CN114011389B - Blood purification material for sepsis and preparation method and application thereof - Google Patents
Blood purification material for sepsis and preparation method and application thereof Download PDFInfo
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- CN114011389B CN114011389B CN202111488489.8A CN202111488489A CN114011389B CN 114011389 B CN114011389 B CN 114011389B CN 202111488489 A CN202111488489 A CN 202111488489A CN 114011389 B CN114011389 B CN 114011389B
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- polyethersulfone
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- blood
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
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Abstract
The invention belongs to the field of medical equipment, and discloses a blood purification material for sepsis, 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 with modified cationic 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 adsorption effect of the finally obtained adsorption material on pathogenic components is obviously enhanced and more comprehensive.
Description
Technical Field
The invention relates to the field of medical equipment, in particular to a blood purification material for sepsis, a preparation method and application thereof.
Background
Blood purification technology is an effective treatment technology applicable to various difficult and complicated conditions, such as acute drug or poison poisoning, sepsis, end-stage renal disease, acute and chronic liver failure, and the like. This is because such diseases result in excessive accumulation of harmful substances in the blood, and the patient cannot detoxify, remove or neutralize the harmful substances through the self-protecting system (such as liver detoxication system, autoimmune system, excretory system, etc.). Therefore, the treatment of the diseases requires artificial efficient removal of harmful substances in blood, so as to achieve the purposes of quickly adjusting the stability of the environment in the body and relieving the illness state. Due to the outstanding curative effect of blood purification technology, the traditional Chinese medicine composition has become a main treatment method for patients suffering from acute poisoning and severe liver and kidney diseases and critical diseases. The blood purification methods commonly used in clinic at present mainly comprise hemodialysis, hemofiltration, hemoperfusion, plasma adsorption, plasma exchange and the like.
Sepsis, which is the life threatening multiple organ failure secondary to infection, is the leading cause of acute kidney injury in patients in intensive care units, with a worldwide morbidity of over 3150 tens of thousands and a yearly mortality of over 530 tens of thousands. Traditional treatment modalities for sepsis include the use of broad-spectrum antibiotics, timely fluid resuscitation, and the use of vascular pressure boosting drugs if necessary. However, broad-spectrum antibiotics are widely used in the treatment of sepsis patients, and the mortality rate of sepsis patients is still as high as 20-50%. In sepsis, both the higher endotoxin concentration in the blood and bacterial load are closely related to the severity of multiple 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 therapies in critical conditions in sepsis patients (progression to severe sepsis and septic shock). The currently commercialized blood purification products for sepsis include toraymycin (only endotoxin adsorbed), oXiris (endotoxin and inflammatory factor adsorbed) and Cytosorb (only inflammatory factor adsorbed) in the united states, which are not reported in the literature as positive results, particularly because these products may not achieve both a pathogen-associated molecular pattern (PAMPS), such as bacteria, fungi, viruses and parasites, and a damage-associated molecular pattern (DAMPS), such as endotoxin, endotoxin and inflammatory factor, during treatment, and a single or incomplete adsorption treatment pattern may seriously affect its therapeutic effect on sepsis.
The breakthrough point for solving the difficulty of sepsis blood purification may be to develop a blood purification material that can effectively remove DAMPS and PAMPS pathogenic substances from blood at the same time. This heterozygous therapeutic modality can minimize two key causative agents in sepsis onset and progression through blood purification: endotoxin and pathogenic bacteria. Meanwhile, in the traditional blood purification treatment process, heparin needs to be injected to prevent anticoagulation of blood, which not only increases treatment cost, but also more importantly increases the risk of serious hemorrhage of patients caused by whole body anticoagulation; in consideration of the special clinical problem that coagulation dysfunction is frequently complicated in the course of the sepsis patients, the blood purification material with self anticoagulation property has better blood compatibility, can influence the coagulation system function of the patients to a smaller extent, and can better prevent severe massive hemorrhage from occurring in the blood purification process or after blood purification.
Therefore, the research and development of the blood purification material and the product which can simultaneously remove the pathogenic substances of the DAMPS and the PAMPS and have anticoagulation property have important clinical significance and great economic and social values for the treatment of sepsis.
Traditional hemodialysis or hemodiafiltration can only remove small molecules, and can not effectively remove macromolecular pathogenic substances, and blood perfusion is needed. And the coupling reagent used in the research of the traditional blood perfusion technology is generally cyanogen bromide, trichlorotriazine, carbonyl diimidazole, sodium periodate, epichlorohydrin and the like, wherein the cyanogen bromide is a highly toxic substance, the synthesis process has great harm to human bodies and the environment, and the ligand is coupled by a cyanogen bromide method and easily falls off into the human bodies, so that great side effects are generated for patients. In addition, the traditional method adopts epichlorohydrin and carbonyl diimidazole as coupling reagent to activate carrier for coupling PMB, and avoids using virulent substance cyanogen bromide, but the preparation process has more reaction steps, and the adsorption material can be synthesized only through five steps of chemical reactions, and the method is complex, so that the obtained adsorption material has large batch-to-batch difference and unstable performance. The endotoxin adsorption material is prepared by a traditional method, and is a polystyrene woven fiber with polymyxin B on the surface, and the technology route is used for easily causing residues of strong-irritation chemical substances chloromethyl ether which are strong carcinogens, so that great potential safety hazards exist. Therefore, development of a blood purification adsorption material capable of comprehensively adsorbing the pathogenic factors of sepsis, and having simple process route, safety and high efficiency is urgently needed.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides a blood purifying material for sepsis, a preparation method and application thereof.
The technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided:
the carrier of the blood purification material is hollow fiber, and the surface of the hollow fiber 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 monomers in the amino acid polymer are 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 polyethylenimine 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 mannoses.
In some examples, the hollow fiber is selected from the group consisting of hollow fiber membranes, flat sheet membranes, tubular membranes, and woven materials 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 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 invention, there is provided:
a blood purifier for sepsis and/or septic shock comprising a blood purification material according to the first aspect of the invention.
In some examples, the blood purifier is selected from a dialyzer, hemofilter, hemodiafilter, plasma separator, adsorption column, perfusion vessel, or a combination of these products.
In some examples, the blood purification material binds gram negative bacilli and endotoxins released thereby, gram positive bacilli and exotoxins released thereby, fungi, viruses, and inflammatory factors.
In a third aspect of the invention, there is provided:
the preparation method of the blood purification material comprises the following steps:
preparing a carboxyl modified carrier by sequentially carrying out an acetylation reaction and an oxidation reaction on the carrier, and further preparing the carrier into hollow fibers;
and (3) covalently coupling functional ligands on the hollow fibers through an acylation reaction and/or an esterification reaction, and performing post-treatment to obtain the blood purifying material.
In some examples, the acetylating reagent 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 some examples, the temperature of the acetylation reaction is from 25 ℃ to 100 ℃.
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,NMethyl pyrrolidoneN,N-at 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 ]][HSO 4 ]At least one of the 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 from 4 hours to 10 hours.
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,NMethyl pyrrolidoneN,N-at 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 a reaction to covalently couple the functional ligand.
In some examples, the functional ligand compound consists of nafamostat mesylate, polymyxin B sulfate, and aminomannose.
In some examples, 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 aminomannose, the concentration of nafamostat mesylate in the buffer solution is 50-100 mg/mL, the concentration of polymyxin B sulfate is 25-150 mg/mL, and the concentration of aminomannose is 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 between 4.5 and 9.5.
In some examples, the time of the covalent coupling reaction is from 8 hours to 24 hours.
The beneficial effects of the invention are as follows:
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 adsorption effect of the finally obtained adsorption material on pathogenic components is obviously enhanced and more comprehensive.
Some examples of blood purification materials of the invention include functional ligands that bind 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, parasites, etc., and damage-associated molecular patterns (DAMPS) such as exotoxins, endotoxins, inflammatory factors, etc., and have self-anticoagulation.
In the examples of the blood purification materials, polyethersulfone is used as a specific matrix, an acetylation reagent and an oxidant are screened out to activate the material, specific carboxyl is introduced to couple with an amino compound ligand, the matrix, the coupling group and the ligand are mutually matched, the adsorption effect is synergistically improved, and compared with the traditional adsorption material, the adsorption effect of the finally obtained adsorption material on pathogenic components is obviously enhanced and more comprehensive.
Drawings
FIG. 1 is a schematic diagram of a method for preparing a blood purification material according to the present invention, in which NH 2 -R represents a ligand, -CONH-R 1 、-CONH -R 2 and-CONH-R 3 Representing three different ligands, respectively.
Description of the embodiments
The invention provides a blood purification material, wherein a carrier of the blood purification material is hollow fiber, and the surface of the hollow fiber 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.
In a specific example, the amino acid monomers in the amino acid polymer are selected from at least one of lysine, arginine, and histidine.
In a specific example, the tertiary/quaternary amine group-containing polymer is selected from at least one of polyethylenimine 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 mannoses.
In a specific example, the hollow fiber surface is covalently coupled modified with 3 functional ligands:
a) Polymyxin sulfate;
b) Nafamostat mesylate;
c) Amino mannose.
In a specific example, the hollow fiber is selected from the group consisting of hollow fiber membranes, flat sheet membranes, tubular membranes, and woven materials 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 hollow fiber woven tube, a hollow fiber woven mesh, or a hollow fiber tubular nonwoven material.
The hollow fiber woven tube is a tubular material woven by hollow fibers, the hollow fiber woven net is a net-shaped material woven by hollow fibers, and the hollow fiber tubular nonwoven material is a tubular material which is 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 polyethersulfone hollow fiber membranes have a pore size of 0.01 μm to 0.699 μm. It is understood that in the present invention, the pore size of the polyethersulfone hollow fiber membranes 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 blood purification material, which comprises the following steps:
the polyether sulfone hollow fiber matrix is respectively subjected to an activation reaction with an acetylation reagent and an oxidation reagent, and then is mixed with a functional ligand to carry out a covalent coupling reaction. The reaction principle is shown in figure 1.
In the invention, active group carboxyl groups are activated and introduced on the surface of a polyethersulfone matrix through an acetylating reagent and an oxidizing reagent, and after film preparation, covalent coupling is carried out, and amidation reaction is carried out on nucleophilic groups amino groups and carboxyl groups of functional ligands.
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 25 ℃ to 100 ℃. It is understood that in the present invention, the temperature of the acetylation reaction includes, but is not limited to, 25 ℃, 35 ℃, 45 ℃, 55 ℃, 65 ℃, 75 ℃, 85 ℃, 95 ℃, 100 ℃.
In a specific example, the time for the acetylation reaction is 1h to 5h. It is understood that in the present invention, the time for the acetylation reaction includes, but is not limited to, 1h, 2 h, 3h, 4h, 5h.
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,NMethyl pyrrolidoneN,N-at least one of dimethylacetamide. The catalyst for the acetylation reaction is aluminum chloride, ferrous chloride, cuprous chloride and [ MORRBSA ]][HSO4]At least one of the ionic liquids.
In one specific example, the polyethersulfone is mixed with an acetylating agent and an acetylating catalyst prior to being combined withN-methyl pyrrolidone mixing; the mass ratio of polyethersulfone to acetylating agent to acetylating catalyst is 1: (0.8-1.5): 0.2-0.6); the dosage ratio of polyethersulfone to organic solvent is 1g: (5-15) mL.
It is understood that in the present invention, the mass ratio of polyethersulfone, acetylating agent, and acetylating 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 dosage ratio of polyethersulfone to organic solvent includes, but is not limited to, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL.
In a 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 ℃, 75 ℃,80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃.
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 the acetylation reaction includes, but is not limited to, 4h, 5h, 6h, 7 h, 8h, 9 h, 10h.
In a specific illustrationIn an example, the oxidant in the oxidation reaction is permanganate; the solvent used in the oxidation reaction is an organic solvent. More specifically, the solvent used in the oxidation reaction is dimethyl sulfoxide,NMethyl pyrrolidoneN,N-at least one of dimethylacetamide. The oxidation catalyst is alkali metal hydroxide.
In a specific example, the acetylated polyethersulfone is mixed with an oxidizing agent and an oxidation catalyst prior to being combined withN-methyl pyrrolidone mixing; the mass ratio of the acetylated polyethersulfone to the oxidation reagent 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 1g: (10-15) mL.
It is 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 ratio of acetylated polyethersulfone to organic solvent used includes, but is not limited to: 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL.
And (3) preparing the carboxylated polyethersulfone into a carboxylated polyethersulfone hollow fiber, processing the obtained hollow fiber membrane, isolating two ends of the hollow fiber membrane by polyurethane glue, and re-opening the fiber at the packaging end part by cutting off the end part of the bundle to obtain the hollow fiber membrane device.
In a specific example, the functional ligand compound is added in the form of a buffer solution in which nafamostat mesylate has a concentration ranging from 50mg/mL to 100mg/mL, polymyxin B sulfate has a concentration ranging from 25mg/mL to 150mg/mL, and mannose has a concentration ranging from 25mg/mL to 100mg/mL. It will be appreciated 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, 100mg/mL; the concentration of polymyxin B sulfate includes, but is not limited to, 25mg/mL, 50mg/mL, 75 mg/mL, 100mg/mL, 125mg/mL, 150mg/mL; the concentration range of mannose includes, but is not limited to, 25mg/mL, 50mg/mL, 75 mg/mL, 100mg/mL, 125mg/mL, 150mg/mL. The mass ratio of carboxylated polyethersulfone to ramoseltamium 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 a 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 ℃, 22 ℃,25 ℃, 27 ℃, 30 ℃.
In a specific example, the time of the covalent coupling reaction is 8h to 24h. 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, 24h.
In a specific example, the pH of the covalent coupling reaction is between 4.5 and 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 method for preparing the modified fiber membrane blood purification material and the application of the modified fiber membrane according to the present invention will be described in further detail with reference to specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides a device for obtaining a hollow fiber membrane through acetylation, carboxylation and processing, which is specifically as follows:
30g of anhydrous aluminum chloride, 400mL of N-methylpyrrolidone and 40g of acetyl chloride were added into a three-necked flask, and after stirring uniformly in a low-temperature water bath, 50g of polyethersulfone dissolved in 250mL of N-methylpyrrolidone was added thereto, the temperature of the reaction system was adjusted to 90℃and the reaction was carried out for 3 hours. After the reaction, the residual solvent was removed by washing with water for injection several times to obtain acetylated polyethersulfone, which was designated as A1.
240mL of N-methylpyrrolidone was added to the above-mentioned acetylated polyethersulfone, and after stirring uniformly, 2.4g of KMnO4, 7.4g of NaOH and 18g of water for injection were added in this order to react for 6 hours at 80 ℃. Settling with dilute hydrochloric acid with pH of 1, filtering and cleaning to obtain carboxylated polyethersulfone, and marking as A2.
And (3) preparing a membrane by using the carboxylated polyethersulfone to obtain carboxylated polyethersulfone hollow fibers, processing the obtained hollow fiber membranes, isolating two ends from each other by using polyurethane glue, and re-opening the fibers at the packaged end parts by cutting off the end parts of the bundles to obtain a hollow fiber membrane device, wherein the hollow fiber membrane device is marked as A3.
Example 2
The embodiment provides a blood purification material taking nafamostat mesylate, polymyxin B sulfate and amino mannose as combined functional ligands, which comprises the following specific steps:
50g of the A3 prepared above was placed in 100mL of a solution containing 50mg/mL of nafamostat mesylate, 25mg/mL of PMB, 25mg/mL of aminomannose (dissolved in PBS pH 7.4), 10g of EDC and 1.5g of NHS were added for a ring-closing circulation reaction at 25℃for 24 hours, and the solution was washed with 20 times of water for injection to obtain a modified fibrous membrane material, which was labeled A4.
Example 3
The embodiment provides a blood purification material with nafamostat mesylate as a functional ligand, which comprises the following specific steps:
50g of the prepared A3 is placed in 100mL of nafamostat mesylate containing 50mg/mL, 10g of EDC and 1.5g of NHS are added for ring-closing circulation reaction at 25 ℃ for 24 hours, and the mixture is washed by water for injection with 20 times of volume, so that a modified fibrous membrane material marked as B4 is obtained.
Example 4
The embodiment provides a blood purification material with polymyxin B sulfate as a functional ligand, which comprises the following specific steps:
50g of the prepared A3 is placed in 100mL of a solution containing 25mg/mL of PMB, 10g of EDC and 1.5g of NHS are added for ring-closure circulation reaction at 25 ℃ for 24 hours, and the solution is washed by water for injection with 20 times of volume, so that a modified fibrous membrane material marked as C4 is obtained.
Example 5
The embodiment provides a blood purification material with amino mannose as a functional ligand, which comprises the following specific steps:
50g of A3 prepared above was placed in 100mL of a solution containing 25mg/mL of aminomannose (dissolved in PBS pH 7.4), 10g of EDC and 1.5g of NHS were added to carry out a ring-closure reaction at 25℃for 24 hours, and the solution was washed with 20 volumes of water for injection to obtain a modified fibrous membrane material, which was labeled as 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 steps:
50g of the A3 prepared above was placed in 100mL of a solution containing 50mg/mL of nafamostat mesylate, 25mg/mL of PMB, 25mg/mL of hyaluronic acid (dissolved in PBS pH 7.4), 10g of EDC and 1.5g of NHS were added for a ring-closing circulation reaction at 25℃for 24 hours, and the solution was washed with 20 times of water for injection to obtain a modified fibrous membrane material, which was labeled E4.
Example 7
The present embodiment provides a blood purification material using heparan, polymyxin B sulfate and hyaluronic acid as combined functional ligands, specifically as follows:
50g of A3 prepared in the above way is placed in 100mL of solution containing 50mg/mL of heparan, 25mg/mL of PMB and 25mg/mL of hyaluronic acid (dissolved by PBS with pH 7.4), 10g of EDC and 1.5g of NHS are added for carrying out a closed loop reaction for 24 hours at 25 ℃, and then the solution is washed by water for injection with 20 times of volume, so as to obtain a modified fibrous membrane material marked as F4.
Example 8
The embodiment provides a blood purification material taking nafamostat mesylate, polylysine and amino mannose as combined functional ligands, which comprises the following specific steps:
50G of the A3 prepared above was placed in 100mL of a solution containing 50mg/mL of nafamostat mesylate, 25mg/mL of polylysine, 25mg/mL of aminomannose (dissolved in PBS pH 7.4), 10G of EDC and 1.5G of NHS were added for a ring-closing circulation reaction at 25℃for 24 hours, and the solution was washed with 20 times of water for injection to obtain a modified fibrous membrane material, which was labeled G4.
Effect verification test one: adsorption Performance test
The blood purification materials A4 to D4 prepared in examples 2 to 8 were subjected to performance test, and the specific operations were as follows:
a fiber membrane device was mounted on an upstanding support, and a peristaltic pump was used to add 5X 10 to a volume of 500mL 7 CFU staphylococcus aureus, 5X 10 7 CFU Pseudomonas aeruginosa, 1EU/mL endotoxin and 10000pg/mL IL-6 bovine plasma solution were circulated at a flow rate of 200mL/min for 2 hours, the experiment was stopped, and residual concentrations of Staphylococcus aureus, pseudomonas aeruginosa, endotoxin and IL-6 in plasma were determined by blood culture using TSA growth medium, respectively. Based on the residual concentration, the percentage of bacteria, endotoxin and IL-6 adsorbed on the membrane of the module was calculated. The results are summarized in table 1.
TABLE 1 removal of pathogenic substances by modified fibrous membranes
And II, effect verification test: blood compatibility test
Blood compatibility tests were performed on the blood purification materials A4 to G4 prepared in examples 2 to 8 described above, and the specific procedures were as follows:
hemolysis experiment: the hemolysis experiment was performed according to GB/T16886.4-2003 medical instrument biological evaluation part 4 and blood interaction test selection and GB/T16175-2008 medical organosilicon Material biological evaluation test method. Taking a sample group tube, respectively adding the blood purification materials A4 to G4 1G prepared in the examples 2 to 8, and then adding the sodium chloride injection 10ml; adding 10ml of sodium chloride injection into each tube of the negative control group; distilled water was added 10ml per tube for the positive control group. Each group operated 3 tubes in parallel. Placing all test tubes into a constant temperature water bath (37+ -1) deg.C, maintaining for 30min, adding 0.2ml diluted rabbit blood into each test tube, mixing gently, and maintaining in the water bath (37+ -1) deg.C for 60 min. The liquid in the pouring tube was centrifuged at 800g for 5 min. The supernatant was pipetted into a cuvette and 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 should be no greater than 0.03, the absorbance of the positive control should be 0.8.+ -. 0.3, otherwise the test should be repeated. Hemolysis ratio = (a-B)/(C-B) ×100%, where a is the sample group absorbance; b is the absorbance of the negative control group; c is the absorbance of the positive control group.
Blood compatibility experiments: taking 4 1G of the blood purification materials A4-G prepared in the examples 2-8, soaking for 10 hours by using normal saline, filling into a column, injecting 10mL of rabbit whole blood which is not anticoagulated by heparin sodium by using a syringe, adsorbing for 2 hours at a flow rate of 20mL/min, and adding a hollow column to perform a control experiment. The changes in the blood components before and after adsorption were measured by a Beckman LH750 hemocyte analyzer.
The results show that:
(1) The hemolysis rates of the blood purification materials A4 to G4 prepared in examples 2 to 8 are all less than 1%, and are lower than 5% required by national standards.
(2) The blood purification materials A4, B4, E4 and G4 prepared in the examples 2, 3, 6 and 8 have little change of main components in blood before and after absorption, and the percentage of drop is less than 2%; the percent decrease in the change in each of the main components in the 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 showed severe coagulation after adsorption, and the percentage of decrease in the variation of each main component in blood was much more than 5% before and after adsorption. The results show that the self-anticoagulation liquid purification material prepared by the invention has good blood compatibility.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above description of the present invention is further illustrated in detail and should not be taken as limiting the practice of the present invention. It is within the scope of the present invention for those skilled in the art to make simple deductions or substitutions without departing from the concept of the present invention.
Claims (9)
1. The carrier of the blood purifying material is hollow fiber, which is characterized in that: the surface of the hollow fiber is covalently coupled and modified with the following 3 functional ligands:
a) Polymyxin B sulfate;
b) Nafamostat mesylate;
c) Amino mannose;
the hollow fiber is prepared by sequentially carrying out acetylation reaction and oxidation reaction on a carrier raw material to prepare a carboxyl modified carrier raw material and further preparing the carboxyl modified carrier raw material.
2. A blood purification material according to claim 1, wherein: 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, polyvinyl alcohol or derivatives and/or mixtures of the polymers.
3. A blood purification material according to claim 1 or 2, wherein: the pore diameter of the hollow fiber is 0.01-0.699 mu m.
4. A blood purifier for sepsis and/or septic shock, characterized by: the blood purification device comprising the blood purification material according to any one of claims 1 to 3.
5. The blood purifier of claim 4, wherein: the blood purifier is selected from dialyzers, hemofilters, hemodiafilters, plasma separators, adsorption columns, perfusion vessels, or combinations of these products.
6. The blood purifier of claim 4 or 5, wherein: the blood purification material combines gram-negative bacillus and endotoxin released by the gram-negative bacillus, gram-positive bacillus and exotoxin, fungi, viruses and inflammatory factors released by the gram-positive bacillus.
7. A preparation method of a blood purification material is characterized in that: the blood purification material according to any one of claims 1 to 3, comprising the steps of:
preparing a carboxyl modified carrier raw material by sequentially carrying out an acetylation reaction and an oxidation reaction on the carrier raw material, and further preparing the carboxyl modified carrier raw material into hollow fibers;
covalently coupling functional ligands on the hollow fibers through an acylation reaction and/or an esterification reaction, and performing aftertreatment to obtain a blood purification material; wherein:
the acetylation reaction has at least one of the following characteristics:
the acetylating agent is at least one of acetyl chloride, acetyl bromide and acetyl iodide or at least one of acetic anhydride and glacial acetic acid serving as substitutes;
the temperature of the acetylation reaction is 25-100 ℃;
the time of the acetylation reaction is 1 to 5 hours;
the solvent adopted in the acetylation reaction is an organic solvent, and the organic solvent is selected from dimethyl sulfoxide,NMethyl pyrrolidoneN,N-at least one of dimethylacetamide;
the acetylation catalyst is selected from aluminum chloride, ferrous chloride, cuprous chloride, [ MORRBSA ]][HSO 4 ]At least one of the 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 hours;
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,NMethyl pyrrolidoneN,N-at least one of dimethylacetamide;
the oxidation catalyst is selected from alkali metal hydroxides;
the reaction of covalently coupling the functional ligand 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 is added in the form of a buffer solution, the functional ligand compound consists of nafamostat mesylate, polymyxin B sulfate and amino mannose, the concentration of the nafamostat mesylate in the buffer solution is 50-100 mg/mL, the concentration of the polymyxin B sulfate is 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 covalent coupling reaction is 8-24 h.
8. The method of manufacturing according to claim 7, wherein:
in the acetylation reaction, polyether sulfone is mixed with an acetylation reagent and an acetylation reaction catalyst and then with the mixtureNMixing methyl pyrrolidone, and mixing polyether sulfone with an acetylating reagent and an acetylating reaction catalyst in a mass ratio of 1: (0.8-1.5): (0.2-0.6), the dosage ratio of polyethersulfone to organic solvent is 1g: (5-15) mL; and/or
In the oxidation reaction, the acetylated polyethersulfone is mixed with an oxidizing agent and an oxidation reaction catalyst and then is mixed withNMixing methyl pyrrolidone, and mixing acetylated polyethersulfone with an oxidizing agent and an oxidation reaction catalyst in a mass ratio of 1: (0.05-0.15): 0.1-0.4); the dosage ratio of the acetylated polyethersulfone to the organic solvent is 1g: (10-15) mL.
9. The method of manufacturing according to claim 7, wherein: the method comprises the following steps:
polyether sulfone, an acetylating reagent and an acetylating catalyst in a mass ratio of 1: (0.8-1.5), mixing (0.2-0.6), wherein the dosage ratio of polyethersulfone to organic solvent is 1g: (5-15) carrying out an acetylation reaction at 25-100 ℃ for 1-5 h;
then carrying out oxidation reaction, wherein the mass ratio of the acetylated polyethersulfone 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 1g: (10-15) mL, wherein the reaction temperature is 70-100 ℃ and the reaction time is 4-10 h, so as to obtain carboxylated polyethersulfone;
preparing a carboxylated polyethersulfone into a carboxylated polyethersulfone hollow fiber membrane, processing the obtained hollow fiber membrane, isolating two ends from each other by polyurethane glue, and re-opening the fiber at the packaging end by cutting off the end of the bundle;
then 50 mg/mL-100 mg/mL of nafamostat mesylate, 25 mg/mL-150 mg/mL of polymyxin B sulfate and 25 mg/mL-100 mg/mL of mannose buffer solution are added, the pH is regulated to 4.5-9.5, the cyclic covalent coupling reaction is carried out for 8-24 hours at the temperature of 20-30 ℃, and the blood purification material is obtained after post treatment.
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