;
the solvent adopted in the oxidation reaction is an organic solvent, and the organic solvent is selected from dimethyl sulfoxide,N-methylpyrrolidone andN,N-at least one of dimethylacetamide;
the oxidation catalyst is selected from alkali metal hydroxides;
the reaction of covalently coupling functional ligands has at least one of the following properties:
the functional ligand compound is added in the form of a buffer solution;
the functional ligand compound consists of nafamostat mesylate, polymyxin B sulfate and amino mannose;
the functional ligand compound is added in a form of buffer solution, the functional ligand compound consists of nafamostat mesilate, polymyxin B sulfate and amino mannose, the concentration of the nafamostat mesilate, the concentration of the polymyxin B sulfate and the concentration of the amino mannose in the buffer solution are respectively 50-100 mg/mL and 25-150 mg/mL, and the concentration of the amino mannose is 25-100 mg/mL;
the temperature of the covalent coupling reaction is 20-30 ℃;
the pH value of the covalent coupling reaction is 4.5-9.5;
the time of the covalent coupling reaction is 8-24 h.
8. The method of claim 7, wherein:
in the acetylation reaction, polyether sulfone is mixed with an acetylation reagent and an acetylation reaction catalyst, and then the mixture is mixed with the acetylation reagent and the acetylation reaction catalystN-methyl pyrrolidone is mixed, and the mass ratio of the polyether sulfone to the acetylation reagent and the acetylation reaction catalyst is 1: (0.8-1.5) and (0.2-0.6), wherein the dosage ratio of the polyether sulfone to the organic solvent is 1 g: (5-15) mL; and/or
In the oxidation reaction, the acetylated polyether sulfone is mixed with an oxidation reagent and an oxidation reaction catalyst and then mixed withNMixing methyl pyrrolidone, wherein the mass ratio of acetylated polyether sulfone to an oxidizing reagent and an oxidation reaction catalyst is 1: (0.05-0.15): (0.1-0.4); the dosage ratio of the acetylated polyether sulfone to the organic solvent is 1 g: (10-15) mL.
9. The method of claim 8, wherein:
the temperature of the acetylation reaction is 25-100 ℃, and the time of the acetylation reaction is 1-5 h; and/or
The temperature of the oxidation reaction is 70-100 ℃, and the reaction time is 4-10 h.
10. The method of claim 7, wherein: the method comprises the following steps:
and (2) mixing polyether sulfone, an acetylation reagent and an acetylation catalyst in a mass ratio of 1: (0.8-1.5) and (0.2-0.6), wherein the dosage ratio of the polyether sulfone to the organic solvent is 1 g: (5-15) mL, performing acetylation at the temperature of 25-100 ℃ for 1-5 h;
then carrying out oxidation reaction, wherein the mass ratio of the acetylated polyether sulfone to the oxidant to the oxidation reaction catalyst is 1: (0.05-0.15): (0.1-0.4), the dosage ratio of the acetylated polyethersulfone to the organic solvent is 1 g: (10-15) mL, the reaction temperature is 70-100 ℃, and the reaction time is 4-10 h;
preparing a membrane from the carboxylated polyether sulfone to obtain a carboxylated polyether sulfone hollow fiber, isolating the two ends of the obtained hollow fiber membrane module from each other by polyurethane glue, and cutting off the end part of the bundle to open the fiber at the end part of the package;
then adding 50-100 mg/mL nafamostat mesilate, 25-150 mg/mL polymyxin B sulfate and 25-100 mg/mL mannose buffer solution, adjusting the pH to 4.5-9.5, carrying out circulating covalent coupling reaction at the temperature of 20-30 ℃ for 8-24 h, and carrying out post-treatment to obtain the blood purification material.
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