CN105664868A - Endotoxin adsorption material for blood purification and preparation method and application of endotoxin adsorption material for blood purification - Google Patents
Endotoxin adsorption material for blood purification and preparation method and application of endotoxin adsorption material for blood purification Download PDFInfo
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Abstract
The invention discloses an endotoxin adsorption material for blood purification and a preparation method and application of the endotoxin adsorption material for blood purification.The endotoxin adsorption material for blood purification is obtained by coupling reaction of an active carrier and genins containing aminos, wherein the ratio of the active carrier to every genin is 10:1-100:1; the active carrier is obtained by reaction between a carrier and a bis-glycidyl ether coupling reagent, wherein the carrier is a spherical natural polymer with the particle size being 0.05-1.5mm, and the volume ratio of the carrier to the bis-glycidyl ether coupling reagent is 1:0.5-1:10.The endotoxin adsorption material for blood purification has the advantages of high specificity, good blood compatibility, high endotoxin adsorption efficiency and capability of being used for blood purification and adsorption treatment of endoxemia clinically.The preparation method is simple, convenient, simple and short in process route and safe for preparation.
Description
Technical field
The present invention relates to biomaterial for medical purpose field, particularly relate to blood purification endotoxin adsorption material and its preparation method and application.
Background technology
Intracellular toxin is the main integral part of gram negative bacillus (gram-negativebacteria, GNB) cytolemma outer wall, the stability of bacterium is played an important role. Intracellular toxin is almost ubiquitous, be a kind of toxicity extremely strong cause inflammation and pyrogenic substances, be the principal causative medium of endotoxemia and septic shock. Endotoxemia be due in blood or intralesional bacterium discharge a large amount of bacterial endotoxin to blood, or input the liquid of a large amount of contaminated with endotoxins and a kind of illness of causing. When body is subject to the traditional for a long time parenteral nutrition of wound (comprising operation), burn, infection, radiotherapy, chemotherapy and acceptance, intestinal permeability increases, the permeability of bacterium and intracellular toxin is increased by intestinal mucosa, and bacterium and intracellular toxin will enter blood in a large number. In some cases, bacteriological infection may be controlled, but intracellular toxin is still by the intestinal mucosa of " leakage ", causes the activation of inflammation and the release of cell medium. Endotoxemia can cause a series of pathophysiological change, the exothermic reaction of such as organism, impels vaso-active substance release and causes microcirculation disturbance. Meanwhile, the minimizing of white corpuscle and thrombocyte can be caused, produce bleeding tendency, also can directly or indirectly damage liver and cause the change of carbohydrate metabolism disturbance and zymetology, protein metabolism. The further development of endotoxemia may cause septic shock, disseminated inravascular coagulation, acute respiratory distress syndrome (SARS), systemic inflammatory response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS), even cause death because of the generation of MOFE (MOF).
At present the treatment of endotoxemia is still lacked ripe experience. Mainly take aggregate measures, comprise control microbemia, reduce intracellular toxin generation and absorption, the application of anti-endotoxin drug, the effect of antagonize endogenous medium and cleaning, absorption etc.Though the therapeutic modality of endotoxemia is a lot, real effective method is also few so far, and from current research progress, the methods for the treatment of that comparing has prospect is Endotoxin adsorption blood purification method. To some great difficult venereal disease diseases, blood purification therapy has unique curative effect, the miracle as " coming back to life " even can occurs, is the important means that clinical treatment is indispensable. Wherein, blood perfusion is by blood by extracorporeal circulation, by having spectrum antidotal effect or the adsorbent units of fixing ligands specific, removes in blood endogenous property or external source poisonous substance or morbid substance, reaches the object of purification blood, alleviation and disease therapy.
1997, under the subsidy of Toray company, PXB is coupled on resin to be prepared into Endotoxin adsorption post product (Toraymyxin) by Japanese researchers, during 1997 to 2002,206 septic patients are treated, from 0.46EU/mL, endotoxin concns in patient's blood can being reduced to 0.15EU/mL, patient's survival rate is to 69%. Domestic only have the Experimental report utilizing gac blood perfusion method absorption intracellular toxin, experimentation on animals shows, intracellular toxin in blood can be directly adsorbed with gac perfusion, owing to gac blood compatibility is poor, intracellular toxin loading capacity is too little, and adsorb non-selectivity, impact use, so effect and not obvious. Affine absorption is a kind of method having very much prospect of selective adsorption intracellular toxin, and the method is selected and specifically adsorbed part, and other compositions in solution are not acted on by a selective adsorption intracellular toxin, is a kind of comparatively ideal method.
One group of polypeptide antibiotics that PXB (PMB) is produced by bacillus polymyxa, its molecular weight is about 1450, hydrophobic amino acid on PMB and the lipid acid on the active part lipid A of intracellular toxin are by hydrophobic bond effect, and the electronegative phosphate of amino positively charged on PMB on lipid A is combined by ionic linkage effect such that it is able to the intracellular toxin that removes in blood plasma. It is prepared into carrier-PMB mixture adsorption column if being fixed on by PMB on a certain carrier, when human plasma is by this adsorption column, intracellular toxin in blood plasma will be adsorbed specifically, thus the endotoxemia caused by intracellular toxin, septic shock just can be treated and alleviate. Endotoxin adsorption treatment it is crucial that the development of Endotoxin adsorption post, be exactly the synthesis of the endotoxin adsorption material in Endotoxin adsorption post specifically, so the synthetic technology being fixed on carrier by PMB is most important. At present, carrier matrix mainly sepharose and the cellulose balls carrier that the endotoxin adsorption material that research uses adopts, coupling reagent generally adopts cyanogen bromide, three chlorotriazines, carbonyl dimidazoles, sodium periodate and epoxy chloropropane etc. Owing to cyanogen bromide is highly toxic substance, building-up process is bigger to human body and environmental hazard; And easily come off with the PMB group of cyanogen bromide method coupling and enter human body, patient is produced bigger side effect. So this synthesis technique is not satisfactory.
The human hairs such as Yuan Zhihe merchant reaches the clouds understand the novel method of PMB-agarose endotoxin adsorption material, they adopt epoxy chloropropane (application number: 03144231.5 respectively, publication number: CN1239210C) and carbonyl dimidazoles (application number: 200710012501.1, publication number: CN100493695C) as coupling reagent activated agarose carrier. Although these two kinds of methods avoid uses highly toxic substance cyanogen bromide, its materials'use prepared is also safer, but its preparation process reactions steps is more, need to synthesize sorbing material through five step chemical reactions, method is complicated, therefore the sorbing material product differences between batches obtained are big, unstable properties.
Summary of the invention
Based on this, it is necessary for the problems referred to above, a kind of endotoxin adsorption material for blood purification and its preparation method and application are provided, the endotoxin adsorption material of blood purification of the present invention has good blood compatibility, by the method for blood perfusion, intracellular toxin in efficient absorption blood samples of patients, can be used for whole blood perfusion, it is possible to for plasma perfusion.
For realizing above-mentioned technical purpose, concrete technical scheme is as follows:
A kind of blood purification endotoxin adsorption material, react with the ligand cou containing amino by comprising active carrier, and the quality ratio range of the aglucon containing amino described in described active carrier and often kind is 10:1～100:1; Described active carrier is by comprising carrier and the rear gained of bisglycidyl ether coupling reagent reaction, and described carrier is the spherical natural polymer of particle diameter 0.05～1.5mm, and the volume proportion scope of described carrier and bisglycidyl ether coupling reagent is 1:0.5～1:10.
Wherein in some embodiments, the volume proportion scope of described carrier and bisglycidyl ether coupling reagent is 1:0.9～1:1.1.
Wherein in some embodiments, described carrier is the one in chitosan microball, sepharose, dextrane gel and cellulose microsphere. Preferred sepharose. After the hydroxyl of carrier surface is carried out epoxidation modification, then immobilized aglucon.
Wherein in some embodiments, the described aglucon containing amino is one or both the combination in polylysine, glycine, arginine, Polymyxin B-sulfate USP (PMB), human serum albumin, bactericidal properties/power/permeability increasing protein (BPI). Preferably sulfuric acid PXB (PMB).
Wherein in some embodiments, described bisglycidyl ether coupling reagent is the one in ethylene glycol bis glycidyl ether, 1,4-butyleneglycol bisglycidyl ether, 1,6-HD bisglycidyl ether. Preferred 1,4-butyleneglycol bisglycidyl ether.
The present invention adopts bisglycidyl ether coupling reagent carry out epoxidation modification and add connecting arm.
Bacterial endotoxin, also known as lipopolysaccharides (LPS), forms the adventitia of gram negative bacterium jointly with protein, phosphatide etc. The molecular weight great majority of LPS monomer are 5000～25000, aglucon to be kept its adsorptive power, after needing guarantee to be bonded with carrier, its stereoeffect is not out of shape, the contact of intracellular toxin and aglucon simultaneously also needs enough spaces, and the microenvironment of endotoxin adsorption material is very big on the impact of its adsorptive power. Aglucon is only fully exposed at vector outside, and the intracellular toxin adsorbed could contact with aglucon without spatial obstacle as much as possible, gives full play to the adsorptive power of aglucon. If there being the interval arm of certain length between material surface and aglucon, it is that aglucon and material surface maintain a certain distance, to ensure that its space structure is constant, intracellular toxin can not be subject to contacting as far as possible with intracellular toxin of spatial obstacle simultaneously, it is to increase the adsorption efficiency of material intracellular toxin. The coupling reagent ethylene glycol bis glycidyl ether main chain that the present invention selects contains 10 atom (X=CH2CH2), 1,4-butyleneglycol bisglycidyl ether main chain contain 12 atom (X=CH2CH2CH2CH2), 1,6-HD bisglycidyl ether main chain contain 14 atom (X=CH2CH2CH2CH2CH2CH2) there is longer length, after being fixed on carrier by aglucon, part can fully be exposed to material surface, and the adsorption efficiency of material aglucon obtained like this is higher, reduces production cost.
Blood purification endotoxin adsorption material of the present invention is taking the spherical natural polymer (preferred chitosan microball, sepharose, dextrane gel or cellulose microsphere) of particle diameter 0.05～1.5mm as carrier, after reacting with bisglycidyl ether coupling reagent, obtain active carrier, then with the macromolecular material of ligand cou containing amino.
The spherical natural polymer of particle diameter 0.05～1.5mm such as chitosan microball, sepharose, dextrane gel or cellulose microsphere contain abundant hydroxyl, can participating in number of chemical reaction and be converted into active group, the aglucon reaction then containing amino with Polymyxin B-sulfate USP etc. is fixed on carrier.The preferred bisglycidyl etherifying reagent of the present invention is as the reagent of activated carrier, these activating reagents all contain two epoxide groups, it is the reagent that a class has very high reaction activity, one of them epoxide group can with the hydroxyl reaction on carrier, another epoxide group can amino with aglucon react under mild conditions, thus is fixed on carrier with covalent by the aglucon containing amino.
The present invention also provides the preparation method of a kind of above-mentioned blood purification endotoxin adsorption material, comprises the following steps:
(1) support-activated
Get described carrier to mix with alkaline aqueous solution, add described bisglycidyl ether coupling reagent, react at 25～50 DEG C, reaction times is 5～16h, the concentration of described alkaline aqueous solution is 0.5～3.5mol/L, volume proportion between described carrier, alkaline aqueous solution and bisglycidyl ether coupling reagent is 1:0.04:0.5～1:2:10, obtains active carrier;
(2) step (1) gained active carrier filtered, wash to neutral;
(3) coupling aglucon
Get and step (2) gained active carrier adds the described aglucon aqueous solution containing amino, the described concentration containing the aglucon aqueous solution of amino is 2～60mg/mL, the quality ratio range of aglucon containing amino described in described active carrier and often kind is 10:1～100:1, control ph reacts 20～72h at 3.0～14.0,37～60 DEG C.
(4) end-block
Step (3) products therefrom is added 0.5～1.5M ethanolamine solutions and carries out end capping.
Due to the obstacle in space, after aglucon and the carrier activated with ethylene glycol bis glycidyl ether etc. react, the cycloalkyl groups that some unreacteds will be also had complete, these groups are the latencies producing non-specific adsorption, it is necessary to its inertia talked about. The present invention selects thanomin as capping reagent, removes unreacted epoxy-activated group.
Wherein in some embodiments, the volume proportion between described carrier, alkaline aqueous solution and bisglycidyl ether coupling reagent is 1:0.04:0.9～1:0.04:1.1.
The present invention also provides the application of above-mentioned blood purification endotoxin adsorption material on the blood perfusion device of preparation treatment endotoxemia.
The present invention also provides the method using above-mentioned blood purification endotoxin adsorption material to carry out blood perfusion, comprise the following steps: under room temperature, getting described blood purification endotoxin adsorption material loads in perfusion post, with the blood plasma of endotoxemia patient or whole blood perfusion, adopt endotoxin concns before and after dynamic turbidimetric detection perfusion and change with blood ingredient before and after Blood cell analyzer detection perfusion; Or described blood purification endotoxin adsorption material is directly added in the blood plasma containing intracellular toxin, Static Adsorption under certain temperature, adopts endotoxin concns before and after dynamic turbidimetric detection absorption.
Wherein in some embodiments, described preparation method comprises the following steps: under room temperature, getting blood purification endotoxin adsorption material described in 5～100g loads in perfusion post, with the blood plasma of endotoxemia patient or whole blood 25～3000mL with the flow velocity perfusion 1～4h of 20～200mL/min, the proportioning of described blood purification endotoxin adsorption material and endotoxemia patient's blood plasma or whole blood is 1:5～1:30, m/v, adopts endotoxin concns before and after dynamic turbidimetric detection perfusion and changes with blood ingredient before and after Blood cell analyzer detection perfusion; Or blood purification endotoxin adsorption material described in 0.2～1.0g is directly added 4～30mL containing in the blood plasma of intracellular toxin, Static Adsorption 1～4h at 25～37 DEG C, shaking speed is 120～200rpm, and the proportioning of described blood purification endotoxin adsorption material and blood plasma is 1:5～1:30, m/v.
Describing based on above, significant advantage and the effect of the present invention be:
1, inventor team is by a large amount of experiment and research, the raw materials such as preferred natural polymer carrier, aglucon, coupling agent, prepare blood purification endotoxin adsorption material, first utilize the hydroxyl of spherical natural polymer carrier surface that it is carried out epoxidation modification, improve epoxy group(ing) amount, add hydrophobic connecting arm, it is to increase the motor capacity of aglucon simultaneously, thus make sorbing material have good Endotoxin adsorption effect.
2, the natural polymer of the preferred certain particle size range of the present invention is carrier, and blood compatibility is good;
3, the preferred bisglycidyl ether of the present invention is as the reagent of active natural polymer carrier, overcomes toxicity and the unstable of cyanogen bromide-activated, thus adds the security of synthesis, extends the work-ing life of material; And bisglycidyl ether molecule contains certain length, between natural polymer carrier surface and aglucon, so just introduce interval arm, for the combination of aglucon and intracellular toxin creates enough spaces, improve the microenvironment of material, thus improve aglucon to intracellular toxin in conjunction with efficiency, decrease the consumption of sorbent material, reduce production cost.
4, activation and be connected interval arm and complete in single step reaction simultaneously, thus preparation process is greatly simplified, decrease the differences between batches of product.
5, the adsorption efficiency height of gained blood purification endotoxin adsorption material of the present invention. External blood plasma and Blood index testing data show, intracellular toxin is had specific adsorption by the blood purification endotoxin adsorption material of the present invention.
Embodiment
Below with reference to embodiment, the technique effect of the design of the present invention, concrete structure and generation is carried out clear, complete description, fully to understand object, the characteristic sum effect of the present invention.
Obviously; described embodiment is a part of embodiment of the present invention, instead of whole embodiment, based on embodiments of the invention; other embodiment that the technician of this area obtains under the prerequisite not paying creative work, all belongs to the scope of protection of the invention.
Following examples are raw materials used is commercially available common raw material.
Embodiment 1
1. the reaction of sepharose and ethylene glycol bis glycidyl ether
(1) support-activated: the NaOH aqueous solution adding sepharose (Cl-6B, particle diameter 300～600 μm) 0.5L, 1.0mol/L in the reactor of 2.0L (includes the NaBH of 5mg/mL4Solution) 20mL, mix, after adding ethylene glycol bis glycidyl ether 500mL, it is placed in constant-temperature table, at 40 DEG C, reacts 5h, terminate reaction, obtain activated carrier;
(2) step (1) gained activated carrier is filtered, respectively successively with the distilled water of 20 times of volumes, ethanol/water (volume ratio is 1:1), dehydrated alcohol, ethanol/water (volume ratio is 1:1) and distilled water flushing;
By for subsequent use at 4 DEG C for the carrier storage that activated; Epoxide group quantity in the gel activated in this way with thio sulfate method detection, records the epoxy-activated group that every milliliter has at least 50 μm of ol, is designated as E1-1.
2. the reaction of sepharose and 1,4-butyleneglycol bisglycidyl ether
(1) support-activated: the NaOH aqueous solution adding sepharose (Cl-6B, particle diameter 300～600 μm) 0.5L, 1.0mol/L in the reactor of 2.0L (includes the NaBH of 5mg/mL4Solution) 20mL, mix, after adding 1,4-butyleneglycol bisglycidyl ether 500mL, it is placed in constant-temperature table, at 40 DEG C, reacts 5h, terminate reaction, obtain activated carrier;
(2) step (1) gained activated carrier is filtered, respectively successively with the distilled water of 20 times of volumes, ethanol/water (volume ratio is 1:1), dehydrated alcohol, ethanol/water (volume ratio is 1:1) and distilled water flushing;
By for subsequent use at 4 DEG C for the carrier storage that activated; Epoxide group quantity in the gel activated in this way with thio sulfate method detection, records the epoxy-activated group that every milliliter has at least 50 μm of ol, is designated as E1-2.
3. the reaction of sepharose and 1,6-HD bisglycidyl ether
(1) support-activated: the NaOH aqueous solution adding sepharose (Cl-6B, particle diameter 300～600 μm) 0.5L, 1.0mol/L in the reactor of 2.0L (includes the NaBH of 5mg/mL4Solution) 20mL, mix, after adding 1,6-HD bisglycidyl ether 500mL, it is placed in constant-temperature table, at 40 DEG C, reacts 5h, terminate reaction, obtain activated carrier;
(2) step (1) gained activated carrier is filtered, respectively successively with the distilled water of 20 times of volumes, ethanol/water (volume ratio is 1:1), dehydrated alcohol, ethanol/water (volume ratio is 1:1) and distilled water flushing;
By for subsequent use at 4 DEG C for the carrier storage that activated; Epoxide group quantity in the gel activated in this way with thio sulfate method detection, records the epoxy-activated group that every milliliter has at least 45 μm of ol, is designated as E1-3.
4, the reaction of chitosan microball and 1,4-butyleneglycol bisglycidyl ether.
(1) support-activated: the NaOH aqueous solution adding chitosan microball (CSbead, particle diameter 300～600 μm) 0.5L, 1.0mol/L in the reactor of 2.0L (includes the NaBH of 5mg/mL4Solution) 20mL, mix, after adding 1,4-butyleneglycol bisglycidyl ether 500mL, it is placed in constant-temperature table, at 40 DEG C, reacts 5h, terminate reaction, obtain activated carrier;
(2) step (1) gained activated carrier is filtered, respectively successively with the distilled water of 20 times of volumes, ethanol/water (volume ratio is 1:1), dehydrated alcohol, ethanol/water (volume ratio is 1:1) and distilled water flushing;
By for subsequent use at 4 DEG C for the carrier storage that activated; Epoxide group quantity in the gel activated in this way with thio sulfate method detection, records the epoxy-activated group that every milliliter has at least 50 μm of ol, is designated as E1-4.
5, the reaction of cellulose microsphere and 1,4-butyleneglycol bisglycidyl ether
(1) support-activated: the NaOH aqueous solution adding cellulose microsphere (Viscopearl-P, particle diameter 300-600 μm) 0.5L, 1.0mol/L in the reactor of 2.0L (includes the NaBH of 5mg/mL4Solution) 20mL, mix, after adding 1,4-butyleneglycol bisglycidyl ether 500mL, it is placed in constant-temperature table, at 40 DEG C, reacts 5h, terminate reaction, obtain activated carrier;
(2) step (1) gained activated carrier is filtered, respectively successively with the distilled water of 20 times of volumes, ethanol/water (volume ratio is 1:1), dehydrated alcohol, ethanol/water (volume ratio is 1:1) and distilled water flushing;
By for subsequent use at 4 DEG C for the carrier storage that activated; Epoxide group quantity in the gel activated in this way with thio sulfate method detection, records the epoxy-activated group that every milliliter has at least 50 μm of ol, is designated as E1-5.
Embodiment 2
The synthesis of endotoxin adsorption material
1, active sepharose (Cl-6B) and polylysine and glycine reactant dextran purification endotoxin adsorption material
Get active sepharose (E1-1) 10g and add the aqueous solution 20mL containing 1.0g polylysine, 0.2g glycine, regulate pH=12, react 24 hours in 60 DEG C;Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-1-1.
2, active sepharose (Cl-6B) and arginine Reactive Synthesis blood purification endotoxin adsorption material
Getting active sepharose (E1-1) 10g to add containing the arginic aqueous solution 60mL of 0.8g, adjust ph is 5.0, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-1-2.
3, active sepharose (Cl-6B) and PMB Reactive Synthesis blood purification endotoxin adsorption material
Get active sepharose (E1-1) 10g, add the PMB solution 10mL (with 0.2M phosphate buffered saline buffer to prepare PMB solution) of 50mg/mL, adjust ph is 7.4, at 37 DEG C of isothermal reaction 24h stopped reaction, clean with distilled water, then with the thanomin of 20mL1mol/L, regulate pH to be 8.0, the unreacted epoxy-activated group of end-blocking, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-1-3.
4, active sepharose (Cl-6B) and human serum albumin Reactive Synthesis blood purification endotoxin adsorption material
Getting active sepharose (E1-1) 10g and add the aqueous solution 60mL containing 0.8g human serum albumin, adjust ph is 3.3, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain endotoxin absorbent E1-1-4.
5, active sepharose (Cl-6B) and BPI Reactive Synthesis blood purification endotoxin adsorption material
Getting the solution 60mL (with 0.1M2-(N-morpholino) methylsulfonic acid damping fluid to prepare BPI solution) that active sepharose (E1-1) 10g adds 2mg/mLBPI, adjust ph is 4.8, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-1-5.
6, active sepharose (Cl-6B) and polylysine and glycine reactant dextran purification endotoxin adsorption material
Get active sepharose (E1-2) 10g and add the aqueous solution 20mL containing 1.0g polylysine, 0.2g glycine, regulate pH=12, react 24 hours in 60 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-2-1.
7, active sepharose (Cl-6B) and arginine Reactive Synthesis blood purification endotoxin adsorption material
Getting active sepharose (E1-2) 10g to add containing the arginic aqueous solution 60mL of 0.8g, adjust ph is 5.0, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours;Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-2-2.
8, active sepharose (Cl-6B) and PMB Reactive Synthesis blood purification endotoxin adsorption material
Get active sepharose (E1-2) 10g, add the PMB solution 10mL (with 0.2M phosphate buffered saline buffer to prepare PMB solution) of 50mg/mL, adjust ph is 7.4, at 37 DEG C of isothermal reaction 24h stopped reaction, clean with distilled water, then with the thanomin of 20mL1mol/L, regulate pH to be 8.0, the unreacted epoxy-activated group of end-blocking, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-2-3.
9, active sepharose (Cl-6B) and human serum albumin Reactive Synthesis blood purification endotoxin adsorption material
Getting active sepharose (E1-2) 10g and add the aqueous solution 60mL containing 0.8g human serum albumin, adjust ph is 3.3, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-2-4.
10, active sepharose (Cl-6B) and BPI Reactive Synthesis blood purification endotoxin adsorption material
Getting the solution 60mL (with 0.1M2-(N-morpholino) methylsulfonic acid damping fluid to prepare BPI solution) that active sepharose (E1-2) 10g adds 2mg/mLBPI, adjust ph is 4.8, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-2-5.
11, active sepharose (Cl-6B) and polylysine and glycine reactant dextran purification endotoxin adsorption material
Get active sepharose (E1-3) 10g and add the aqueous solution 20mL containing 1.0g polylysine, 0.2g glycine, regulate pH=12, react 24 hours in 60 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-3-1.
12, active sepharose (Cl-6B) and arginine Reactive Synthesis blood purification endotoxin adsorption material
Getting active sepharose (E1-3) 10g to add containing the arginic aqueous solution 60mL of 0.8g, adjust ph is 5.0, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-3-2.
13, active sepharose (Cl-6B) and PMB Reactive Synthesis blood purification endotoxin adsorption material
Get active sepharose (E1-3) 10g, add the PMB solution 10mL (with 0.2M phosphate buffered saline buffer to prepare PMB solution) of 50mg/mL, adjust ph is 7.4, at 37 DEG C of isothermal reaction 24h stopped reaction, clean with distilled water, then with the thanomin of 20mL1mol/L, regulate pH to be 8.0, the unreacted epoxy-activated group of end-blocking, 37 DEG C of concussion reactions 4 hours;Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-3-3.
14, active sepharose (Cl-6B) and human serum albumin Reactive Synthesis blood purification endotoxin adsorption material
Getting active sepharose (E1-3) 10g and add the aqueous solution 60mL containing 0.8g human serum albumin, adjust ph is 3.3, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-3-4.
15, active sepharose (Cl-6B) and BPI Reactive Synthesis blood purification endotoxin adsorption material
Getting the solution 60mL (with 0.1M2-(N-morpholino) methylsulfonic acid damping fluid to prepare BPI solution) that active sepharose (E1-3) 10g adds 2mg/mLBPI, adjust ph is 4.8, reacts 24 hours in 37 DEG C; Clean with distilled water after having reacted; And then add the ethanolamine solutions of 20mL1.0mol/L, regulate pH to be 8.0, end capping, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-3-5.
16, active chitosan microballoon (CSbead) and PMB Reactive Synthesis blood purification endotoxin adsorption material
Get active chitosan microballoon (E1-4) 10g, add the PMB solution 10mL (with 0.2M phosphate buffered saline buffer to prepare PMB solution) of 50mg/mL, adjust ph is 7.4, at 37 DEG C of isothermal reaction 24h stopped reaction, clean with distilled water, then with the thanomin of 20mL1mol/L, regulate pH to be 8.0, the unreacted epoxy-activated group of end-blocking, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-4-1.
17, activated cellulose microballoon (Viscopearl-P) and PMB Reactive Synthesis blood purification endotoxin adsorption material
Get activated cellulose microballoon (E1-5) 10g, add the PMB solution 10mL (with 0.2M phosphate buffered saline buffer to prepare PMB solution) of 50mg/mL, adjust ph is 7.4, at 37 DEG C of isothermal reaction 24h stopped reaction, clean with distilled water, then with the thanomin of 20mL1mol/L, regulate pH to be 8.0, the unreacted epoxy-activated group of end-blocking, 37 DEG C of concussion reactions 4 hours; Clean with distilled water after having reacted, obtain blood purification endotoxin adsorption material E1-5-1.
Embodiment 3
Absorption intracellular toxin experiment
The endotoxin concns of endotoxemia patient is generally less than 1EU/mL, and experiment setting absorption starting point concentration is 1EU/mL. Get the pyrogen-free Erlenmeyer flask of 10mL, add the obtained blood purification endotoxin adsorption material 0.2g of embodiment 2 respectively, add the blood plasma 6mL containing intracellular toxin 1EU/mL again, concussion absorption 2 hours (temperature 37 DEG C, concussion speed 180rpm), then measure the rear endotoxin concns of absorption by dynamic turbidimetric, and calculate sorbent material to its adsorptive capacity and clearance rate, shown in result table 1.
In table 1 embodiment 2, each blood purification endotoxin adsorption material is to the adsorptive capacity of intracellular toxin and clearance rate
Can be found out by test result, blood purification endotoxin adsorption material in the embodiment of the present invention all has good Endotoxin removal rate, further, result according to table 1, contrast blood purification endotoxin adsorption material E1-1-1vs.E1-2-1, the adsorption effect of E1-1-3vs.E1-2-3, it can be seen that, after the connecting arm of introducing different lengths, intracellular toxin clearance rate is all significantly increased by the blood purification endotoxin adsorption material of immobilized different aglucon.Although E1-1-1 and E1-2-1 has higher elimination effect, but owing to adopting two aglucon polylysine and glycine reactant need to carry out under pH is 12 and 60 DEG C of conditions, reaction conditions is harsher, suitability for industrialized production more complicated, introduce two aglucon simultaneously, control and detection to its coupling density increase difficulty, therefore pay the utmost attention to E1-1-3, E1-2-3, E1-3-3, can find out the adsorption effect that E1-2-3 can reach higher simultaneously.
Embodiment 4
Hemolytic experiment
Hemolytic experiment is carried out according to " GB/T16886.4-2003 BiologicalEvaluationofMedicalDevice the 4th part and blood interaction test and Selection ", " GB/T16175-2008 medical organic silicon material biological assessment test method ".
Sample thief group often pipe add the obtained blood purification endotoxin adsorption material 2g of embodiment 2, then add sodium chloride injection 10ml; Negative control group often pipe add sodium chloride injection 10ml; Positive controls often pipe add distilled water 10ml. Often organize parallel running 3 to manage. After water bath with thermostatic control (37 ± 1) DEG C insulation 30min put into by whole test tube, often prop up test tube and add 0.2ml dilution rabbit blood, mixed even gently, put (37 ± 1) DEG C water-bath resume insulation 60min. Pour out liquid in pipe with the centrifugal 5min of 800g. Aspirate supernatant moves in cuvette, with spectrophotometer in 545nm wavelength place mensuration absorbancy. Sample combination control group absorbancy all gets the mean value of 3 pipes. The absorbancy of negative control pipe should be not more than 0.03, and the absorbancy of positive control pipe should be 0.8 ± 0.3, otherwise should again test.
Hemolysis rate=(A-B)/(C-B) × 100%
Wherein A sample sets absorbancy;
B negative control group absorbancy;
C positive controls absorbancy.
The hemolysis rate that result obtains embodiment 2 gained blood purification endotoxin adsorption material is all less than 3%, lower than national standard require lower than 5%.
Embodiment 5
The animal experiment of blood purification endotoxin adsorption material and Compatibility Evaluation
Blood purification being used endotoxin adsorption material E1-2-32g, after regeneration cleaned by the sodium deoxycholate with 1%, cleans by apirogen water, physiological saline soaks 1h, refills in the post of Ф 20 × 50mm, fully rinses pillar with physiological saline. With new zealand rabbit (regular grade, 3～3.5kg) for experimental subjects, after rabbit is anaesthetized, blood is pumped with the speed of 20ml/min from the femoral artery of rabbit, entering Endotoxin adsorption post through blood plasma pump, after absorption, pump enters in the femoral vein of rabbit again, blood perfusion 2h. Before and after perfusion, extract the blood heparin sodium anti-freezing of rabbit respectively, the composition transfer in blood before and after detection perfusion, remaining centrifugal after get upper plasma and carry out endotoxin content test. In experimentation and after experiment in 24h, all physiology indications of experimental animal rabbit are normal. Adopt endotoxin concns before and after dynamic turbidimetric detection perfusion. Before perfusion, plasma endotoxin content is 0.705EU/m, and after perfusion, plasma endotoxin content is 0.130EU/ml. Normal new zealand rabbit plasma endotoxin content is 0.067～0.135EU/ml. Before perfusion, in blood, albumin content is 30.5g/L, and after perfusion, in blood, albumin content is 29.6g/L. Normal new zealand rabbit albumin content is 27～50g/L.
Embodiment 6
The adsorption experiment of blood purification endotoxin adsorption material in blood of human body and blood plasma
Under room temperature, getting 10g blood purification endotoxin adsorption material E1-2-3 loads in perfusion post, getting the flow velocity perfusion 2h of whole blood 300mL with 20mL/min of endotoxemia patient, endotoxin concns before and after employing dynamic turbidimetric detection absorption also adsorbs front and back blood ingredient change with Blood cell analyzer detection;Or at 37 DEG C, blood purification endotoxin adsorption material 1g directly being added the blood plasma of 30mL endotoxemia patient, Static Adsorption 2h, shaking speed is 180rpm, and wherein blood purification endotoxin adsorption material and blood plasma proportioning are 1:30, m/v. Before perfusion, plasma endotoxin content is 0.503EU/m, and after perfusion, plasma endotoxin content is 0.049EU/ml. Normal people's plasma endotoxin content is less than 0.053EU/ml. Before perfusion, in blood, albumin content is 45.6g/L, and after perfusion, in blood, albumin content is 43.4g/L. Normal people's albumin content is 40～55g/L.
Result shows, blood purification endotoxin adsorption material in the embodiment of the present invention, before and after perfusion, in blood, the change of each main ingredient is little, the percentage ratio of decline is all within 5%, thus show that the blood purification endotoxin adsorption material of the embodiment of the present invention has good blood compatibility, there is the prospect that can be applicable to blood purification.
Each technology feature of the above embodiment can combine arbitrarily, for making description succinct, each all possible combination of technology feature in above-described embodiment is not all described, but, as long as the combination of these technology features does not exist contradiction, all it is considered to be the scope that this specification sheets is recorded.
The above embodiment only have expressed several enforcement modes of the present invention, and it describes comparatively concrete and detailed, but can not therefore be construed as limiting the scope of the patent. , it is also possible to make some distortion and improvement, it should be appreciated that for the person of ordinary skill of the art, without departing from the inventive concept of the premise these all belong to protection scope of the present invention. Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. a blood purification endotoxin adsorption material, it is characterised in that, react with containing the ligand cou of amino by comprising active carrier, the quality ratio range of the aglucon containing amino described in described active carrier and often kind is 10:1～100:1; Described active carrier is by comprising carrier and the rear gained of bisglycidyl ether coupling reagent reaction, and described carrier is the spherical natural polymer of particle diameter 0.05～1.5mm, and the volume proportion scope of described carrier and bisglycidyl ether coupling reagent is 1:0.5～1:10.
2. blood purification endotoxin adsorption material according to claim 1, it is characterised in that, the volume proportion scope of described carrier and bisglycidyl ether coupling reagent is 1:0.9～1:1.1.
3. blood purification endotoxin adsorption material according to claim 1 and 2, it is characterised in that, described carrier is the one in chitosan microball, sepharose, dextrane gel and cellulose microsphere.
4. blood purification endotoxin adsorption material according to claim 1 and 2, it is characterized in that, the described aglucon containing amino is one or both the combination in polylysine, glycine, arginine, Polymyxin B-sulfate USP, human serum albumin, bactericidal properties/power/permeability increasing protein.
5. blood purification endotoxin adsorption material according to claim 1 and 2, it is characterized in that, described bisglycidyl ether coupling reagent is the one in ethylene glycol bis glycidyl ether, 1,4-butyleneglycol bisglycidyl ether, 1,6-HD bisglycidyl ether.
6. the preparation method of blood purification endotoxin adsorption material described in the arbitrary item of Claims 1 to 5, it is characterised in that, comprise the following steps:
(1) support-activated
Get described carrier to mix with alkaline aqueous solution, add described bisglycidyl ether coupling reagent, react at 25～50 DEG C, reaction times is 5～16h, the concentration of described alkaline aqueous solution is 0.5～3.5mol/L, volume proportion between described carrier, alkaline aqueous solution and bisglycidyl ether coupling reagent is 1:0.04:0.5～1:2:10, obtains active carrier;
(2) step (1) gained active carrier filtered, wash to neutral;
(3) coupling aglucon
Get and step (2) gained active carrier adds the described aglucon aqueous solution containing amino, the described concentration containing the aglucon aqueous solution of amino is 2～60mg/mL, the quality ratio range of aglucon containing amino described in described active carrier and often kind is 10:1～100:1, control ph reacts 20～72h at 3.0～14.0,37～60 DEG C.
(4) end-block
Step (3) products therefrom is added 0.5～1.5M ethanolamine solutions and carries out end capping.
7. preparation method according to claim 6, it is characterised in that, the volume proportion between described carrier, alkaline aqueous solution and bisglycidyl ether coupling reagent is 1:0.04:0.9～1:0.04:1.1.
8. application on the blood perfusion device of preparation treatment endotoxemia of blood purification endotoxin adsorption material described in the arbitrary item of Claims 1 to 4.
9. one kind uses the method that the blood purification endotoxin adsorption material described in the arbitrary item of claim 1～4 carries out blood perfusion, it is characterized in that, comprise the following steps: under room temperature, getting described blood purification endotoxin adsorption material loads in perfusion post, with the blood plasma of endotoxemia patient or whole blood perfusion, adopt endotoxin concns before and after dynamic turbidimetric detection perfusion and change with blood ingredient before and after Blood cell analyzer detection perfusion; Or described blood purification endotoxin adsorption material is directly added in the blood plasma containing intracellular toxin, Static Adsorption under certain temperature, adopts endotoxin concns before and after dynamic turbidimetric detection absorption.
10. blood purification endotoxin adsorption material according to claim 9 carries out the method for blood perfusion, it is characterized in that, comprise the following steps: under room temperature, getting blood purification endotoxin adsorption material described in 5～100g loads in perfusion post, with the blood plasma of endotoxemia patient or whole blood 25～3000mL with the flow velocity perfusion 1～4h of 20～200mL/min, the proportioning of described blood purification endotoxin adsorption material and endotoxemia patient's blood plasma or whole blood is 1:5～1:30, m/v, adopt endotoxin concns before and after dynamic turbidimetric detection perfusion and change with blood ingredient before and after Blood cell analyzer detection perfusion, or blood purification endotoxin adsorption material described in 0.2～1.0g is directly added 4～30mL containing in the blood plasma of intracellular toxin, Static Adsorption 1～4h at 25～37 DEG C, shaking speed is 120～200rpm, and the proportioning of described blood purification endotoxin adsorption material and blood plasma is 1:5～1:30, m/v.
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| CN107789691A (en) * | 2016-09-07 | 2018-03-13 | 天津市阳权医疗器械有限公司 | It is exclusively used in treating the disposable blood perfusion device of endotoxemia |
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| CN109211988A (en) * | 2017-07-06 | 2019-01-15 | 国立大学法人信州大学 | Endotoxic detection method and detection device |
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| CN109211988A (en) * | 2017-07-06 | 2019-01-15 | 国立大学法人信州大学 | Endotoxic detection method and detection device |
| CN107486176A (en) * | 2017-09-11 | 2017-12-19 | 广州康盛生物科技有限公司 | A kind of sorbing material for blood purification and preparation method thereof |
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| CN110711276B (en) * | 2019-09-06 | 2022-05-17 | 武汉瑞法医疗器械有限公司 | Preservation solution for stabilizing adsorption performance of adsorbent |
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