CN116492991B - Method for preparing filling material of blood perfusion device capable of removing TNF-alpha in blood - Google Patents
Method for preparing filling material of blood perfusion device capable of removing TNF-alpha in blood Download PDFInfo
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- CN116492991B CN116492991B CN202310428160.5A CN202310428160A CN116492991B CN 116492991 B CN116492991 B CN 116492991B CN 202310428160 A CN202310428160 A CN 202310428160A CN 116492991 B CN116492991 B CN 116492991B
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- 210000004369 blood Anatomy 0.000 title claims abstract description 21
- 239000008280 blood Substances 0.000 title claims abstract description 21
- 108060008682 Tumor Necrosis Factor Proteins 0.000 title claims abstract description 19
- 230000008081 blood perfusion Effects 0.000 title claims abstract description 19
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 title claims abstract description 17
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- 238000000034 method Methods 0.000 title claims description 8
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- 239000000945 filler Substances 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960000598 infliximab Drugs 0.000 claims abstract description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 18
- 239000003292 glue Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000012948 isocyanate Substances 0.000 claims abstract description 11
- 150000002513 isocyanates Chemical class 0.000 claims abstract description 11
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 9
- 229910000389 calcium phosphate Inorganic materials 0.000 claims abstract description 9
- 239000001506 calcium phosphate Substances 0.000 claims abstract description 9
- 235000011010 calcium phosphates Nutrition 0.000 claims abstract description 9
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 9
- 239000011780 sodium chloride Substances 0.000 claims abstract description 9
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 238000002791 soaking Methods 0.000 claims abstract description 6
- 230000001951 hemoperfusion Effects 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- 230000000004 hemodynamic effect Effects 0.000 claims abstract description 3
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- 230000001070 adhesive effect Effects 0.000 claims description 10
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 claims description 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
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- 102000004127 Cytokines Human genes 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3687—Chemical treatment
-
- 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
- B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
- B01J20/0203—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of metals not provided for in B01J20/04
- B01J20/0274—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of metals not provided for in B01J20/04 characterised by the type of anion
- B01J20/0288—Halides of compounds other than those provided for in B01J20/046
-
- 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
- B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
- B01J20/0203—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of metals not provided for in B01J20/04
- B01J20/0274—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of metals not provided for in B01J20/04 characterised by the type of anion
- B01J20/0292—Phosphates of compounds other than those provided for in B01J20/048
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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
- B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
- B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
- B01J20/046—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium containing halogens, e.g. halides
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
- B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
- B01J20/048—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium containing phosphorus, e.g. phosphates, apatites, hydroxyapatites
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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
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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
- B01J20/261—Synthetic macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds
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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
- B01J20/3085—Chemical treatments not covered by groups B01J20/3007 - B01J20/3078
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/28—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2201/00—Foams characterised by the foaming process
- C08J2201/04—Foams characterised by the foaming process characterised by the elimination of a liquid or solid component, e.g. precipitation, leaching out, evaporation
- C08J2201/054—Precipitating the polymer by adding a non-solvent or a different solvent
- C08J2201/0545—Precipitating the polymer by adding a non-solvent or a different solvent from an aqueous solvent-based polymer composition
- C08J2201/0546—Precipitating the polymer by adding a non-solvent or a different solvent from an aqueous solvent-based polymer composition the non-solvent being organic
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2300/00—Characterised by the use of unspecified polymers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Analytical Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Cardiology (AREA)
- Animal Behavior & Ethology (AREA)
- Anesthesiology (AREA)
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Abstract
The invention discloses a preparation method of a hemoperfusion apparatus filler capable of removing TNF-alpha in blood, which comprises the following steps: (1) Mixing sodium chloride, polyvinyl alcohol, calcium phosphate, UV glue, triallyl isocyanate and cumene hydroperoxide with water as a reaction solvent, and heating under ultraviolet irradiation to partially cure the UV glue to obtain particles; (2) Soaking the obtained particles in ethanol under the condition of avoiding light; (3) And mixing the particles with infliximab solution, and completely solidifying the UV gel by ultraviolet irradiation to obtain the blood perfusion device filler. Compared with the prior art, the filling material of the blood perfusion device has good biocompatibility, the matrix has no macroporous structure, the absorption function of macroporous resin is not needed, the hemodynamics are more stable, the thrombosis is reduced, the thrombus risk of a patient is reduced, the filling material of the blood perfusion device simply eliminates TNF-alpha in blood, the filling material has no influence on other substance components in blood, and the specificity is stronger.
Description
Technical Field
The invention belongs to a filler, and in particular relates to a preparation method of a blood perfusion device filler capable of removing TNF-alpha in blood.
Background
Blood perfusion is a blood purification technique in which the blood of a patient is introduced into a perfusion apparatus containing a solid adsorbent, and exogenous or endogenous toxins, drugs or metabolic wastes which cannot be removed by dialysis in the blood are removed by adsorption. Is mainly used for rescuing drug and poison poisoning, and can also be used for removing macromolecular toxin in chronic renal failure maintenance dialysis patients together with hemodialysis.
At present, solid adsorbents filled in the perfusion device are polystyrene resin or activated carbon, most of the solid adsorbents depend on direct supply of suppliers, autonomous research and development of users are less, types of substances which can be adsorbed by the adsorbents are limited, and molecular weight of the adsorbed substances cannot be accurately controlled, so that most of the blood perfusion devices are non-specifically adsorbed. In clinical use of the blood perfusion device, it often happens that some pathogenic substances are effectively adsorbed and other body fluid components with approximate molecular weights are adsorbed together. This can lead to loss of beneficial bodily fluid components of the human body, causing some potential health risks.
At present, some users modify and reprocess the solid adsorbent to different degrees, but the filler base material is limited to the product attribute of the resin supplier, and is difficult to flexibly select in practical clinical application. The existing adsorbent filler base materials provided by most adsorbent suppliers have large batch-to-batch difference, unstable biocompatibility, incomplete contact between the filler and harmful substances in blood, and low adsorption efficiency. And because the existing modification or modification method introduces various chemical reagents when the resin is modified by chemical bonds, partial reagents are toxic and harmful or have unstable chemical properties, and the problem of biocompatibility is not well solved.
Alpha tumor necrosis factor (TNF-alpha) is a pro-inflammatory cytokine produced primarily by macrophages and monocytes and is involved in normal inflammatory and immune responses. TNF- α production is increased in a number of pathological conditions, including sepsis, malignancy, heart failure, and chronic inflammatory disease. An increase in tumor necrosis factor is found in both the blood and joints of patients with severe rheumatoid arthritis. TNF-alpha has direct damaging effects on body tissues, but also has the effect of activating and amplifying other inflammatory factors. In the development of many diseases associated with excessive inflammatory responses, the removal of TNF- α is an effective measure for the treatment of the related diseases. Infliximab is commonly used in clinic for intravenous injection to antagonize TNF-alpha, so as to achieve the purpose of treating diseases. However, the side effects of the monoclonal antibody drug, such as allergy, infusion reaction, systemic vasculitis, autoimmune syndrome and the like, in the body are difficult to avoid, and some patients stop taking the drug because of being difficult to tolerate, and antibodies can be generated in the body after repeated infusions, so that the curative effect is reduced.
Disclosure of Invention
In order to avoid the defects of the conventional blood perfusion device filler, the invention provides a preparation method of the blood perfusion device filler capable of removing TNF-alpha in blood. The filler particles of the blood perfusion device are automatically constructed by a UV glue layering pore-forming curing method, infliximab is fixed in the curing process of the UV glue, infliximab fixed by the particles can form a compound with TNF-alpha in blood, so that the content of the TNF-alpha in the blood is reduced, and the defects of conventional resin particles can be avoided.
The technical scheme adopted by the invention for achieving the purpose is as follows:
the preparation method of the hemoperfusion apparatus filler capable of removing TNF-alpha in blood comprises the following steps:
(1) Mixing sodium chloride, polyvinyl alcohol, calcium phosphate, UV glue, triallyl isocyanate and cumene hydroperoxide with water as a reaction solvent, and heating under ultraviolet irradiation to partially cure the UV glue to obtain particles;
(2) Soaking the particles obtained in the step (1) in ethanol under the light-shielding condition;
(3) Mixing the particles treated in the step (2) with infliximab solution, and completely solidifying the UV gel by ultraviolet irradiation to obtain the hemoperfusion apparatus filler.
Calcium phosphate is used as a core, sodium chloride and polyvinyl alcohol together play roles of preventing excessive aggregation of particles and preventing excessive rapid solidification of UV glue, triallyl isocyanate plays a role of a cross-linking agent, and cumene hydroperoxide plays a role of an initiator.
The technical principle of the invention is as follows:
firstly, partially solidifying the UV adhesive, then, utilizing the characteristic that the UV adhesive is insoluble in ethanol and the triallyl isocyanate and the cumene hydroperoxide are soluble in ethanol, dissolving and removing the triallyl isocyanate and the cumene hydroperoxide from the partially solidified UV adhesive by using the ethanol, so that a pore structure capable of containing infliximab is formed on the surface of particles, and after infliximab is adsorbed, completely solidifying the UV adhesive layer, thereby firmly fixing infliximab in the pores of the particles.
Preferably, the mass ratio of the UV adhesive to the triallyl isocyanate to the cumene hydroperoxide is 2-2.5:1:1.5-2.
Preferably, the mass ratio of the sodium chloride to the polyvinyl alcohol to the calcium phosphate to the UV adhesive is 1.5-2:1:0.3-0.5:5-8.
Preferably, the initial concentration of the UV glue in the reaction system is 20-40 g/L.
Preferably, the heating temperature in step (1) is 65 to 75 ℃, more preferably, the heating is performed by a gradient heating method.
Preferably, the specific process of gradient temperature rise is as follows: the reaction was carried out at a temperature of 65℃for 1 hour, at 70℃for 6 hours and at 75℃for 3 hours. The curing speed of the UV adhesive can be better controlled by adopting a gradient heating reaction, so that the UV adhesive is gradually cured.
The UV power can be reduced in the partial curing stage of the UV glue, and the UV power can be increased again in the complete curing stage of the UV glue so as to shorten the curing time.
Preferably, in the step (1), the wavelength of ultraviolet light is 365nm and the power is 6mW.
Preferably, in the step (3), the wavelength of ultraviolet light is 365nm and the power is 20mW.
The beneficial effects are that:
1. the filler matrix of the blood perfusion device utilizes the layering solidification of UV glue to firmly fix infliximab in particles so as to avoid falling off. The chemical bond of infliximab is not influenced in the preparation process, so that the maximum enzyme activity is reserved;
2. the porous structure on the surface provides a sufficient channel for combining infliximab and TNF-alpha to form a complex while enzyme is immobilized, and simultaneously, the effective contact area of blood components and infliximab is larger, the contact time is longer, the reaction is more complete, and the clearance rate of TNF-alpha is higher;
3. the filler matrix of the blood perfusion device is formed by solidifying UV glue, has good biocompatibility, does not have a macroporous structure, does not depend on the adsorption of macroporous resin, has more stable hemodynamics, reduces thrombosis and reduces the thrombus risk of patients;
4. compared with the traditional disposable filling material of the blood perfusion device, the filling material of the invention can simply remove TNF-alpha in blood, has no influence on other substance components in blood, and has stronger specificity;
5. the reaction of the filling material and the single substance in the blood is more efficient, the treatment time of the whole blood perfusion is shortened, the possibility of treatment risk is reduced, the medical resource utilization rate is improved, and greater economic and social benefits are created.
Drawings
FIG. 1 is a photograph of a filler of the present invention.
Detailed Description
The technical scheme of the invention is further described in detail below by combining examples.
The raw materials used in the examples of the present invention are conventional commercially available products unless otherwise specified.
Example 1
A three-necked flask with a stirrer, a condenser and a thermometer in a volume of 1L was taken, 500ml of deionized water was added, 3.6g of sodium chloride, 2.0g of polyvinyl alcohol and 0.8g of calcium phosphate were sequentially added, and the temperature was raised to 50℃and stirred for dissolution. After sufficient dissolution, the whole reaction system was completely protected from light. Under the continuous stirring action, 14.0g of UV glue, 6.0g of triallyl isocyanate and 10.0g of cumene hydroperoxide are added. The flask was continuously irradiated with an ultraviolet lamp of wavelength 365nm and power 6mW. The flask was heated to 65℃in a water bath and reacted for 1 hour, 70℃for 6 hours and 75℃for 3 hours, and the whole reaction was kept under irradiation by an ultraviolet lamp.
And under the whole light-shielding condition, filtering and washing the particles obtained after the reaction, washing the particles with absolute ethyl alcohol for 3 times, soaking the particles for 24 hours, filtering the particles, and washing the particles with deionized water. 200mg of infliximab was dissolved in 150ml of water for injection, and the above-prepared particles were added. The shaking is continued for 2.5 hours at room temperature, and an ultraviolet lamp with the wavelength of 365nm and the power of 20mW is continuously irradiated above the solution while shaking. After the reaction was completed, the product was filtered off, washed 3 times with PBS solution and dried in vacuo. Obtaining filler particles with infliximab immobilized on the surfaces and in the pores. As shown in fig. 1, the prepared filler particles were uniform in size.
The obtained product is used as a filling column of a blood perfusion device to assemble the blood perfusion device capable of specifically removing TNF-alpha in blood. TNF- α perfusion effect test with plasma: (10 g of filler and 100ml of plasma)
Example 2
A three-necked flask with a stirrer, a condenser and a thermometer in a volume of 1L was taken, 500ml of deionized water was added thereto, followed by adding 4.0g of sodium chloride, 2.0g of polyvinyl alcohol and 1.0g of calcium phosphate in this order, heating to 50℃and stirring for dissolution. After sufficient dissolution, the whole reaction system was completely protected from light. Under the continuous stirring action, 16.0g of UV glue, 7.0g of triallyl isocyanate and 12.0g of cumene hydroperoxide are added. The flask was continuously irradiated with an ultraviolet lamp of wavelength 365nm and power 6mW. The flask was heated to 65℃in a water bath and reacted for 1 hour, 70℃for 6 hours and 75℃for 3 hours, and the whole reaction was kept under irradiation by an ultraviolet lamp.
And under the whole light-shielding condition, filtering and washing the particles obtained after the reaction, washing the particles with absolute ethyl alcohol for 3 times, soaking the particles for 24 hours, filtering the particles, and washing the particles with deionized water. 200mg of infliximab was dissolved in 150ml of water for injection, and the above-prepared particles were added. The shaking is continued for 2.5 hours at room temperature, and an ultraviolet lamp with the wavelength of 365nm and the power of 20mW is continuously irradiated above the solution while shaking. After the reaction was completed, the product was filtered off, washed 3 times with PBS solution and dried in vacuo. Obtaining filler particles with infliximab immobilized on the surfaces and in the pores.
Example 3
A three-necked flask with a stirrer, a condenser and a thermometer in a volume of 1L was taken, 500ml of deionized water was added, 3.0g of sodium chloride, 2.0g of polyvinyl alcohol and 0.6g of calcium phosphate were sequentially added, and the temperature was raised to 50℃and stirred for dissolution. After sufficient dissolution, the whole reaction system was completely protected from light. Under the continuous stirring action, 10.0g of UV glue, 5.0g of triallyl isocyanate and 8.0g of cumene hydroperoxide are added. The flask was continuously irradiated with an ultraviolet lamp of wavelength 365nm and power 6mW. The flask was heated to 65℃in a water bath and reacted for 1 hour, 70℃for 6 hours and 75℃for 3 hours, and the whole reaction was kept under irradiation by an ultraviolet lamp.
And under the whole light-shielding condition, filtering and washing the particles obtained after the reaction, washing the particles with absolute ethyl alcohol for 3 times, soaking the particles for 24 hours, filtering the particles, and washing the particles with deionized water. 200mg of infliximab was dissolved in 150ml of water for injection, and the above-prepared particles were added. The shaking is continued for 2.5 hours at room temperature, and an ultraviolet lamp with the wavelength of 365nm and the power of 20mW is continuously irradiated above the solution while shaking. After the reaction was completed, the product was filtered off, washed 3 times with PBS solution and dried in vacuo. Obtaining filler particles with infliximab immobilized on the surfaces and in the pores.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The preparation method of the hemoperfusion apparatus filler capable of removing TNF-alpha in blood comprises the following steps:
(1) Mixing sodium chloride, polyvinyl alcohol, calcium phosphate, UV glue, triallyl isocyanate and cumene hydroperoxide with water as a reaction solvent, and heating under ultraviolet irradiation to partially cure the UV glue to obtain particles;
(2) Soaking the particles obtained in the step (1) in ethanol under the light-shielding condition;
(3) Mixing the particles treated in the step (2) with infliximab solution, and completely solidifying the UV gel by ultraviolet irradiation to obtain the filling material of the blood perfusion device;
the mass ratio of the UV adhesive to the triallyl isocyanate to the cumene hydroperoxide is 2-2.5:1:1.5-2;
the mass ratio of the sodium chloride to the polyvinyl alcohol to the calcium phosphate to the UV adhesive is 1.5-2:1:0.3-0.5:5-8.
2. The method of manufacturing according to claim 1, characterized in that: in the reaction system, the initial concentration of the UV adhesive is 20-40 g/L.
3. The method of manufacturing according to claim 1, characterized in that: the heating temperature of the step (1) is 65-75 ℃.
4. A method of preparation according to claim 3, characterized in that: heating by gradient heating method.
5. The method of manufacturing according to claim 4, wherein: the specific process of gradient temperature rise is as follows: the reaction was carried out at a temperature of 65℃for 1 hour, at 70℃for 6 hours and at 75℃for 3 hours.
6. The method of manufacturing according to claim 1, characterized in that: in the step (1), the wavelength of ultraviolet light was 365nm and the power was 6mW.
7. The method of manufacturing according to claim 1, characterized in that: in the step (2), the wavelength of ultraviolet light is 365nm, and the power is 20mW.
8. The method of manufacturing according to claim 7, wherein: the reaction time was 2.5 hours.
9. A hemodynamic filler capable of removing TNF- α from blood, comprising: the hemoperfusion cartridge packing is prepared according to the preparation method of any one of claims 1 to 8.
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