CN111468079A - Preparation method of anticoagulant hemoperfusion adsorption material - Google Patents

Preparation method of anticoagulant hemoperfusion adsorption material Download PDF

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CN111468079A
CN111468079A CN201910062470.3A CN201910062470A CN111468079A CN 111468079 A CN111468079 A CN 111468079A CN 201910062470 A CN201910062470 A CN 201910062470A CN 111468079 A CN111468079 A CN 111468079A
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adsorbing material
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microspheres
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孙圳
严静
罗章凯
张文
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CHONGQING XIERKANG BLOOD PURIFICATION EQUIPMENT RESEARCH DEVELOPMENT CO LTD
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Abstract

The invention relates to a preparation method of a high anticoagulation hemoperfusion adsorption material, which is characterized in that the adsorption material is prepared by coating a carrier with a coating liquid prepared from a membrane material polyether sulfone resin and a polyvinylpyrrolidone-polymethacrylate-polyacrylic acid triblock copolymer by a fluidized bed spraying method and grafting heparin on the membrane, wherein the thickness of the membrane is 10-100 nm. The adsorbing material prepared by the invention has good biocompatibility and anticoagulation performance, small influence on red blood cells, low hemolysis rate and no cytotoxicity. The method is simple to operate, changes the conventional coating mode, and can effectively slow down the coagulation phenomenon of the adsorbent during perfusion. The drying time after the conventional static coating is shortened, the surface hydrophilicity of the prepared adsorbing material microsphere is obviously improved, and the anticoagulation performance is obviously improved. The preparation method has the advantages of simple process, environmental protection, safety and low cost, and can be used for large-scale industrial production.

Description

Preparation method of anticoagulant hemoperfusion adsorption material
Technical Field
The invention belongs to the field of blood perfusion, and particularly relates to a preparation method of a blood perfusion adsorbing material with high anticoagulation property.
Background
In recent years, with the improvement of the blood purification technology level, blood perfusion becomes a new choice for millions of patients with autoimmune diseases and patients with severe sepsis, etc. besides hemodialysis. The blood perfusion absorbs some endogenous or exogenous toxins and metabolites in the blood through the adsorbent, so as to achieve the purpose of purifying the blood.
The types of solid adsorbents in blood perfusion are various, including anion resin, styrene resin, acrylic resin, carbonized resin and the like, and the adsorbents are key factors for determining perfusion curative effect. The carbonized resin is used as a common adsorbing material for blood perfusion, has high purity, good mechanical strength and large specific surface area, is widely applied to the field of biological medicine, and has obvious curative effect on removing molecular substances. However, the problem of carbon powder falling of carbonized resin has been concerned with the aspects of blood compatibility and anticoagulation performance, and people in the 70 th era chang and the like begin to carry out activated carbon coating treatment, apply the activated carbon coating treatment to a patient with chronic renal failure through blood perfusion and succeed in the treatment of the chronic renal failure, and solve the problems of blood embolism, white blood cells and platelet reduction caused by poor blood compatibility and the falling of tiny carbon particles in blood perfusion, so that the blood perfusion technology is developed in a breakthrough manner. The selection of coating materials and coating methods are also the direction of great research by scientists. The adsorption performance, biocompatibility and anticoagulation performance of the coated resin carbon become important indexes for evaluating the good performance of the adsorbent.
The invention intends to prepare triblock copolymer with good biocompatibility and blend with polyether sulfone to be used as coating liquid, a fluidized bed spray coating method is adopted for coating, carboxyl on the surface of the film provides a binding site for further heparinization, and then heparin is introduced to the surface of the coated resin carbon by adopting a surface grafting method, so that the resin carbon adsorbent with biocompatibility and anticoagulation performance is obtained, the surface of the adsorbent contains heparin molecules, the good biocompatibility and anticoagulation performance of the heparin are obtained, the life quality of a hemoperfusion patient is improved, complications are reduced, and the death rate is reduced.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for obtaining resin carbon microspheres with good biocompatibility and anticoagulation performance by introducing active sites reacting with heparin through a fluidized bed spray coating method and grafting the heparin onto the surfaces of the resin carbon microspheres.
The preparation process of the invention is as follows:
1. preparation of coating solution
Dissolving monomers of Vinyl Pyrrolidone (VP), Methyl Methacrylate (MMA) and Acrylic Acid (AA) in dimethyl acetamide (DMAC) according to different mass ratios, uniformly mixing, adding an initiator of dibenzoyl peroxide (BPO) (accounting for 0.01 wt% of the total mass of the monomers) and a chain transfer agent of 2-mercaptoethanol (accounting for 0.15 wt% of the mass of the monomers), magnetically stirring for 15-60 min, introducing nitrogen to remove oxygen, reacting at 60-80 ℃ for 6-12 h, precipitating the obtained reaction liquid in deionized water, and washing with the deionized water for multiple times to obtain the polymer P (VP-MMA-AA). Dissolving the copolymer and polyether sulfone (PES) in DMAC to obtain an envelope liquid with polyether sulfone resin (PES) mass fraction of 1-5% and copolymer mass fraction of 1-5%, and standing and defoaming.
2. Fluidized bed coating film
Placing the prepared resin carbon microspheres in a fluidized bed storage bin, introducing compressed air, boiling the resin carbon, then injecting a coating liquid, wherein the coating liquid is in a mist shape, gradually forming a film in the repeated contact process of the resin carbon and the coating liquid, coating for 5-10 min, after the coating is finished, introducing heated air at 30-60 ℃ into a storage bin, continuously boiling the resin carbon for 0.5-1.0 h, finishing the ventilation, and taking out the resin carbon to obtain the resin carbon microspheres with the functional group carboxyl on the surfaces.
3. Heparin grafting
Preparing a heparin aqueous solution according to the weight of 0.01-1% of the resin carbon by mass, adding a carbodiimide (EDC) carboxyl activating agent, then adding the coated resin carbon microspheres into the aqueous solution, reacting for 5-10 hours at-20 ℃ to room temperature, washing the obtained heparinized resin carbon microspheres with deionized water, removing residual heparin and EDC on the surface, and finally obtaining the heparinized resin carbon microspheres.
The invention prepares triblock copolymer coating material by a reversible addition-fragmentation chain transfer free radical polymerization (RAFT) method, blends the triblock copolymer coating material with polyether sulfone material to obtain coating liquid, then carries out spray coating on the prepared resin carbon in a fluidized bed, introduces bindable sites, and grafts heparin onto the surface of the coated resin carbon microsphere to obtain the resin carbon microsphere with good biocompatibility and anticoagulation performance.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1:
a preparation method of an anti-coagulation blood perfusion adsorbing material comprises the following steps.
(1) Selecting monomers of styrene and divinylbenzene according to the weight ratio of 1: 2, obtaining resin microspheres by adopting a suspension polymerization method, and carbonizing the resin microspheres to obtain the resin carbon microspheres.
(2) Three monomers, namely Vinyl Pyrrolidone (VP), Methyl Methacrylate (MMA) and Acrylic Acid (AA), are mixed according to a mass ratio of 4: 4: dissolving 1 in DMAC, stirring uniformly, adding 0.01 wt% of BPO and 0.15 wt% of 2-mercaptoethanol, stirring for 15min by magnetic force, introducing nitrogen, reacting for 6h at 80 ℃, precipitating the obtained reaction solution in deionized water, washing with the deionized water for multiple times to obtain a triblock copolymer P (VP-MMA-AA), and adding PES: p (VP-MMA-AA): DMAC = 5: 1: PES and the copolymer were dissolved in DMAC at a mass ratio of 100 (m/m) to prepare a coating solution, which was then allowed to stand for defoaming.
(3) And (2) placing the resin carbon microspheres obtained in the step (1) in a fluidized bed bin, introducing compressed air, boiling the resin carbon, then injecting a coating liquid, wherein the coating liquid is in a mist shape, gradually forming a film in the repeated contact process of the resin carbon and the coating liquid, coating for 5min, finishing coating, heating the air to 40 ℃, continuously boiling the resin carbon until the temperature of an air outlet is consistent with the temperature of the bin, finishing ventilation, and taking out the resin carbon to obtain the resin carbon microspheres with the functional groups on the surfaces.
The resin charcoal obtained in this example, without heparin introduced on the surface thereof, was subjected to detection, and its specific surfaceProduct: 1508m2The adsorption rate of the resin charcoal after canning is 5.6 percent for albumin, 5.8 percent for total protein and VB12The adsorption rate of the compound is 90%, the adsorption rate of the compound to sodium pentobarbital is 99%, the adsorption rate of the compound to creatinine is 95%, the adsorption rate of the compound to lysozyme is 78%, and the hemolysis rate is 4.5%.
Example 2:
a preparation method of an anti-coagulation blood perfusion adsorbing material comprises the following steps.
(1) Selecting monomers of styrene and divinylbenzene according to the weight ratio of 1: 2, obtaining resin microspheres by adopting a suspension polymerization method, and carbonizing the resin microspheres to obtain the resin carbon microspheres.
(2) Three monomers, namely Vinyl Pyrrolidone (VP), Methyl Methacrylate (MMA) and Acrylic Acid (AA), are mixed according to a mass ratio of 4: 5: 2 is dissolved in DMAC, the mixture is stirred uniformly, 0.01 wt% of BPO and 0.15 wt% of 2-mercaptoethanol are added, the mixture is stirred magnetically for 30min, nitrogen is introduced, the mixture reacts at 60 ℃ for 12h, the obtained reaction solution is precipitated in deionized water, and the deionized water is washed for multiple times to obtain a triblock copolymer P (VP-MMA-AA), and the weight ratio of the VP-MMA-AA is calculated according to PES: p (VP-MMA-AA): DMAC = 4: 1: PES and the copolymer were dissolved in DMAC at a mass ratio of 100 (m/m) to prepare a coating solution, which was then allowed to stand for defoaming.
(3) And (2) placing the resin carbon microspheres obtained in the step (1) in a fluidized bed bin, introducing compressed air, boiling the resin carbon, then injecting a coating liquid, wherein the coating liquid is in a mist shape, gradually forming a film in the repeated contact process of the resin carbon and the coating liquid, coating for 8min, finishing coating, heating the air to 40 ℃, continuously boiling the resin carbon until the temperature of an air outlet is consistent with the temperature of the bin, finishing ventilation, and taking out the resin carbon to obtain the resin carbon microspheres with the functional groups on the surfaces.
(4) Preparing 1 wt% heparin aqueous solution, adding EDC, adding the surface modified resin carbon microspheres obtained in (3) into the solution, reacting for 24h at 0 ℃, cleaning the obtained heparinized resin carbon microspheres with deionized water, and removing residual heparin and EDC on the surfaces to finally obtain the heparinized resin carbon microspheres.
Heparin is introduced into the resin carbon obtained in the embodiment by a fluidized bed coating method, and the resin carbon is takenDetection was carried out, and the specific surface area thereof: 1704m2The adsorption rate of the resin charcoal after canning is 0.6 percent for albumin, 1.4 percent for total protein and VB12The adsorption rate of (A) was 90%, the adsorption rate to sodium pentobarbital was 99%, the adsorption rate to creatinine was 93%, the adsorption rate to lysozyme was 70%, and the hemolysis rate was 1.2%.
Example 3:
a preparation method of an anti-coagulation blood perfusion adsorbing material comprises the following steps.
(1) Selecting monomers of styrene and divinylbenzene according to the weight ratio of 1: 2, obtaining resin microspheres by adopting a suspension polymerization method, and carbonizing the resin microspheres to obtain the resin carbon microspheres.
(2) Three monomers, namely Vinyl Pyrrolidone (VP), Methyl Methacrylate (MMA) and Acrylic Acid (AA), are mixed according to a mass ratio of 4: 4: 0.5 is dissolved in DMAC, the mixture is stirred uniformly, 0.01 wt% of BPO and 0.15 wt% of 2-mercaptoethanol are added, the mixture is magnetically stirred for 45min, nitrogen is introduced, the mixture reacts for 10h at 70 ℃, the obtained reaction solution is precipitated in deionized water, the deionized water is washed for multiple times to obtain a triblock copolymer P (VP-MMA-AA), and the weight ratio of the VP: p (VP-MMA-AA): DMAC = 5: 2: PES and the copolymer were dissolved in DMAC at a mass ratio of 100 (m/m) to prepare a coating solution, which was then allowed to stand for defoaming.
(3) And (2) placing the resin carbon microspheres obtained in the step (1) in a fluidized bed bin, introducing compressed air, boiling the resin carbon, then injecting a coating liquid, wherein the coating liquid is in a mist shape, gradually forming a film in the repeated contact process of the resin carbon and the coating liquid, coating for 8min, finishing coating, heating the air to 30 ℃, continuously boiling the resin carbon until the temperature of an air outlet is consistent with the temperature of the bin, finishing ventilation, and taking out the resin carbon to obtain the resin carbon microspheres with the functional groups on the surfaces.
(4) Preparing 0.1 wt% heparin aqueous solution, adding EDC, adding the surface modified resin carbon microspheres obtained in (3) into the solution, reacting for 12h at room temperature, cleaning the obtained heparinized resin carbon microspheres with deionized water, and removing residual heparin and EDC on the surface to finally obtain the heparinized resin carbon microspheres.
This example yielded a coated charcoal, which was taken out of the treeThe specific surface area of the charcoal is as follows: 1568m2The adsorption rate of the resin charcoal after canning is 2.6 percent for albumin, 1.8 percent for total protein and VB12The adsorption rate of (A) was 93%, the adsorption rate for sodium pentobarbital was 99%, the adsorption rate for creatinine was 94%, the adsorption rate for lysozyme was 75%, and the hemolysis rate was 1.5%.
Example 4:
a preparation method of an anti-coagulation blood perfusion adsorbing material comprises the following steps.
(1) Selecting monomers of styrene and divinylbenzene according to the weight ratio of 1: 2, obtaining resin microspheres by adopting a suspension polymerization method, and carbonizing the resin microspheres to obtain the resin carbon microspheres.
(2) Three monomers, namely Vinyl Pyrrolidone (VP), Methyl Methacrylate (MMA) and Acrylic Acid (AA), are mixed according to a mass ratio of 4: 4: 2 is dissolved in DMAC, the mixture is stirred uniformly, 0.01 wt% of BPO and 0.15 wt% of 2-mercaptoethanol are added, the mixture is stirred for 60min by magnetic force, nitrogen is introduced, the mixture reacts for 8h at 70 ℃, the obtained reaction solution is precipitated in deionized water, and the deionized water is washed for multiple times to obtain a triblock copolymer P (VP-MMA-AA), and the weight ratio of the VP-MMA-AA is calculated according to PES: p (VP-MMA-AA): DMAc = 2: 1: PES and the copolymer were dissolved in DMAC at a mass ratio of 100 (m/m) to prepare a coating solution, which was then allowed to stand for defoaming.
(3) And (2) placing the resin carbon microspheres obtained in the step (1) in a fluidized bed bin, introducing compressed air, boiling the resin carbon, then injecting a coating liquid, wherein the coating liquid is in a mist shape, gradually forming a film in the repeated contact process of the resin carbon and the coating liquid, coating for 10min, finishing coating, heating the air to 35 ℃, continuously boiling the resin carbon until the temperature of an air outlet is consistent with the temperature of the bin, finishing ventilation, and taking out the resin carbon to obtain the resin carbon microspheres with the functional groups on the surfaces.
(4) Preparing 0.8 wt% heparin aqueous solution, adding EDC, adding the surface modified resin carbon microspheres obtained in (3) into the solution, reacting for 8h at 30 ℃, cleaning the obtained heparinized resin carbon microspheres with deionized water, and removing residual heparin and EDC on the surface to finally obtain the heparinized resin carbon microspheres.
The resin charcoal obtained in this example was not coated with a coating film, and the resin was taken outCarbon detection, specific surface area: 1638m2The adsorption rate of the resin charcoal after canning is 1.8 percent for albumin, 1.9 percent for total protein and VB12The adsorption rate of (A) was 93%, the adsorption rate for sodium pentobarbital was 99%, the adsorption rate for creatinine was 95%, the adsorption rate for lysozyme was 77%, and the hemolysis rate was 1.3%.
The contrast shows that the adsorption rate of the resin carbon microspheres subjected to heparinization on albumin and total protein is obviously reduced after canning, and the anticoagulation performance and the blood compatibility of the resin carbon microspheres are obviously improved.

Claims (5)

1. The preparation method of the adsorption material for high anticoagulation hemoperfusion is characterized in that: comprises the following steps:
the method comprises the following steps: preparation of polyvinylpyrrolidone-polymethyl methacrylate-polyacrylic acid triblock copolymer
Preparing a polyvinylpyrrolidone-polymethyl methacrylate-polyacrylic acid triblock copolymer P (VP-MMA-AA) by a reversible addition-fragmentation chain transfer radical polymerization (RAFT) method by using a vinylpyrrolidone monomer, methyl methacrylate and acrylic acid;
step two: preparation of coating solution
Blending the polyvinylpyrrolidone-polymethyl methacrylate-polyacrylic acid triblock copolymer P (VP-MMA-AA) prepared in the step one with polyether sulfone PES (polyether sulfone) to form a coating;
step three: coating film
Coating the adsorption carrier by using the coating liquid prepared in the step two through a fluidized bed spray coating method to prepare a coated adsorption material, wherein the thickness of the coated adsorption material is 10-100 nm;
step four: grafting reaction
And (4) introducing functional group carboxyl to the surface of the coated adsorbing material prepared in the third step, and then performing amidation reaction with heparin molecules to obtain the adsorbing material with good biocompatibility and anticoagulation performance.
2. The method for preparing a triblock copolymer according to claim 1, wherein: a terpolymer P (VP-MMA-AA) with anticoagulant activity is prepared by reversible addition-fragmentation chain transfer radical polymerization (RAFT), and the preparation method is as follows: dissolving monomer polyvinylpyrrolidone, polymethyl methacrylate and polyacrylic acid in dimethyl acetamide (DMAC) according to different mass ratios, uniformly mixing, adding initiator Azobisisobutyronitrile (AIBN) (accounting for 0.01-0.05 wt% of the total mass of the monomers) and chain transfer agent (accounting for 0.05-0.5 wt% of the mass of the monomers), magnetically stirring for 15-60 min, introducing nitrogen to remove oxygen, reacting at 60-80 ℃ for 6-12 h, precipitating the obtained polymer in deionized water, and washing with deionized water for multiple times to obtain polyvinylpyrrolidone-polymethyl methacrylate-polyacrylic acid triblock copolymer P (VP-MMA-AA).
3. The method for preparing the coating solution according to claim 1, wherein: dissolving a triblock copolymer and polyether sulfone resin (PES) in Dimethylacetamide (DMAC) to obtain an envelope solution with the mass fraction of 1-5% of PES and the mass fraction of 1-5% of copolymer, and standing and defoaming.
4. The encapsulation method according to claim 1, wherein: placing the adsorbing material microspheres in a fluidized bed, introducing compressed air, boiling the adsorbing material in the fluidized bed, then injecting a coating liquid, coating the resin carbon for 5-10 min to obtain the adsorbing material microspheres with the film thickness of 10-100 nm, wherein the surfaces of the adsorbing material microspheres contain carboxyl groups, and functional sites are provided for introducing heparin.
5. The preparation method for heparinizing the surface of the coated adsorbing material microsphere according to claim 1, which is characterized by comprising the following steps of: dissolving heparin in deionized water, preparing a heparin aqueous solution, adding a carbodiimide (EDC) carboxyl activating agent, then adding the coated adsorbing material microspheres into the aqueous solution, carrying out a grafting reaction, cleaning the obtained heparinized adsorbing material microspheres with the deionized water, removing surface unreacted substances, and drying to obtain the adsorbing material microspheres with good biocompatibility and anticoagulation activity.
CN201910062470.3A 2019-01-23 2019-01-23 Preparation method of anticoagulant hemoperfusion adsorption material Pending CN111468079A (en)

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CN108530670A (en) * 2018-02-07 2018-09-14 四川大学 Based on carragheen from anti-freezing heparan microballoon and the preparation method and application thereof

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CN105348541A (en) * 2015-12-21 2016-02-24 珠海健帆生物科技股份有限公司 Blood purification adsorbent and preparation method thereof
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CN108530670A (en) * 2018-02-07 2018-09-14 四川大学 Based on carragheen from anti-freezing heparan microballoon and the preparation method and application thereof

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Application publication date: 20200731