CN114042441B - Method for modifying and immobilizing heparin on surface of hemoperfusion resin microsphere and adsorbent prepared by method - Google Patents
Method for modifying and immobilizing heparin on surface of hemoperfusion resin microsphere and adsorbent prepared by method Download PDFInfo
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- CN114042441B CN114042441B CN202111500469.8A CN202111500469A CN114042441B CN 114042441 B CN114042441 B CN 114042441B CN 202111500469 A CN202111500469 A CN 202111500469A CN 114042441 B CN114042441 B CN 114042441B
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- heparin
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- shellac
- lac
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- 239000011347 resin Substances 0.000 title claims abstract description 99
- 229920005989 resin Polymers 0.000 title claims abstract description 99
- 239000004005 microsphere Substances 0.000 title claims abstract description 92
- 229920000669 heparin Polymers 0.000 title claims abstract description 69
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960002897 heparin Drugs 0.000 title claims abstract description 45
- 239000003463 adsorbent Substances 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 38
- 230000003100 immobilizing effect Effects 0.000 title claims abstract description 18
- 230000001951 hemoperfusion Effects 0.000 title description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 46
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 46
- 230000004048 modification Effects 0.000 claims abstract description 24
- 238000012986 modification Methods 0.000 claims abstract description 24
- 230000008081 blood perfusion Effects 0.000 claims abstract description 21
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- 238000001704 evaporation Methods 0.000 claims abstract description 7
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical group CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims description 24
- 229960001008 heparin sodium Drugs 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000008213 purified water Substances 0.000 claims description 9
- 238000002791 soaking Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 239000012466 permeate Substances 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229940095529 heparin calcium Drugs 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 230000000004 hemodynamic effect Effects 0.000 claims description 2
- 230000035515 penetration Effects 0.000 claims 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 abstract description 48
- 229920001800 Shellac Polymers 0.000 abstract description 42
- 229940113147 shellac Drugs 0.000 abstract description 42
- 235000013874 shellac Nutrition 0.000 abstract description 42
- 239000004208 shellac Substances 0.000 abstract description 42
- 210000004369 blood Anatomy 0.000 abstract description 22
- 239000008280 blood Substances 0.000 abstract description 22
- 230000015271 coagulation Effects 0.000 abstract description 18
- 238000005345 coagulation Methods 0.000 abstract description 18
- 230000010100 anticoagulation Effects 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 38
- 230000000052 comparative effect Effects 0.000 description 21
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 11
- 238000001179 sorption measurement Methods 0.000 description 10
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 7
- 229940109239 creatinine Drugs 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 206010053567 Coagulopathies Diseases 0.000 description 6
- 230000035602 clotting Effects 0.000 description 6
- 239000003517 fume Substances 0.000 description 6
- 229960001412 pentobarbital Drugs 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000011056 performance test Methods 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000005445 natural material Substances 0.000 description 2
- 229960002275 pentobarbital sodium Drugs 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000008383 multiple organ dysfunction Effects 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28016—Particle form
- B01J20/28021—Hollow particles, e.g. hollow spheres, microspheres or cenospheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
- B01J20/3206—Organic carriers, supports or substrates
- B01J20/3208—Polymeric carriers, supports or substrates
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Abstract
The scheme belongs to the technical field of blood purification, and discloses a method for modifying and immobilizing heparin on the surface of a blood perfusion resin microsphere and an adsorbent prepared by the method. The method comprises the following steps: the resin microsphere is soaked in ammonia water solution containing lac and heparin salt, heated and evaporated to make the lac adhere to the outer surface of the resin microsphere and the surface of the holes of the resin microsphere, so as to realize hydrophilic modification and immobilization of heparin. The shellac used in the scheme is dissolved in ammonia water solution, and the shellac is adhered to the surfaces of holes of the resin microspheres to realize modification in the process of heating and evaporating the ammonia water, and the hydrophilic ends of shellac molecules are exposed on the surfaces of the holes to improve the blood compatibility of the shellac molecules; simultaneously, the immobilized heparin has excellent anticoagulation performance, and can reduce the coagulation phenomenon when blood contacts with the resin microsphere. The preparation method is simple and effective, is suitable for various resin type blood perfusion products clinically used at present, and improves the safety of clinical application.
Description
Technical Field
The scheme belongs to the technical field of blood purification, and particularly relates to a method for modifying and immobilizing heparin on the surface of a blood perfusion resin microsphere and an adsorbent prepared by the method.
Background
Blood perfusion is a blood purification technique in which the blood of a patient is introduced into a perfusion apparatus containing an adsorbent, and exogenous or endogenous toxins, drugs or metabolic wastes which cannot be removed by dialysis in the blood are removed by adsorption. Blood perfusion technology has been rapidly developed in recent decades as one of the basic therapeutic modes of blood purification, with an increasing range of applications. The resin microsphere is the most common blood perfusion adsorbent in the current market, is mainly used for rescuing drug and poison poisoning, and can also be used for removing medium-macromolecule toxins in chronic renal failure maintenance dialysis patients by being used with hemodialysis.
The blood perfusion resin microsphere is generally prepared by polymerizing styrene and divinylbenzene, and has rich pore structure, thus having adsorption effect on various toxin molecules. Because the benzene ring in the resin microsphere has strong hydrophobicity, blood cells (such as blood platelets) in blood can be adhered and aggregated on the surface of the resin microsphere in the clinical use process, so that coagulation is caused. Therefore, hydrophilic modification of the pore surfaces of the resin microspheres is generally required to improve the blood compatibility of the adsorbent. Currently, the blood perfusion resin microspheres used on the market are subjected to hole surface modification by using collodion (nitrocellulose). Dissolving collodion in ethanol, mixing with resin microsphere, stirring, filtering, and air drying to obtain modified resin microsphere adsorbent. Although collodion improves the blood compatibility of the adsorbent to some extent, the adsorbent has very limited improvement in its anticoagulant ability and is still prone to clotting when contacted with blood. Therefore, when performing blood perfusion, a certain amount of heparin is generally required to be intravenously injected into a patient to perform systemic anticoagulation so as to ensure smooth performance of the blood perfusion treatment. If the heparin amount is too large, it may cause bleeding in the body that is difficult to control, and even cause multiple organ dysfunction. Because collodion is insoluble in water, heparin can not be immobilized on the resin microspheres while the surface of the resin holes is modified, and the coagulation phenomenon often occurs in clinical whole blood perfusion. Therefore, a method for hydrophilic modification and immobilization of heparin on the surface of the hole of the resin microsphere is sought, and the resin microsphere with anticoagulation capacity on the surface is developed, so that the method has important significance in reducing the heparin dosage and improving the treatment safety in the blood perfusion treatment process.
Disclosure of Invention
In view of the above, the present invention aims to overcome at least one of the disadvantages in the prior art, and provides a new simple and effective method for modifying and immobilizing heparin on the surface of blood perfusion resin microspheres, which solves the technical problems of insufficient improvement of blood compatibility and short clotting time of the existing surface modification technology.
In order to solve the technical problems, the following technical scheme is adopted:
In a first aspect, the present solution provides a method for modifying and immobilizing heparin on the surface of a hemoperfusion resin microsphere: the resin microsphere is soaked in ammonia water solution containing lac and heparin salt, heated and evaporated to self-assemble the lac on the outer surface of the resin microsphere and the surface of the holes of the resin microsphere, so as to realize hydrophilic modification and immobilization of heparin.
The method comprises the steps of dissolving shellac in an ammonia water solution, adding a proper amount of heparin salt, mixing and dissolving, adding resin microspheres, stirring at normal temperature to enable shellac and heparin salt to permeate into holes of the resin microspheres, heating and evaporating ammonia water to enable shellac to be self-assembled and attached to the outer surfaces of the resin microspheres and the surfaces of the holes of the resin microspheres, and simultaneously immobilizing heparin molecules on the surfaces of the resin microspheres. In the scheme, the shellac is self-assembled and adhered on the surface of the resin microsphere (comprising the outer surface and the hole surface thereof), the shellac is adhered on the surface of the resin microsphere through hydrophobic interaction, and the hydrophilic group of the shellac is exposed outside, so that the blood compatibility of the obtained adsorbent can be improved; the immobilized heparin salt has excellent anticoagulation performance, and can reduce the phenomenon of coagulation when blood contacts with resin microspheres, thereby improving the anticoagulation performance. The scheme is simple and effective, is suitable for various resin blood perfusion products clinically used at present, and improves the safety of clinical application.
In a second aspect, the present disclosure provides a hemodynamic adsorbent prepared by the method of the first aspect.
Compared with the prior art, the scheme has the following beneficial effects:
The lac used in the scheme is dissolved in ammonia water solution, and is adhered to the outer surface of the resin microsphere and the surface of the hole of the resin microsphere in the process of heating and evaporating the ammonia water, the hydrophilic end can be exposed on the surface of the resin microsphere to improve the blood compatibility of the resin microsphere, and meanwhile, the immobilized heparin has excellent anticoagulation performance, so that the coagulation phenomenon of blood in contact with the resin microsphere can be reduced. The preparation method is simple and effective, is suitable for various resin type blood perfusion products clinically used at present, and improves the safety of clinical application.
The implementation of the scheme is characterized by improving the clinical treatment effect and safety on blood perfusion. Adsorption data and anticoagulation experiments show that after the resin microspheres are treated by the preparation method of the scheme, the adsorption quantity of creatinine, pentobarbital sodium and VB12 is slightly reduced, and the coagulation time is prolonged from 20 minutes to 40-120 minutes, so that the requirements of clinical perfusion on avoiding coagulation are met.
Drawings
FIG. 1 is a chemical structural formula of shellac.
FIG. 2 is a graph of the variable relationship between toxin clearance and shellac concentration.
FIG. 3 is a graph of the variable relationship between clotting time and added heparin concentration.
Detailed Description
The proposal provides a method for modifying and immobilizing heparin on the surface of the hemoperfusion resin microsphere, which is simple and effective, is suitable for producing various resin hemoperfusion products used clinically at present, and improves the safety of clinical application.
The method for modifying and immobilizing heparin on the surface of the hemoperfusion resin microsphere comprises the following steps: the resin microsphere is soaked in ammonia water solution containing lac and heparin salt, heated and evaporated to self-assemble the lac on the outer surface of the resin microsphere and the surface of the holes of the resin microsphere, so as to realize hydrophilic modification and immobilization of heparin.
Shellac (shellac) is a natural substance obtained from secretion of shellfishes, and is mainly composed of lactone and lactide formed by esterification polymerization of lac acid and shellac acid, the average molecular weight of which is known to be about 1000 at present and can be represented by C 60H90O5, the chemical structure of which is shown in figure 1, and the surface of which contains abundant hydroxyl and carboxyl. Shellac is completely non-toxic and is initially used as a food additive, and the purified bleached shellac is called white shellac. White shellac can be dissolved in ethanol and alkaline water solution, and has coating formability after drying, so that the shellac can be used as an edible coating material with high safety from natural substances, is commonly used for coating tablets such as candies, medicines and the like, but the hydrophilic modification of resin microspheres is not reported.
The method comprises the steps of dissolving shellac in an ammonia water solution, adding a proper amount of heparin salt, mixing and dissolving, adding resin microspheres, stirring at normal temperature to enable shellac and heparin salt to permeate into holes of the resin microspheres, heating and evaporating ammonia water to enable shellac to self-assemble and adhere to the surfaces of the holes of the resin microspheres, and simultaneously immobilizing heparin molecules on the surfaces of adsorbents. In the scheme, the shellac realizes hydrophilic modification on the surfaces of the holes of the resin microspheres, and hydrophilic groups of the shellac are exposed, so that the blood compatibility of the adsorbent can be improved; the immobilized heparin salt has excellent anticoagulation performance, and can reduce the phenomenon of coagulation when blood contacts with resin microspheres, thereby improving the anticoagulation performance.
Because the lac can be dissolved in alkaline aqueous solution, the hydrophobic alkyl of the lac can be attached to the hole surface of the resin microsphere by controlling the conditions, and the hydrophilic carboxyl part is exposed at the same time, so that the biocompatibility of the resin microsphere is enhanced. Meanwhile, the heparin salt can be dissolved in alkaline aqueous solution, and the shellac can carry out surface modification on the resin microsphere and simultaneously can carry the heparin salt on the outer surface of the resin microsphere and the surfaces of holes of the resin microsphere, so that the anticoagulation performance of the resin microsphere is improved. In the scheme, the surface modification of the holes of the resin microspheres and the immobilized heparin are carried out simultaneously, a novel and simple preparation method is provided, and the problem that the blood perfusion resin microspheres produce blood coagulation in the clinical use process is solved.
Specifically, the method for modifying and immobilizing heparin on the surface of the hemoperfusion resin microsphere comprises the following steps:
S1, infiltration: soaking the resin microsphere in ammonia water solution containing lac and heparin salt, and stirring at room temperature for 0.5-2 hours to enable the lac and the heparin salt to permeate into holes of the resin microsphere;
S2, surface modification: heating and evaporating ammonia water to self-assemble lac on the outer surface of the resin microsphere and the surface of the hole of the resin microsphere, so as to realize hydrophilic modification and immobilization of heparin;
S3, washing: washed with purified water.
Preferably, in the permeation step, the concentration of the aqueous ammonia solution is 0.05 to 0.5mol/L. The concentration of the lac in the ammonia water solution is 0.05-1% (g/mL); the concentration of heparin salt in the ammonia water solution is 0.1-1 g/L, and the heparin salt is selected from heparin sodium, heparin calcium or heparin lithium, and more preferably heparin sodium.
Preferably, in the surface modification step, the heating temperature is 50 to 80 ℃.
Further, the method for modifying and immobilizing heparin on the surface of the hemoperfusion resin microsphere comprises the following steps:
S1, infiltration: soaking the resin microsphere in an ammonia water solution containing 0.05-1% (g/mL) of shellac and 0.1-1 g/L of heparin sodium, wherein the concentration of the ammonia water is 0.05-0.5 mol/L, and stirring at room temperature for 0.5-2 hours to enable the shellac and the heparin sodium to permeate into holes of the resin microsphere;
s2, surface modification: heating and evaporating ammonia water at 50-80 ℃ to enable shellac to self-assemble on the outer surface of the resin microsphere and the surface of the hole of the resin microsphere, so as to realize hydrophilic modification and immobilization of heparin;
S3, washing: washed with purified water.
Therefore, the scheme also provides the hemoperfusion adsorbent prepared by the method.
In order for those skilled in the art to better understand the present solution, the present solution is further described below with reference to specific embodiments. The process methods used in the examples are conventional methods unless otherwise specified; the materials used, unless otherwise specified, are all commercially available.
Wherein, macroporous adsorption resin is purchased from Tianjin let-off resin science and technology Co., ltd, and the model is: YKDH-19; shellac was purchased from kyoto biotechnology limited.
Example 1
1.5G of shellac was added to 150mL of an aqueous ammonia solution having a concentration of 0.5mol/L, and dissolved by stirring. 150mg of heparin sodium was further added to prepare 150mL of an aqueous ammonia solution containing 1.0% (g/mL) of lac and 1g/L of heparin sodium. 100mL of hemoperfusion resin microspheres are added into the solution for soaking, and the solution is slowly stirred for 2 hours, so that lac and heparin sodium are facilitated to diffuse into holes of the adsorbent. And then heating to 80 ℃ in a fume hood until the ammonia water solution is completely evaporated, thus obtaining the adsorbent with modified shellac surface and immobilized heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the adsorbent finished product.
Example 2
0.75G of shellac was added to 150mL of an aqueous ammonia solution having a concentration of 0.2mol/L, and dissolved by stirring. Then, 75mg of heparin sodium was further added to prepare 150mL of an aqueous ammonia solution containing 0.5% (g/mL) of lac and 0.5g/L of heparin sodium. 100mL of hemoperfusion resin microspheres are added into the solution for soaking, and the solution is slowly stirred for 1h, so that lac and heparin sodium are facilitated to diffuse into holes of the adsorbent. And then heating to 80 ℃ in a fume hood until the ammonia water solution is completely evaporated, thus obtaining the adsorbent with modified shellac surface and immobilized heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the adsorbent finished product.
Example 3
0.30G of shellac was added to 150mL of an aqueous ammonia solution having a concentration of 0.2mol/L, and dissolved by stirring. Then, 75mg of heparin sodium was further added to prepare 150mL of an aqueous ammonia solution containing 0.2% (g/mL) of shellac and 0.5g/L of heparin sodium. 100mL of hemoperfusion resin microspheres are added into the solution for soaking, and the solution is slowly stirred for 1h, so that lac and heparin sodium are facilitated to diffuse into holes of the adsorbent. And then heating to 70 ℃ in a fume hood until the ammonia water solution is completely evaporated, thus obtaining the adsorbent with modified shellac surface and immobilized heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the adsorbent finished product.
Example 4
0.15G of shellac was added to 150mL of an aqueous ammonia solution having a concentration of 0.2mol/L, and dissolved by stirring. 30mg of heparin sodium was further added to prepare 150mL of an aqueous ammonia solution containing 0.1% (g/mL) shellac and 0.2g/L heparin sodium. 100mL of hemoperfusion resin microspheres are added into the solution for soaking, and the solution is slowly stirred for 1h, so that lac and heparin sodium are facilitated to diffuse into holes of the adsorbent. And then heating to 70 ℃ in a fume hood until the ammonia water solution is completely evaporated, thus obtaining the adsorbent with modified shellac surface and immobilized heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the adsorbent finished product.
Example 5
0.15G of shellac was added to 150mL of an aqueous ammonia solution having a concentration of 0.1mol/L, and dissolved by stirring. 15mg of heparin sodium was further added to prepare 150mL of an aqueous ammonia solution containing 0.1% (g/mL) of shellac and 0.1g/L of heparin sodium. 100mL of hemoperfusion resin microspheres are added into the solution for soaking, and the solution is slowly stirred for 0.5h, so that lac and heparin sodium are facilitated to diffuse into holes of the adsorbent. And then heating to 80 ℃ in a fume hood until the ammonia water solution is completely evaporated, thus obtaining the adsorbent with modified shellac surface and immobilized heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the adsorbent finished product.
Example 6
0.075G shellac is added to 150mL of an aqueous ammonia solution having a concentration of 0.05mol/L, and dissolved by stirring. 15mg of heparin sodium was further added to prepare 150mL of an aqueous ammonia solution containing 0.05% (g/mL) shellac and 0.1g/L heparin sodium. 100mL of hemoperfusion resin microspheres are added into the solution for soaking, and the solution is slowly stirred for 0.5h, so that lac and heparin sodium are facilitated to diffuse into holes of the adsorbent. And then heating to 50 ℃ in a fume hood until the ammonia water solution is completely evaporated, thus obtaining the adsorbent with modified shellac surface and immobilized heparin. And finally, filtering and collecting the adsorbent, washing with purified water, and drying to obtain the adsorbent finished product.
Comparative example 1
Resin microspheres without any treatment.
Comparative example 2
Resin microspheres (Zhuhai Jianfan products) surface-modified with collodion are commercially available.
Comparative example 3
Resin microspheres (Langfang Aier products) surface-modified with collodion are commercially available.
Comparative example 4
Example 1 was repeated except that the aqueous ammonia solution was replaced with an aqueous Na 2CO3 solution.
Example 5
Example 1 was repeated except that the aqueous ammonia solution was replaced with an aqueous NaOH solution.
The following tests were carried out on the above examples and comparative examples:
1. adsorption performance test: according to the adsorption performance test method of the standard YY0464-2009 'disposable blood perfusion device', the adsorption performance of the resin microsphere sample on sodium pentobarbital, creatinine and VB12 is tested;
2. Total clotting assay: 1mL of the sample to be tested is added to a glass test tube, rinsed 3 times with physiological saline, and then 2mL of fresh rabbit blood is added along the tube wall. After 5min the tube was tilted every 1min until the blood in the tube did not flow, at which time the clotting time was noted.
The results of the final performance tests for each example and comparative example are shown in the following table:
| Sample of | Sodium pentobarbital (%) | Creatinine (%) | VB12(％) | Coagulation time (min) |
| Example 1 | 62.1 | 62.5 | 53.2 | 86 |
| Example 2 | 65.2 | 65.4 | 58.2 | 82 |
| Example 3 | 72.8 | 73.2 | 63.2 | 76 |
| Example 4 | 78.9 | 78.4 | 68.6 | 65 |
| Example 5 | 82.1 | 81.4 | 72.2 | 55 |
| Example 6 | 83.4 | 82.2 | 75.1 | 51 |
| Comparative example 1 | 93.8 | 91.2 | 81.4 | 26 |
| Comparative example 2 | 80.1 | 79.6 | 70.2 | 52 |
| Comparative example 3 | 78.2 | 80.1 | 67.5 | 46 |
| Comparative example 4 | 87.1 | 85.5 | 78.6 | 31 |
| Comparative example 5 | 86.8 | 85.8 | 78.5 | 32 |
The above table data shows that: ① After the shellac surface modification, the coagulation time is obviously prolonged (each example and comparative examples 2 and 3 are compared with comparative example 1), which shows that the shellac surface modification has very important influence on improving the blood compatibility of the resin microsphere. ② Compared with collodion treatment (each example is compared with comparative examples 2 and 3), the treatment of the scheme can obviously prolong the coagulation time, and the coagulation time is sequentially prolonged along with the increase of the content of the immobilized heparin. ③ Compared with collodion treatment (each example is compared with comparative examples 2 and 3), the method for modifying the surface of the lac and immobilizing the heparin in the scheme sequentially reduces the clearance rate of sodium pentobarbital, creatinine and VB12 with the increase of the lac content, but does not reduce much. ④ Compared with collodion treatment (examples 5 and 6 are compared with comparative examples 2 and 3), the method for modifying the surface of lac and immobilizing heparin in the scheme has the advantages that when the lac content is low, the clearance rate and the clotting time of sodium pentobarbital, creatinine and VB12 are improved compared with those of the comparative examples. ⑤ Compared with the collodion treatment (example 4 is compared with comparative examples 2 and 3), the method for modifying the surface of the lac and immobilizing the heparin in the scheme has the advantages that when the lac content is 0.1% (g/mL), the clearance rate of the sodium pentobarbital, creatinine and VB12 in the example is equivalent to that in the comparative example, but the coagulation time is greatly improved. ⑥ In this scheme, the coagulation time is obviously reduced by using other alkali compared with ammonia water (compared with each example in comparative examples 4 and 5), and the coagulation time is not obviously improved compared with the original resin microsphere (comparative example 1), which means that lac is not modified on the surface of the hole, and heparin is not immobilized on the resin microsphere.
In conclusion, the method for modifying and immobilizing heparin on the surface of the resin microsphere hole of the scheme can obviously prolong the coagulation time and improve the anticoagulation performance of the adsorbent, thereby increasing the safety of clinical blood perfusion. Adsorption data and anticoagulation experiments show that after the resin microspheres are treated by the preparation method of the scheme, the adsorption quantity of creatinine, pentobarbital sodium and VB12 is slightly reduced, and the coagulation time is prolonged from 20 minutes to 40-120 minutes, so that the requirements of clinical perfusion on avoiding coagulation are met.
Furthermore, in addition to the raw materials used in the above examples, the heparin salt may be selected from heparin calcium or heparin lithium.
It is apparent that the above examples of the present solution are merely examples for clearly illustrating the present solution and are not limiting of the embodiments of the present solution. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present solution should be included in the protection scope of the present solution claims.
Claims (4)
1. A method for modifying and immobilizing heparin on the surface of a blood perfusion resin microsphere is characterized in that the resin microsphere is soaked in an ammonia water solution containing lac and heparin salt, heated and evaporated, so that the lac is self-assembled on the outer surface of the resin microsphere and the surface of a hole of the resin microsphere, and hydrophilic modification and heparin immobilization are realized; the method specifically comprises the following steps:
Penetration: soaking the resin microsphere in ammonia water solution containing lac and heparin salt, and stirring at room temperature for 0.5-2 hours to enable the lac and the heparin salt to permeate into holes of the resin microsphere; the concentration of the ammonia water solution is 0.2-0.5 mol/L, the concentration of the lac in the ammonia water solution is 0.1-1% (g/mL), and the concentration of the heparin salt in the ammonia water solution is 0.2-1 g/L;
Surface modification: heating and evaporating ammonia water to self-assemble lac on the outer surface of the resin microsphere and the surface of the hole of the resin microsphere, so as to realize hydrophilic modification and immobilization of heparin; the heating temperature is 50-80 ℃; washing: washed with purified water.
2. The method of claim 1, wherein in the infiltrating step, the heparin salt is heparin sodium, heparin calcium or heparin lithium.
3. The method of modifying and immobilizing heparin on the surface of a blood perfusion resin microsphere according to claim 2, wherein in the osmosis step, the heparin salt is heparin sodium.
4. A hemodynamic adsorbent produced by the method of any one of claims 1-3.
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