WO2021132628A1 - 酸化セリウムのナノ粒子、分散体、酸化剤、抗酸化剤および酸化セリウムのナノ粒子の製造方法 - Google Patents

酸化セリウムのナノ粒子、分散体、酸化剤、抗酸化剤および酸化セリウムのナノ粒子の製造方法 Download PDF

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WO2021132628A1
WO2021132628A1 PCT/JP2020/048918 JP2020048918W WO2021132628A1 WO 2021132628 A1 WO2021132628 A1 WO 2021132628A1 JP 2020048918 W JP2020048918 W JP 2020048918W WO 2021132628 A1 WO2021132628 A1 WO 2021132628A1
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cerium oxide
nanoparticles
cerium
dispersion
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French (fr)
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翔太 関口
崇光 本白水
正照 伊藤
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Toray Industries Inc
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Toray Industries Inc
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Priority to US17/788,687 priority patent/US12291461B2/en
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Definitions

  • the present invention relates to nanoparticles of cerium oxide, a dispersion containing the nanoparticles, a method for producing nanoparticles of cerium oxide, and an oxidizing agent and an antioxidant containing the nanoparticles of cerium oxide or a dispersant.
  • titanium oxide has a property of oxidatively decomposing an organic substance due to its photocatalytic property, and is evaluated by a decomposition reaction of an organic dye or the like.
  • oxidative decomposition properties are expected to be used not only as an antibacterial agent but also for decomposing various harmful substances such as small molecules such as acetaldehyde and ammonia, allergens, and viruses.
  • cerium oxide nanoparticles have the same catalytic activity as oxidoreductases such as catalase, oxidase, peroxidase, and superoxide dismutase, and are expected to be applied as oxidants and antioxidants. There is. Since these catalytic activities do not require a special light source such as ultraviolet rays, they can be expected to be used for applications different from titanium oxide.
  • nanoparticles tend to aggregate, so a method is used in which a compound serving as a stabilizer is allowed to coexist during synthesis and the obtained nanoparticles are stably dispersed.
  • cerium oxide nanoparticles for example, cerium (III) ions are oxidized with hydrogen peroxide using polyacrylic acid as a stabilizer to obtain a particle dispersion, or cerium (cerium) in aqueous ammonia using dextran as a stabilizer.
  • cerium (cerium) in aqueous ammonia using dextran as a stabilizer.
  • Alkaline neutralization of ions is performed to obtain a particle dispersion.
  • Non-Patent Document 1 describes a method for synthesizing nanoparticles of cerium oxide whose surface is coated with polyacrylic acid or dextran.
  • Non-Patent Document 1 discloses that, in particular, when polyacrylic acid is used as a stabilizer, the oxidase activity, which is a value indicating oxidation performance, is increased.
  • Patent Document 1 describes a synthesis method using pyridine as a reaction solvent when producing ceria nanoparticles wrapped with a surfactant such as oleylamine. It is disclosed that the ceria nanoparticles thus synthesized become water-soluble by being further capped with polyethylene glycol phospholipid to form a complex, and have catalase activity, which is a property exhibiting antioxidant performance.
  • Patent Document 2 describes a method for synthesizing a complex in which nicotine, which is a compound having pyridine in a partial structure, is adsorbed on nanoceria. It is disclosed that this complex can be used as a biological antioxidant in the treatment of neurodegenerative disorders.
  • Patent Document 3 describes a method for synthesizing nanoparticles of cerium oxide whose surface is coated with a chelating agent such as citric acid or ethylenediamine disuccinic acid (EDDS).
  • a chelating agent such as citric acid or ethylenediamine disuccinic acid (EDDS).
  • citric acid / EDDS is used as a stabilizer, the catalase activity, which is a value indicating antioxidant performance, is increased.
  • the present inventors have investigated applications for utilizing the oxidizing performance and antioxidant performance of cerium oxide nanoparticles.
  • oxidation performance was examined as in the comparative example described later, cerium oxide nanoparticles whose surface was coated with polyacrylic acid described in Non-Patent Document 1 and commercially available cerium oxide nanoparticles were used.
  • the result was that the decomposition rate was low even when the organic dye was oxidatively decomposed.
  • Regarding the antioxidant performance as shown in the comparative example described later, there is a problem that the catalase activity of the ceria nanoparticle complex produced by the method described in Patent Document 1 is low.
  • the present inventors focused on a method for producing nanoparticles of cerium oxide, and particularly examined a stabilizer.
  • a dispersion containing nanoparticles of cerium oxide produced by mixing a solution of an aromatic heterocyclic compound with a solution containing cerium (III) ions or a cerium (III) salt and adding an oxidizing agent was obtained.
  • oxidative decomposition of organic dyes using it we found that the decomposition rate was high. Further, they have found that the dispersion thus produced has high catalase activity and radical scavenging ability showing antioxidant performance, and completed the present invention.
  • the present invention is as follows. (1) It has no substituent or has at least one substituent selected from the group consisting of a methyl group, an ethyl group, an amino group, an aminomethyl group, a monomethylamino group, a dimethylamino group and a cyano group.
  • a solution of an aromatic heterocyclic compound containing 8 carbon atoms and 1 to 4 nitrogen atoms in a ring structure is mixed with a solution containing cerium (III) ions or a cerium (III) salt, and an oxidizing agent is added.
  • the compound is pyrazole, imidazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, indazole, benzoimidazole, azaindole, pyrazolopyrimidine, purine, benzotriazole, quinoxaline, cinnoline, quinazoline, phthalazine,
  • the nanoparticles of cerium oxide according to any one of (1) to (3), which are naphthylidine and pteridine.
  • a solution of an aromatic heterocyclic compound containing 8 carbon atoms and 1 to 4 nitrogen atoms in a ring structure is mixed with a solution containing cerium (III) ions or a cerium (III) salt, and an oxidizing agent is added.
  • the dispersion containing the nanoparticles of cerium oxide of the present invention By using the dispersion containing the nanoparticles of cerium oxide of the present invention, harmful substances can be oxidatively decomposed in a higher yield than the conventional nanoparticles of cerium oxide, and in a higher yield than the conventional nanoparticles of cerium oxide. It is possible to eliminate active species.
  • FIG. 1 is a diagram showing CeL3 end XANES spectra of cerium oxide nanoparticles prepared in Example 1 and Comparative Example 2 measured in Example 18.
  • FIG. 2 is a diagram showing CeL3-end XANES spectra of cerium oxide nanoparticles prepared in Examples 12 and 4 measured in Example 18.
  • FIG. 3 is a diagram showing CeL3 end XANES spectra of cerium oxide crystals, cerium carbonate (III), cerium nitrate (III), and ammonium cerium nitrate (IV) measured in Reference Example 2.
  • the dispersion containing nanoparticles of cerium oxide of the present invention may be referred to as the dispersion of the present invention or the dispersion liquid of the present invention in the present specification.
  • one of the raw materials is a salt of water-soluble cerium, and the synthesis is carried out in water or a solvent compatible with water.
  • preferred embodiments of the aromatic heterocyclic compound used in the present invention include 2 to 8 carbon atoms and. It contains 1 to 4 nitrogen atoms in the ring structure.
  • aromatic heterocyclic compound used in the present invention include, in addition to the above characteristics, monocyclic or bicyclic compounds having a 5-membered or 6-membered ring structure.
  • aromatic heterocyclic compounds include pyrazole, imidazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, indazole, benzoimidazole, azaindole, pyrazolopyrimidine, purine, benzotriazole.
  • the above aromatic heterocyclic compound has a methyl group, an ethyl group, an amino group, an aminomethyl group, a monomethylamino group, a dimethylamino group, or a cyano as a substituent that does not significantly change the form of complex formation or the solubility in a reaction solvent. It may be a derivative having a substituent such as a group.
  • the nanoparticles of cerium oxide are composed of a mixture of Ce 2 O 3 and Ce O 2. It is known that cerium oxide can actually include a form as a hydroxide or an oxyhydroxide in addition to the form of the above oxide.
  • the ratio of ce 2 O 3 and CeO 2 can be calculated by including cerium (III) and X-ray photoelectron spectroscopy as the ratio of the cerium (IV) (XPS).
  • cerium oxide nanoparticles of the present invention or the dispersion containing them do not have a substituent or consist of a group consisting of a methyl group, an ethyl group, an amino group, an aminomethyl group, a monomethylamino group, a dimethylamino group and a cyano group.
  • a method for producing nanoparticles of cerium oxide of the present invention or a dispersion containing the same will be described.
  • the first step has no substituents or has at least one substituent selected from the group consisting of a methyl group, an ethyl group, an amino group, an aminomethyl group, a monomethylamino group, a dimethylamino group and a cyano group.
  • a solution of an aromatic heterocyclic compound containing 2 to 8 carbon atoms and 1 to 4 nitrogen atoms in the ring structure (hereinafter, may be referred to as "aromatic heterocyclic compound") and cerium (hereinafter referred to as "aromatic heterocyclic compound") and cerium ( III)
  • the solution of the aromatic heterocyclic compound used in this step can be prepared by dissolving the aromatic heterocyclic compound in any solvent.
  • the solvent is preferably water or a solvent compatible with water.
  • solvents compatible with water include methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, tetrahydrofuran, acetone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), glycerol, ethylene glycol, oligoethylene. Glycol and the like can be mentioned.
  • Pyrazole, imidazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine are preferably soluble in water, indazole, benzoimidazole, azaindole, pyrazolopyrimidine, purine, benzotriazole, quinoxaline, cinnoline, quinazoline.
  • Phthalazine, naphthylidine, and pteridine are preferably dissolved in 50% ethylene glycol. If the aromatic heterocyclic compound is difficult to dissolve, it may be dissolved by heating or ultrasonic treatment.
  • the amount of the aromatic heterocyclic compound may be in the range of 0.1 to 100 molar equivalents with respect to the cerium (III) ion.
  • the method of mixing the solution of the aromatic heterocyclic compound with the solution containing cerium (III) ion or the cerium (III) salt is as follows: a solution of the aromatic heterocyclic compound and a solution containing cerium (III) ion, respectively. It may be prepared and mixed, or if the solvent of the solution of the aromatic heterocyclic compound is water or a solvent compatible with water, cerium (III) is added to the solution of the aromatic heterocyclic compound. Salt may be added and mixed.
  • the solution containing cerium (III) ion may be prepared by dissolving the cerium (III) salt in an arbitrary solvent.
  • the cerium (III) salt for example, cerium nitrate (III) hexahydrate may be used.
  • the amount of the cerium (III) salt can be mixed with the solution of the aromatic heterocyclic compound so that the final concentration of the reaction solution is in the range of 0.01% by mass to 10% by mass.
  • the mixed solution is preferably mixed for at least 5 minutes until the solution becomes uniform.
  • the solution containing the aromatic heterocyclic compound and the cerium (III) ion preferably does not contain a trivalent or higher carboxylic acid, for example, the compound shown below. Even if it is contained, the amount thereof is preferably 0.1 equivalent or less, more preferably 0.01 equivalent or less, relative to cerium (III) ion.
  • trivalent or higher carboxylic acid examples include nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), ethylenediaminediaminediaminetetraacetic acid (EDDS), glycol etherdiaminetetraacetic acid (EGTA), and diethylenetriaminopentaacetic acid (diethylenetriaminopentaacetic acid) DTPA), citric acid, hydroxyethylethylenediaminetetraacetic acid (HEDTA), polyacrylic acid and / or salts thereof.
  • NTA nitrilotriacetic acid
  • EDTA ethylenediaminetetraacetic acid
  • EDDS ethylenediaminediaminediaminetetraacetic acid
  • EGTA glycol etherdiaminetetraacetic acid
  • DTPA diethylenetriaminopentaacetic acid
  • citric acid hydroxyethylethylenediaminetetraacetic acid
  • the second step is a step of adding an oxidizing agent to the mixed solution obtained in the first step.
  • the oxidizing agents used in the second step are nitric acid, potassium nitrate, hypochlorous acid, chloric acid, chloric acid, perchloric acid, halogen, hydrogen sulfide, permanganate, chromic acid, dichromic acid, oxalic acid, Examples thereof include hydrogen sulfide, sulfur dioxide, sodium thiosulfate, sulfuric acid and hydrogen peroxide. Of these, hydrogen peroxide is particularly preferable.
  • the amount to be added may be 0.1 equivalent or more and 10 equivalent or less, preferably 0.5 equivalent or more and 2 equivalent or less, as a molar equivalent with respect to the cerium (III) ion.
  • cerium (III) ion When an oxidizing agent is added to a mixed solution of an aromatic heterocyclic compound and cerium (III) ion, cerium (III) ion is oxidized to cerium (IV), and cerium oxide composed of a mixture of Ce 2 O 3 and Ce O 2
  • cerium oxide composed of a mixture of Ce 2 O 3 and Ce O 2
  • the particle formation reaction is initiated.
  • the solution is colored yellow, orange, red, brown, or the like. This is the coloration caused by the conversion of cerium (III) ions to cerium (IV), and the degree of coloring is the ratio of cerium (III) and cerium (IV) present on the surface of the nanoparticles of cerium oxide. decide. The end of the reaction can be judged by the point where the color change disappears.
  • the particle formation reaction depends on pH, and the reaction proceeds from weakly acidic to basic. Since the pH tends to be acidic as the reaction progresses, it is preferable to adjust the reaction solution to pH 5 or higher, and more preferably to pH 6 or higher from the time of adding the oxidizing agent to the end of the reaction. , It is more preferable to adjust the pH to 7 or higher. In adjusting the pH, an aqueous sodium hydroxide solution, an aqueous ammonia solution, or the like can be used. The reaction is usually completed in about 5 minutes to 1 hour, and a dispersion containing nanoparticles of cerium oxide of the present invention is obtained.
  • the dispersion of the present invention may be used as it is after the reaction is completed, but it remains in the dispersion after the reaction is completed by filtering with an ultrafiltration membrane or dialyzing with a semipermeable membrane.
  • the unreacted oxidizing agent, cerium (III) ion, and excess aromatic heterocyclic compound can be removed before use.
  • the dispersion of the present invention can be dried using an evaporator, a freeze dryer, or the like to take out nanoparticles of cerium oxide.
  • the dispersion of the present invention may contain nanoparticles of cerium oxide and water as a solvent, as well as other solvent components compatible with water.
  • solvent components include methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, tetrahydrofuran, acetone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), glycerol, ethylene glycol, oligoethylene glycol and the like. Be done.
  • These solvent components can be contained in an amount of 90% by volume or less.
  • solvent components may be added to the dispersion after the reaction is completed, may be added after filtering with an ultrafiltration membrane, may be used as a dialysate, or may be added to the dispersion after dialysis. Good. It may be added to dried cerium oxide nanoparticles to form a dispersion.
  • the dispersion of the present invention may contain an ionic component.
  • an ionic component acetic acid, phthalic acid, succinic acid, carbonic acid, Tris (hydroxymethyl) aminomethane (Tris), 2-Morphorinoethanesulfonic acid, monohydrate (MES), Bis (2-hydroxy) as components imparting buffering performance.
  • ionic components can be added so that the final concentration is in the range of 0.1 mM to 1 M.
  • These ionic components may be added to the dispersion after the reaction is completed, may be added after filtering with an ultrafiltration membrane, may be used as a dialysate, or may be added to the dispersion after dialysis. Good. It may be added to dried cerium oxide nanoparticles to form a dispersion.
  • the pH of the dispersion of the present invention may be adjusted after purification.
  • the pH of the dispersion of the present invention may be in the range of pH 2 to 12, preferably pH 4 to 10, and more preferably pH 5 to 8.
  • the pH may be adjusted by adding a buffer solution, or may be adjusted by adding an acid such as nitric acid, sulfuric acid or hydrochloric acid, or a base such as sodium hydroxide or potassium hydroxide.
  • the dispersion of the present invention may be stored as it is after the reaction is completed, or the dispersion after the reaction is stored as a purified product filtered through an ultrafiltration membrane or a purified product dialyzed by a semipermeable membrane. You may. Further, it may be stored as a dispersion liquid containing the above-mentioned solvent component and ionic component, or may be stored after adjusting the pH. When stored as a dispersion, refrigerated storage is preferable.
  • the nanoparticles of cerium oxide of the present invention can be obtained as a dried product by taking them out from the dispersion produced as described above and drying them. For example, the solution after completion of the reaction is filtered through an ultrafiltration membrane or dialyzed against a translucent membrane, and the unreacted oxidizing agent and cerium (III) ions remaining in the solution after completion of the reaction are formed. Nanoparticles of cerium oxide can be obtained by removing excess aromatic heterocyclic compound and then drying using an evaporator or a freeze dryer. Specifically, ultrafiltration membranes such as Merck's Amicon Ultra and GE Healthcare's Vivaspin, and translucent membranes such as Spectrum's Spectra / Pore can be used.
  • the drying conditions of the extracted dispersion may be the temperature and atmospheric pressure conditions at which the solvent becomes a gas in the phase diagram.
  • the evaporator may be set so that the temperature is 40 ° C. and 50 hPa or less to remove water.
  • the evaporator for example, N-1200A manufactured by Tokyo Rika Kikai Co., Ltd. can be used.
  • the freeze-dryer may be set so as to have a temperature of ⁇ 40 ° C. and 20 Pa, and water may be removed.
  • FDU-1200 manufactured by Tokyo Rika Kikai Co., Ltd. can be used. It can also be dried by heating in an oil bath so that the temperature becomes 100 ° C. or higher, or by heating in a constant temperature dryer so that the temperature becomes 80 ° C. or higher.
  • the hydrodynamic diameter of the cerium oxide nanoparticles in the dispersion of the present invention is measured by dynamic light scattering to derive an autocorrelation function, analyzed by the Marquart method, and average particle size from the number conversion histogram. Calculate as. ELS-Z manufactured by Otsuka Electronics Co., Ltd. is used for the measurement of dynamic light scattering.
  • the hydrodynamic diameter of the cerium oxide nanoparticles in the dispersion may be 1 or more and 1000 nm or less, and preferably 1 or more and 200 nm or less.
  • the hydrodynamic diameter of the cerium oxide nanoparticles in the dispersion of the present invention can be adjusted by the molar equivalent of the aromatic heterocyclic compound to the cerium (III) ion. If the molar equivalent is low, particles having a large particle size can be obtained, and if the molar equivalent is high, particles having a small particle size can be obtained.
  • Information on the valence and structure of the atom of interest is obtained from XANES, and in EXAFS analysis, the local structure of the sample and the atomic species around the atom of interest are obtained by Fourier transform of the real spectrum (corresponding to FT-EXAFS / radial distribution function). Information on valence and distance can be obtained.
  • the energy states of cerium (III) and cerium (IV) related to the redox reaction of cerium oxide are reflected in the peak position and peak intensity ratio of the maximum absorption in the XANES spectrum.
  • the cerium oxide nanoparticles of the present invention have a maximum absorption between 5276.0 to 5279.0 eV and 5735.0 to 5739.0 eV in the Ce L3 edge XANES spectrum obtained by X-ray absorption fine structure spectrum measurement.
  • the dispersion of the present invention may be sterilized prior to use. Examples of the sterilization method include a method of passing through a sterilization filter.
  • the nanoparticles of cerium oxide of the present invention or the dispersion containing the nanoparticles can be used as an oxidizing agent.
  • it can be used as a uniform catalyst in an organic synthesis reaction or polymer polymerization or a wet etching solution for a semiconductor by utilizing an oxidizing action.
  • it can be used as a solution in place of the oxidase solution by utilizing the oxidizing action.
  • it can be used for detection reactions and tissue staining using antibody-antigen reactions and nucleic acid hybridization instead of oxidase and peroxidase solutions, or it can be coated on electrodes to immobilize cerium oxide nanoparticles. It can be used for chemical detection reactions.
  • it can be used as a bleaching agent / disinfectant utilizing an oxidizing action for decomposing / removing stains, odors, allergens, viruses, bacteria, fungi, and molds.
  • a bleaching agent for cleaning clothes, tableware, kitchens, toilets, washrooms, bathrooms, medical devices, and the like.
  • it can be added to pools, bathtubs, hot springs as a disinfectant, or used as a body soap, hand-washing detergent, disinfectant, mouthwash, mouthwash, and the like.
  • the performance as such an oxidizing agent can be evaluated by a fading reaction of an organic dye, which will be described later.
  • the nanoparticles of cerium oxide of the present invention or the dispersion containing the nanoparticles are added at the time of molding fibers, tubes, beads, rubber, films, plastics, etc. as additives for imparting oxidation performance. Or, by applying it to these surfaces, it can be used for deodorant, anti-allergic, anti-virus, anti-bacterial and anti-mold processing. Examples of those processed with the nanoparticles or dispersions of the present invention include drainage chrysanthemum crack covers for kitchen sinks, drain plugs, window glass fixing packings, mirror fixing packings, bathrooms, wash basins and kitchens.
  • the product processed with the nanoparticles or dispersion of the present invention can be used in various fields as a sanitary material.
  • the fading reaction of organic dyes is also used to evaluate the photocatalytic performance of titanium oxide, and the decomposition rate of the obtained dyes is used as an index of the characteristics of oxidative decomposition of organic substances.
  • the decomposition rate of the dye is calculated as follows. First, the dispersion of the present invention and an organic dye such as Acid Orange 7 (AO7) are mixed and allowed to stand for a predetermined time. As a control, the same treatment is performed on a solution of AO7 that does not contain nanoparticles of cerium oxide. After the reaction, the absorption spectra of all the solutions are measured. For the analysis, the absorbance at 485 nm, which is the maximum absorption wavelength of AO7, is used. The difference between the absorbance of the control and the absorbance of the solution containing the dispersion of the present invention is taken, and the ratio of the control to the absorbance is calculated as the decomposition rate.
  • AO7 Acid Orange 7
  • a preferred embodiment of the oxidizing agent of the present invention has no substituent or is selected from the group consisting of a methyl group, an ethyl group, an amino group, an aminomethyl group, a monomethylamino group, a dimethylamino group and a cyano group. It contains an aromatic heterocyclic compound having at least one substituent and containing 2 to 8 carbon atoms and 1 to 4 nitrogen atoms in the ring structure, and nanoparticles of cerium oxide at 40 ° C. for 1 hour. It is a dispersion liquid containing nanoparticles of cerium oxide having a decomposition rate of 30% or more in the decomposition reaction of acid orange.
  • the decomposition rate of acid orange in the decomposition reaction of acid orange at 40 ° C. for 1 hour is 30% or more, it can be used as an oxidizing agent.
  • the decomposition rate in the decomposition reaction of acid orange at 40 ° C. for 1 hour is preferably 50% or more, and particularly preferably 70% or more.
  • the nanoparticles of cerium oxide of the present invention or the dispersion containing the nanoparticles can be used as an antioxidant.
  • the antioxidant refers to a substance that has reducing properties, suppresses lipid peroxidation, and reacts with active oxygen (superoxide ion, hydroxyl radical, hydrogen peroxide, etc.) to suppress its action ( Standard Chemical Glossary 2nd Edition, Maruzen Publishing).
  • active oxygen superoxide ion, hydroxyl radical, hydrogen peroxide, etc.
  • it can be used as a reducing agent in an organic chemical reaction or a radical terminator in polymer polymerization.
  • it can be used to protect cells from oxidative stress by adding it to a cell culture solution or applying it to a culture container such as a petri dish by utilizing its antioxidant effect.
  • the skin can be used to protect the skin from lipid peroxides and active oxygen.
  • it can be used as an alternative substance to an antioxidant enzyme solution by utilizing its antioxidant action.
  • the electrodes are coated to immobilize the nanoparticles of cerium oxide, which can be used for a hydrogen peroxide detection reaction or an electrochemical detection reaction. It can also be used as a neutralizing solution for hydrogen peroxide industrially used in the production of foods, semiconductors, fibers and pulp and paper, sterilization of public baths, and removal of slime in pipes. Such performance can be evaluated by the catalase activity described later.
  • the dispersion of the present invention can be added as an antioxidant during molding of rubber or plastic, or added to fuels, detergents, foods and animal feeds.
  • the performance as such an antioxidant can be evaluated by a scavenging reaction of an active species described later.
  • the nanoparticles of cerium oxide of the present invention or the dispersion containing the nanoparticles can be used as an antioxidant as a drug for humans or animals related to oxidative stress and inflammation.
  • a local, enteric or parenteral method such as injection, infusion or transplantation, stroke, multiple sclerosis, amyotrophic laterality
  • Oxidative stress-related diseases such as lateral sclerosis and ischemia-reperfusion injury can be used for prevention and treatment.
  • the dispersion of the present invention on the surface of a medical device such as a cannula, catheter or stent as an antioxidant or an artificial organ represented by a dialysis membrane, inflammation is reduced locally or systemically. You can also let it.
  • the value of catalase activity can be determined according to the protocol using the AmplexRed Catalase Assay Kit (A22180) of Thermo Fisher Scientific Co., Ltd. as shown in Special Table 2018-508568.
  • the Reaction Buffer included in the kit, the dispersion of the present invention, and the aqueous hydrogen peroxide solution are mixed and allowed to stand for 30 minutes to decompose hydrogen peroxide.
  • the reaction solution is passed through a 30 kD ultrafiltration membrane, the flow-through solution is mixed with the Working Solution included in the kit, and the reaction is carried out at 37 ° C. for 30 minutes.
  • the Resorufin produced by the reaction is excited at 544 nm and the fluorescence intensity at 590 nm is measured.
  • the catalase activity of the dispersion of the present invention is calculated by comparing with a calibration curve prepared with a standard of catalase having an activity value known in the kit.
  • EnzyChrom Catalase Assay Kit of BioAssay System Co., Ltd. can also be used for the measurement of catalase activity.
  • a preferred embodiment of the antioxidant of the present invention has no substituent or is selected from the group consisting of a methyl group, an ethyl group, an amino group, an aminomethyl group, a monomethylamino group, a dimethylamino group and a cyano group.
  • An aromatic heterocyclic compound having at least one substituent and containing 2 to 8 carbon atoms and 1 to 4 nitrogen atoms in the ring structure, and cerium oxide nanoparticles, and the concentration of cerium oxide nanoparticles.
  • the catalase activity in the decomposition reaction of hydrogen peroxide solution using AmplexRed Catalase Assay Kit (A22180) is 0.5 U / ml or more, it can be used as an antioxidant.
  • the Catalers activity is preferably 0.7 U / ml or more, particularly preferably 0.8 U / ml or more.
  • the scavenging reaction of the active species is described in Y. Xue, J. et al. Phys. Chem. C 2011, 115, 4433-4438. It can be measured as a dye retention rate by a method as shown in. Specifically, an aqueous iron (II) chloride solution and an aqueous hydrogen peroxide solution are mixed to generate hydroxyl radicals by a Fenton reaction. The dispersion of the present invention is added thereto to carry out a radical scavenging reaction. This mixed solution is mixed with an organic dye such as methylene blue and allowed to stand for a predetermined time. As a control, the same treatment is performed on the solution containing no dispersion of the present invention.
  • an organic dye such as methylene blue
  • a methylene blue solution having the same concentration as the reaction solution is prepared as a reference solution, and the absorption spectrum of the above solution is measured.
  • the absorbance at 664 nm, which is the maximum absorption wavelength of methylene blue is used.
  • Difference in absorbance ( ⁇ I 0 ) between the absorbance (I 0 ) of the reference solution and control (I c ), and difference in absorbance (I) and control (I c ) of the solution containing the dispersion of the present invention (I c) ⁇ I) is calculated.
  • the ratio of the latter ( ⁇ I) to the former ( ⁇ I 0 ) is calculated as the decomposition rate and used as the dye retention rate. This value is a value indicating the radical scavenging performance.
  • the dye retention rate can also be determined by using methyl violet instead of methylene blue.
  • reagents were purchased from Fujifilm Wako Pure Chemical Industries, Ltd., Tokyo Kasei Co., Ltd., and Sigma-Aldrich Japan GK, and used as they were without any particular purification.
  • the zeta potential / particle measurement system ELS-Z manufactured by Otsuka Electronics Co., Ltd. was used for measuring the hydrodynamic diameter of the dispersion liquid containing the nanoparticles of cerium oxide of the present invention.
  • As the heat block ND-SO1 manufactured by Nisshin Rika Co., Ltd. was used.
  • a SpectraMax iD3 manufactured by MOLECULAR DEVICE was used as the plate reader.
  • Comparative Example 1 Dispersion solution containing nanoparticles of cerium oxide using polyacrylic acid as a stabilizer
  • nanoparticles of cerium oxide were prepared for comparison of oxidative activity.
  • To 10 ml of a 1 mass% sodium polyacrylate aqueous solution 200 ⁇ l of a 10 mass% cerium (III) nitrate hexahydrate aqueous solution was added, and the mixture was stirred at room temperature for 5 minutes. Then, 200 ⁇ l of a 1.2 mass% hydrogen peroxide aqueous solution was added, and the mixture was heated to 40 ° C. and reacted for 1 hour.
  • the reaction solution was purified with a 30 kD ultrafiltration membrane to obtain a yellow dispersion containing nanoparticles of cerium oxide.
  • Example 1 Preparation of dispersion of nanoparticles of cerium oxide using pyridine as a stabilizer
  • pyridine as a stabilizer
  • 200 ⁇ l of a 10 mass% cerium (III) nitrate hexahydrate aqueous solution was added to 10 ml of a 12 mg / 10 ml pyridine aqueous solution.
  • the pH was adjusted to 7, and the mixture was stirred at room temperature for 5 minutes.
  • 200 ⁇ l of a 1.2 mass% hydrogen peroxide aqueous solution was added, and the mixture was reacted at room temperature for 1 hour.
  • the reaction solution was purified with a 30 kD ultrafiltration membrane to obtain an orange dispersion containing nanoparticles of cerium oxide.
  • Example 2 Preparation of dispersion of nanoparticles of cerium oxide using pyrazole as a stabilizer
  • the reaction was carried out under the same conditions as in Example 1 except that the stabilizer was a 10 mg / 10 ml pyrazole aqueous solution.
  • the stabilizer was a 10 mg / 10 ml pyrazole aqueous solution.
  • Example 3 Preparation of dispersion of nanoparticles of cerium oxide using imidazole as a stabilizer
  • the reaction was carried out under the same conditions as in Example 1 except that the stabilizer was a 10 mg / 10 ml imidazole aqueous solution.
  • the stabilizer was a 10 mg / 10 ml imidazole aqueous solution.
  • Example 4 Dispersion of nanoparticles of cerium oxide using 1-methylimidazole as a stabilizer
  • the stabilizer was a 12 mg / 10 ml 1-methylimidazole aqueous solution. The reaction was carried out under the conditions of (1) to obtain an orange aqueous solution containing nanoparticles of cerium oxide.
  • Example 5 Dispersion of nanoparticles of cerium oxide using 1,2,3-triazole as a stabilizer In Example 1, except that the stabilizer was a 10 mg / 10 ml aqueous solution of 1,2,3-triazole. Reacted under the same conditions as in Example 1 to obtain an orange aqueous solution containing nanoparticles of cerium oxide.
  • Example 6 Dispersion of nanoparticles of cerium oxide using 1,2,4-triazole as a stabilizer In Example 1, except that the stabilizer was a 10 mg / 10 ml aqueous solution of 1,2,4-triazole. Reacted under the same conditions as in Example 1 to obtain an orange aqueous solution containing nanoparticles of cerium oxide.
  • Example 7 Dispersion of nanoparticles of cerium oxide using 2- (aminomethyl) pyridine as a stabilizer
  • the stabilizer was a 16 mg / 10 ml 2- (aminomethyl) pyridine aqueous solution. Reacted under the same conditions as in Example 1 to obtain an orange aqueous solution containing nanoparticles of cerium oxide.
  • Example 8 Dispersion of nanoparticles of cerium oxide using 2-cyanopyridine as a stabilizer
  • the stabilizer was a 16 mg / 10 ml 2-cyanopyridine aqueous solution. The reaction was carried out under the conditions of (1) to obtain an orange aqueous solution containing nanoparticles of cerium oxide.
  • Example 9 Dispersion of nanoparticles of cerium oxide using 4-dimethylaminopyridine as a stabilizer
  • Example 1 except that the stabilizer was a 19 mg / 10 ml aqueous solution of 4-dimethylaminopyridine.
  • the reaction was carried out under the same conditions as in the above to obtain an orange aqueous solution containing nanoparticles of cerium oxide.
  • Example 10 Dispersion of nanoparticles of cerium oxide using pyridazine as a stabilizer
  • the reaction was carried out under the same conditions as in Example 1 except that the stabilizer was a 12 mg / 10 ml aqueous solution of pyridazine.
  • An orange aqueous solution containing nanoparticles of cerium oxide was obtained.
  • Example 11 Dispersion of nanoparticles of cerium oxide using pyrimidine as a stabilizer
  • the reaction was carried out under the same conditions as in Example 1 except that the stabilizer was a 12 mg / 10 ml aqueous solution of pyrimidine.
  • An orange aqueous solution containing nanoparticles of cerium oxide was obtained.
  • Example 12 Dispersion of nanoparticles of cerium oxide using benzimidazole as a stabilizer
  • the stabilizer was 18 mg / 10 ml of a 50% ethylene glycol aqueous solution of benzimidazole. The reaction was carried out under the same conditions to obtain an orange aqueous solution containing nanoparticles of cerium oxide.
  • Example 13 Dispersion of nanoparticles of cerium oxide using adenine as a stabilizer
  • the reaction was carried out under the same conditions as in Example 1 except that the stabilizer was a 26 mg / 10 ml adenine aqueous solution.
  • An orange aqueous solution containing nanoparticles of cerium oxide was obtained.
  • Example 14 Measurement of hydrodynamic diameter of dispersion liquid containing nanoparticles of cerium oxide The hydrodynamic diameter of the dispersion liquid containing nanoparticles of cerium oxide prepared in Examples 1 to 13 is measured by dynamic light scattering (DLS). It was measured. The solvent used for the measurement was water, and the average particle size of the hydrodynamic diameter was obtained by number conversion. The obtained values are shown in Table 1.
  • Example 15 Measurement of oxidation performance by dye decomposition test
  • 30 ⁇ l of the dispersion liquid of the present invention prepared in Examples 1 to 13 prepared so as to be 2 mg / ml, 0.5 mg / ml as a sample containing an organic substance 60 ⁇ l of Acid Orange 7 (AO7) and 1.41 ml of distilled water were added, respectively, and the mixture was allowed to stand at 40 ° C. for 1 hour using a heat block to carry out a dye decomposition reaction.
  • AO7 Acid Orange 7
  • a commercially available dispersion of cerium oxide nanoparticles (IV) (Merck, 796077) was diluted to 0.2 mg / ml, 12.2 mg of pyridine was added to 10 ml of the diluted solution, and the mixture was stirred at room temperature for 1 hour. Then, the solution was purified with a 30 kD ultrafiltration membrane to obtain a brown aqueous solution containing nanoparticles of cerium oxide.
  • Example 16 Measurement of antioxidant performance by measurement of catalase activity
  • Catalase activity was measured according to a protocol using AmplexRed Catalase Assay Kit (A22180) manufactured by Thermo Fisher Scientific Co., Ltd. Briefly, 50 ⁇ l of Reaction Buffer, 25 ⁇ l of the dispersion liquid of the present invention prepared in Examples 1 to 13 of 16 ⁇ g / ml, and 25 ⁇ l of a 40 ⁇ M hydrogen peroxide aqueous solution were mixed and allowed to stand for 30 minutes to decompose hydrogen peroxide. Was done.
  • the reaction solution was passed through a 30 kD ultrafiltration membrane, 100 ⁇ l of the flow-through solution was mixed with 50 ⁇ l of Working Solution, and the mixture was reacted at 37 ° C. for 30 minutes.
  • the Resorufin produced by the reaction was excited at 544 nm and the fluorescence intensity at 590 nm was measured.
  • the catalase activity of the dispersion was calculated from a calibration curve prepared with a standard of catalase having an known activity value. The results are shown in Table 3. From this result, it was confirmed that the dispersion liquid containing the nanoparticles of cerium oxide of the present invention prepared in Examples 1 to 13 has high catalase activity.
  • Comparative Example 2 was prepared by post-adding pyridine
  • Comparative Example 3 was prepared by using a stabilizer different from the present invention
  • Comparative Example 4 was prepared by post-adding benzimidazole.
  • the antioxidant performance of the dispersion was measured in the same manner, but the catalase activity was lower than that of the dispersion of the present invention.
  • the catalase activity of the ceria nanoparticle complex described in Patent Document 1 is estimated to be about 0.033 U / ml. Is done. The estimated values are shown in Table 3. The catalase activity of the ceria nanoparticle composite of Reference Example 1 was significantly lower than that of the dispersions of the present invention prepared in Examples 1 to 13.
  • Example 17 Measurement of antioxidant performance by radical scavenging test using 2,2-Diphenyl-1-picrylydrazyl (DPPH) Prepared to be 0.5 mg / ml with 100 ⁇ l of 0.3 mM DPPH ethanol solution. 100 ⁇ l of the dispersion solution of the present invention prepared in Example 12 was mixed and allowed to stand at room temperature for 30 minutes. As a control, the same treatment was performed on a solution containing no nanoparticles of cerium oxide. In addition, a reference solution was prepared by mixing 100 ⁇ l of a 0.3 mM DPPH ethanol solution and 100 ⁇ l of distilled water. The absorption spectrum of the above solution was measured.
  • DPPH 2,2-Diphenyl-1-picrylydrazyl
  • the absorbance at 517 nm which is the maximum absorption wavelength of DPPH
  • the difference between the absorbance of the reference solution and the absorbance of the control, and the difference between the absorbance of the present dispersion and the absorbance of the control were calculated.
  • the ratio of the latter absorbance difference to the former absorbance difference was calculated as the DPPH retention rate (%), and the value obtained by subtracting the DPPH retention rate from 100 was defined as the DPPH elimination rate (%).
  • the results are shown in Table 4. From this result, it was confirmed that the dispersion liquid containing the nanoparticles of cerium oxide of the present invention has high radical scavenging performance.
  • the radical scavenging performance of the dispersions of nanoparticles prepared in Comparative Examples 2 and 3 was measured in the same manner, but the DPPH scavenging rate was lower than that of the dispersion of the present invention.
  • Example 18 XAFS observation X-rays were measured by irradiating the dispersion liquid (8 mg / ml) of the nanoparticles of cerium oxide of the present invention prepared in Examples 1 and 12 with X-rays and measuring the amount of absorption thereof.
  • the X-ray Absorption Fine Structure spectrum was measured.
  • the measurement conditions are as follows: the experimental facility is the High Energy Accelerator Research Organization Photon Factory BL12C, the spectroscope is the Si (111) 2 crystal spectroscope, the absorption end is the Ce L3 absorption end, and the detection method is the transmission method.
  • the vessel was an ion chamber.
  • the CeL3 end XANES spectra are shown in FIGS. 1 and 2, respectively.
  • the absorption edge (E0) is defined as 5224.4 eV of the spectrum, the average value of absorption in the range of E0 to -150 to -30 eV is 0, and the average value of absorption in the range of E0 to +150 to +400 eV is 1.
  • the cerium oxide nanoparticles prepared in Example 1 had maximum absorption at 5728.306 eV and 5736.407 eV, and the cerium oxide nanoparticles prepared in Example 12 had maximum absorption at 5728.145 eV and 5736.246 eV, respectively. Was there.
  • the cerium oxide nanoparticles of Comparative Example 2 had maximum absorption at 5729.426 eV and 5736.246 eV, and the cerium oxide nanoparticles of Comparative Example 4 had maximum absorption at 5729.426 eV and 5736.407 eV, respectively.
  • These cerium oxide nanoparticles have a maximum absorption between 5735.0 and 5739.0 eV, but do not have a maximum absorption between 5276.0 to 5279.0 eV, and the cerium oxide nanoparticles of the present invention have no maximum absorption. It was found that it shows a spectrum different from that of nanoparticles.

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CN118019715A (zh) * 2021-09-29 2024-05-10 东丽株式会社 氧化铈的纳米粒子、分散液、抗病毒剂、抗菌剂、树脂组合物、树脂制品、纤维材料、纤维制品和制造氧化铈的纳米粒子的方法
KR20240067898A (ko) 2021-09-29 2024-05-17 도레이 카부시키가이샤 산화세륨의 나노 입자, 분산액, 항바이러스제, 항균제, 수지 조성물, 수지 제품, 섬유 재료, 섬유 제품 및 산화세륨의 나노 입자를 제조하는 방법

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