WO2011096230A1 - Particules magnétiques, leur procédé de production et préparation médicinale contenant lesdites particules magnétiques - Google Patents

Particules magnétiques, leur procédé de production et préparation médicinale contenant lesdites particules magnétiques Download PDF

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WO2011096230A1
WO2011096230A1 PCT/JP2011/000638 JP2011000638W WO2011096230A1 WO 2011096230 A1 WO2011096230 A1 WO 2011096230A1 JP 2011000638 W JP2011000638 W JP 2011000638W WO 2011096230 A1 WO2011096230 A1 WO 2011096230A1
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magnetic
particles
particle
drug
magnetic particles
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PCT/JP2011/000638
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English (en)
Japanese (ja)
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禎尚 並木
仁孝 北本
輝顕 渕上
亮 河村
勝 中川
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学校法人慈恵大学
国立大学法人東京工業大学
国立大学法人東北大学
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Priority to JP2011552707A priority Critical patent/JP5526156B2/ja
Publication of WO2011096230A1 publication Critical patent/WO2011096230A1/fr

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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
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6925—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to magnetic particles and a method for producing the same. Moreover, it is related with the magnetic particle containing formulation containing the above-mentioned magnetic particle.
  • Magnetic particles are attracting attention as functional particles, and various reports have been made.
  • magnetic particles in which magnetic nanoparticles Fe 3 O 4 and poly (diallyldimethylammonium chloride) (PDADMAC) or poly (allylamine hydrochloride) (PAH) are alternately laminated on the core of polystyrene latex (non-patent document) 1) has been proposed.
  • a drug delivery system drug delivery system
  • drug delivery system is attracting attention as a technique for effectively and intensively delivering a drug to a target lesion such as an organ or tissue.
  • This technique can be expected to reduce the amount of drugs to be administered and the number of administrations, and to achieve highly efficient treatment.
  • Non-Patent Document 2 proposes magnetic fine particle nanocrystals coated with polyethyleneimine.
  • polyethyleneimine has strong toxicity, there has been a problem that its use in vivo is greatly limited.
  • there has been no report of clinical trials for gene therapy of drugs using polyethyleneimine as the main raw material there is a problem that it is difficult to realize immediate clinical application.
  • FIG. 14 shows a schematic diagram of a liposome having magnetic fine particles disclosed in Patent Document 4.
  • the liposome 100 includes a lipid bilayer membrane 101, a hydrophobic portion 102, a hydrophilic portion 103, a closed space 104, and magnetic fine particles 105.
  • the enclosed space 104 in the liposome 100 contains a drug, and the foreskin of the liposome 100 contains magnetic fine particles 105 as a constituent component.
  • FIG. 15 shows a schematic diagram of self-association type magnetic lipid nanoparticles proposed by the present inventor Namiki et al. (Patent Document 5, Non-Patent Document 3).
  • This self-associating magnetic nanoparticle 200 contains magnetic fine particle nanocrystal 201, fat-soluble surfactant 202, and fat-soluble drug 203.
  • the magnetic fine particle nanocrystal 201 is coated with a fat-soluble surfactant 202, and the fat-soluble surfactant 202 is further coated with a fat-soluble drug 203.
  • FIG. 16 the schematic diagram of the formulation containing the magnetic particle disclosed by patent document 6 is shown.
  • gold particles 303 are bonded to the surfaces of the magnetic particles 302, and an organic compound 304 having a linking group such as a mercapto group is chemically bonded to the gold particles 303.
  • the surface is covered with a lipid membrane 305.
  • a physiological functional substance 306 such as an antibody and an antitumor active substance 307 are bonded to the surface of the lipid membrane 305 via a connecting substance 308.
  • the optimal drug form varies depending on the target tissue or organ to which the drug is delivered, and further on the purpose of treatment.
  • the optimal dosage form varies depending on the type of drug. Therefore, if a new formulation using magnetic particles different from the known examples can be proposed, the number of drugs that can use the drug delivery system can be increased. In addition, by making it possible to select an optimal drug form and dosage form, improvement of drug efficacy, reduction of side effects, and the like can be expected.
  • the present invention has been made in view of the above problems, and its object is to provide a magnetic particle having a novel structure, a method for producing the same, and a preparation containing magnetic particles.
  • the magnetic particle-containing preparation comprises a sintered body of metal-based nanoparticles having a hollow inside and containing nanoparticles containing at least part of any one of Fe, Co, and Ni, and A magnetic rod-like shape in which a solid body is projected two-dimensionally, image-processed with a transmission electron microscope image, and a porosity calculated from a transmission portion with respect to the entire area in the contour is 1% or more and 50% or less It comprises a magnetic particle having a skeleton and a coating layer covering at least a part of the surface layer of the magnetic particle, and contains a drug in at least one of the magnetic cage skeleton and the coating layer.
  • the magnetic particle according to the first aspect of the present invention includes a magnetic rod-like skeleton having a hollow inside, and the magnetic rod-like skeleton contains nanoparticles containing at least a part of any one of Fe, Co, and Ni. Ratio of the transmission part to the total area within the contour of the sintered body when the sintered body is made of a sintered body of metal-based nanoparticles, and the sintered body is projected two-dimensionally and image-processed by a transmission electron microscope image The porosity determined from the above is 1% or more and 50% or less.
  • the method for producing magnetic particles according to the present invention comprises preparing pre-template particles made of an inorganic material, modifying the surface of the pre-template particles, preparing template particles having a first polarity on the surface, and producing the template particles.
  • metal-based nanoparticles having nanoparticles having a second polarity opposite to the first polarity and containing at least part of any one of Fe, Co, and Ni are adsorbed or in situ It is made to sinter by making it grow and then performing a hydrothermal treatment.
  • the magnetic particles according to the second aspect of the present invention are prepared by preparing pre-template particles made of an inorganic material, modifying the surface of the pre-template particles, preparing template particles having a first polarity on the surface, Adsorbing metal-based nanoparticles having a second polarity opposite to the first polarity and containing nanoparticles containing at least part of any one of Fe, Co, and Ni on the template particle surface, or the It was obtained by growing in the field.
  • the magnetic particles having a novel structure, a production method thereof, and a magnetic fine particle-containing preparation can be provided.
  • FIG. 1 is a schematic conceptual diagram of magnetic particles according to Embodiment 1.
  • FIG. 1B is a schematic perspective view of the IB-IB cutting part in FIG. 1A.
  • FIG. FIG. 3 is a schematic conceptual diagram of a magnetic particle-containing preparation according to Embodiment 2.
  • FIG. 3B is a schematic perspective view of the IIIB-IIIB cut portion of FIG. 3A.
  • FIG. 4 is a schematic partial enlarged view of a coating layer according to Embodiment 2.
  • FIG. 4 is a schematic partial enlarged view of a coating layer according to Embodiment 2.
  • FIG. 4 is a schematic partial enlarged view of a coating layer according to Embodiment 2.
  • FIG. 4 is a schematic partial enlarged view of a coating layer according to Embodiment 2.
  • FIG. 4 is a schematic partial enlarged view of a coating layer according to Embodiment 2.
  • the typical conceptual diagram of the magnetic particle containing formulation which concerns on a modification Explanatory drawing which shows an example in the case of utilizing the magnetic particle containing formulation which concerns on Embodiment 2 as a drug delivery system.
  • FIG. 5 is a schematic partial enlarged view of a coating layer according to Embodiment 3.
  • FIG. 1 is a transmission electron microscope image of magnetic particles according to Example 1.
  • FIG. 4 is a transmission electron microscope image of magnetic particles according to Example 2.
  • FIG. 4 is a transmission electron microscope image of magnetic particles according to Example 3.
  • FIG. 7 is a transmission electron microscope image of magnetic particles according to Example 4.
  • FIG. 7 is a transmission electron microscope image of magnetic particles according to Example 5.
  • FIG. 7 is a transmission electron microscope image of magnetic particles according to Example 6.
  • FIG. 7 is a transmission electron microscope image of magnetic particles according to Example 7.
  • FIG. 10 is a diagram for explaining a method for calculating a porosity from a transmission electron microscope image of magnetic particles according to Example 7.
  • 9 is a transmission electron microscope image of magnetic particles according to Example 8.
  • FIG. FIG. 10 is a diagram for explaining a method for calculating a porosity from a transmission electron microscope image of magnetic particles according to Example 7.
  • FIG. 10 is a diagram for explaining a method of calculating a porosity from a transmission electron microscope image of magnetic particles according to Example 8.
  • FIG. The elements on larger scale of FIG. 11A.
  • FIG. The graph which shows the cell survival rate of Example 10 and Comparative Examples 3-5.
  • 6 is a schematic diagram of a liposome having magnetic fine particles described in Patent Document 4.
  • FIG. FIG. 6 is a schematic diagram of self-association type magnetic lipid nanoparticles described in Patent Document 5.
  • FIG. 6 is a schematic diagram of magnetic particles described in Patent Document 6.
  • 6 is a transmission electron microscope image of magnetic particles according to Comparative Example 1.
  • FIG. 6 is a transmission electron microscope image of magnetic particles according to Comparative Example 1.
  • FIG. 6 is a transmission electron microscope image of
  • FIG. 1A is a conceptual diagram showing an example of a magnetic particle 1 according to Embodiment 1
  • FIG. 1B is a schematic perspective view taken along the line IB-IB in FIG. 1A.
  • the magnetic particle 1 according to Embodiment 1 is composed of a magnetic rod-like skeleton 10.
  • the magnetic saddle-like skeleton 10 forms a substantially spherical skeleton, and the inside thereof has a hollow structure 12.
  • the magnetic cage skeleton 10 is made of a sintered body of metal-based nanoparticles containing nanoparticles containing at least part of any of Fe (iron), Co (cobalt), and Ni (nickel).
  • a large number of porous voids 11 are formed in the magnetic cage skeleton 10.
  • the gap 11 is formed so as to communicate the inside and the outside of the magnetic rod-like skeleton 10 that defines the contour.
  • the void ratio which is the ratio of the voids 11, was obtained by the following method. That is, the sintered body of the magnetic cage skeleton 10 is projected two-dimensionally, and this is subjected to image processing with a 100 keV transmission electron microscope (Hitachi H7100 transmission electron microscope), and binarized in black and white. At this time, the minimum brightness is 0%, the maximum brightness is 100%, and the brightness of 80% or more is determined to be white.
  • the porosity is defined as the ratio of the transmission part (the area determined to be white by the above-described black and white binarization) to the entire area within the approximate outline of the sintered body.
  • the porosity calculated by the above method is 1% or more and 50% or less.
  • the porosity of the magnetic rod-like skeleton 10 is less than 1%, the production of the magnetic particles according to the present invention and the production of the preparation-containing magnetic fine particles may be difficult. On the other hand, if the porosity exceeds 50%, it may be difficult to maintain the skeleton.
  • the porosity is preferably 5% or more and 30% or less from the viewpoint of production stability.
  • the size and shape of the void 11 are not particularly limited as long as the skeleton of the magnetic cage skeleton 10 can be maintained.
  • the magnetic saddle-like skeleton 10 is projected two-dimensionally and the transmission part is calculated by binarizing in black and white, it is smaller than the actual porosity. Value.
  • a method of measuring the porosity more accurately a method of examining gas adsorption such as nitrogen and examining the amount of gas adsorption per unit mass or volume is preferable.
  • gas adsorption such as nitrogen and examining the amount of gas adsorption per unit mass or volume
  • the thickness of the magnetic cage skeleton 10 is not particularly limited, but is preferably 5 nm or more and 50 nm or less. By setting the thickness of the magnetic saddle-like skeleton 10 to 5 nm or more, structural defects can be suppressed and stable production can be achieved. Moreover, content rate of the chemical
  • the shape of the magnetic rod-like skeleton 10 is not particularly limited, and can be, for example, an elliptical sphere shape or a rod shape by controlling the shape of the template particles described later.
  • the material of the magnetic rod-like skeleton 10 can form a sintered body, and at least a part thereof is a metal system containing nanoparticles containing at least a part of Fe, Co, or Ni. If it is a nanoparticle, it can be used without a restriction
  • a nanoparticle containing at least a part of any one of Fe, Co, and Ni refers to a nanoparticle including a part of one of Fe, Co, and Ni, as well as Fe, Co, and Ni. Nanoparticles containing two or more types of Ni in part are also included.
  • the “metal-based nanoparticles” include nanoparticles such as metal oxides and metal nitrides in addition to nanoparticles composed only of metals.
  • suitable materials for the sintered body precursor for forming the sintered body include the following.
  • transition metal-noble metal alloys such as iron platinum alloy (FePt), cobalt platinum alloy (CoPt), iron palladium alloy (FePd), cobalt platinum alloy (CoPt), (2) magnetite (Fe 3 O 4 ), maghemite ( ⁇ -diiron trioxide / ⁇ -Fe 2 O 3 ), iron oxide compounds including manganese (Mn) ferrite, (3) rare earth-transitions such as iron neodymium boron (NdFeB), samarium cobalt alloy (SmCo) Examples include metal alloys, transition metal alloys such as (4) iron (Fe), iron cobalt alloys (FeCo), nickel iron alloys (NiFe), and (5) iron nitride compounds such as Fe 16 N 2 .
  • metal-based nanoparticles containing metal oxides can also be suitably applied.
  • what contains the trace amount of other elements can also be applied suitably.
  • an iron platinum alloy to which a third element such as Cu or Ag is added can be suitably applied.
  • the material of the magnetic rod-like skeleton 10 is preferably a metal-based nanoparticle exhibiting ferromagnetism.
  • magnetite triiron tetroxide / Fe 3 O 4
  • Maghemite ⁇ -diiron trioxide ⁇ ⁇ -Fe 2 O 3
  • iron monoxide iron nitride, iron, iron platinum alloy, iron palladium alloy, etc.
  • the magnetic cage skeleton 10 may be composed of only a single material or a plurality of materials.
  • the material and content of nanoparticles containing at least a part of any one of Fe, Co, and Ni are appropriately selected so as to have a magnetic force according to the purpose of use.
  • the metal-based nanoparticles may be composed only of nanoparticles containing at least part of any one of Fe, Co, and Ni, but may be blended with other metal-based nanoparticles.
  • the kind of metal element to be used is not particularly limited, and can be appropriately selected depending on the application. For example, an alloy made of a combination of one or more selected from copper, chromium, titanium, tantalum, tungsten, nickel, molybdenum, manganese, aluminum, and yttrium, or a single metal may be used.
  • the particle size of the magnetic rod-like skeleton 10 is not particularly limited, and can be appropriately selected depending on the application.
  • the particle diameter of the magnetic rod-like skeleton 10 can be easily controlled by controlling the size of the template particles described later. From the viewpoint of ease of production, the thickness is preferably 50 nm or more, and preferably 10 ⁇ m or less. When used in a magnetic induction drug transmission system for cancer treatment, it is desirable that the particle diameter be 50 nm or more and 400 nm or less in consideration of the permeability of the blood vessel wall of the new blood vessel.
  • an aqueous dispersion of pre-template particles 21 (see FIG. 2A) is prepared.
  • Suitable materials for the pre-template particles 21 include silica (SiO 2 ), titanium oxide (TiO 2 ), magnesium fluoride (MgF 2 ), aluminum fluoride (AlF 3 ), lithium fluoride (LiF), and sodium fluoride.
  • the pre-template particles 21 may be made of a single material, or may be particles in which a plurality of materials are mixed. Moreover, the particle
  • the preparation method of the pre-molded particles 21 is not particularly limited. For example, rolling granulation, fluidized bed granulation, stirring granulation, crushing / pulverization granulation, compression granulation, extrusion granulation, fusion granulation, It can be granulated using physical granulation methods such as mixed granulation, spray cooling granulation, spray drying granulation, precipitation / precipitation granulation, freeze drying granulation, suspension aggregation granulation, dripping cooling granulation, etc. it can. Classify as necessary. If the pre-molded particle 21 is available as a commercial product, it may be used.
  • the range of the particle size of the pre-template particles 21 is not particularly limited, but is usually about 10 nm to 10 ⁇ m. If the particle size exceeds 10 ⁇ m, the pre-template particles 21 may not be dispersed in the solvent.
  • the shape of the pre-template particle 21 is not particularly limited, but is usually a spherical shape or a generally spherical shape.
  • the shape of the hollow magnetic particle 1 can be adjusted by the shape of the pre-template particle 21 as described above.
  • an aqueous dispersion of the template particle 22 in which the surface of the pre-template particle 21 is coated with a coating layer (not shown) having the first polarity is prepared. Since the template particle 22 is coated with the coating layer, the particle size is larger than that of the pre-template particle 21.
  • the thickness of the coating layer is not particularly limited, and can be set as appropriate without departing from the spirit of the present invention.
  • the coating layer does not necessarily have to be covered over the entire surface of the pre-template particle 21, and there may be an uncoated region.
  • the method of coating the coating layer on the pre-template particles 21 is not particularly limited, but a method of coating by electrostatic coupling is simple. In the case where the pre-template particle 21 is a negatively charged particle, a positively charged coating layer can be coated. Further, when the pre-template particle 21 is a positively charged particle, a negatively charged coating layer can be covered. It is also possible to coat the negatively charged coating layer with a positively charged coating layer.
  • the coating layer is not particularly limited as long as the template particle 22 can express the first polarity, and examples thereof include ionic polymers (cationic polymers and anionic polymers).
  • ionic polymers include polymers having a charged functional group in the main chain or side chain.
  • examples of the ionic polymer having a positive charge generally include those having a positive charge such as a quaternary ammonium group or an amino group or having a functional group capable of being charged. Specific examples include polyethyleneimine (PEI), polyallylamine hydrochloride (PAH), polydiallyldimethylammonium chloride (PDDA), polyvinylpyridine (PVP), and polylysine.
  • PEI polyethyleneimine
  • PAH polyallylamine hydrochloride
  • PDDA polydiallyldimethylammonium chloride
  • PVP polyvinylpyridine
  • examples of the ionic polymer having a negative charge generally include those having a negative charge or a functional group capable of being charged, such as sulfonic acid, sulfuric acid, and carboxylic acid.
  • Specific examples include polystyrene sulfonic acid (PSS), polyvinyl sulfate (PVS), dextran sulfate, chondroitin sulfate, polyacrylic acid (PAA), polymethacrylic acid (PMA), polymaleic acid, and polyfumaric acid.
  • the zeta potential of the obtained aqueous dispersion is preferably +5 mV or more when the first polarity is positive. If it is less than +5 mV, the template particles 2 may be aggregated and settled in water. Although an upper limit is not specifically limited, Usually, it is +80 mV or less. On the other hand, when the first polarity is negative, it is preferably ⁇ 5 mV or less for the same reason as described above. The lower limit is not particularly limited, but is usually ⁇ 80 mV or more.
  • metal-based nanoparticles containing nanoparticles containing at least part of any one of Fe, Co, and Ni, which are materials for forming the magnetic rod-like skeleton 10 on the surface of the template particle 22.
  • the material is also adsorbed or grown in situ (also referred to as “magnetic-metal nanoparticles 23”).
  • the adhesion type magnetic particles 2 see FIG. 2C.
  • a solution in which a material for forming the magnetic rod-like skeleton 10 is dissolved in a uniform dispersion of the template particles 22 is added, and these are adsorbed on the template particles 22 or grown in situ.
  • the magnetic-metal-based nanoparticle 23 to be added has a polarity opposite to the polarity of the surface of the template particle 22. That is, the magnetic-metal-based nanoparticles 23 are of the second polarity having a polarity opposite to the first polarity of the surface of the template particle 22.
  • the shape of the magnetic-metal-based nanoparticle 23 is not particularly limited, and an amorphous powder, a flat powder, a spherical powder, a rod-shaped powder, and the like can be appropriately selected according to the application and purpose.
  • an amorphous powder, a flat powder, a spherical powder, a rod-shaped powder, and the like can be appropriately selected according to the application and purpose.
  • the magnetic-metal-based nanoparticles 23 are a blend, a plurality of shapes may be mixed.
  • the magnetic-metal-based nanoparticles 23 may contain components to be removed in a sintering process described later.
  • the average particle diameter of the magnetic-metal-based nanoparticles 23 is not particularly limited, but is preferably 1 nm or more, and preferably 50 nm or less from the viewpoint of improving the drug content.
  • the magnetic-metal-based nanoparticles 23 are not necessarily magnetic before sintering, and include those that exhibit magnetic properties by sintering.
  • the average particle diameter of the magnetic-metal nanoparticles 23 is more preferably 25 nm or less, and particularly preferably 15 nm or less, from the viewpoint of suppressing the enlargement of the magnetic particle-containing preparation 7.
  • a material with high magnetic anisotropy having high magnetic induction characteristics is preferable even if the magnetic nanoparticles containing Fe, Co, and Ni have a small particle diameter.
  • Preferred materials for the magnetic nanoparticles include FePt particles and composites of FePt particles and nanoparticles containing other magnetic metal elements.
  • the preferable range of the average particle diameter of the magnetic-metal-based nanoparticles 23 other than the magnetic nanoparticles is also the same.
  • the attached magnetic particles 2 are treated by a hydrothermal reaction.
  • the magnetic-metal-based nanoparticles 23 adsorbed or grown in situ are fused to obtain the fused magnetic particles 3 (see FIG. 2D).
  • the template particles 22 are removed, and hollow magnetic particles 1 as shown in FIG. 1A are obtained.
  • the hydrothermal reaction is preferably in a subcritical state, and particularly preferably in a supercritical state.
  • the conditions for the hydrothermal reaction in subcritical or supercritical water are not particularly limited. In order to obtain hollow magnetic particles 1, the conditions are such that the template particles can be dissolved and removed. As the size of the template particles increases, the reaction time increases. Moreover, if the porosity of the nanoparticle containing the magnetic metal element obtained is small, reaction time will become long. It depends on the type and size of the template material and the coverage of the nanoparticles in the adhering magnetic particles 2. In the case of silica fine particles having a particle diameter of about 300 nm, for example, 400 ° C., 37 MPa, reaction time 3 hours, and the like can be used.
  • the manufacturing method which obtains the hollow magnetic particle 1 was demonstrated in this Embodiment 1, a desired magnetic particle can be utilized according to a use.
  • the adhesion-type magnetic particles 2 and the fusion-type magnetic particles 3 can be produced as the magnetic particles.
  • only the coating layer of the template particles 22 can be removed, and magnetic particles composed of the magnetic cage skeleton 10 and the pre-template particles 21 can be used.
  • magnetic particles composed of pre-template particles in which the size of the pre-template particles 21 is reduced and the magnetic rod-like skeleton 10 can also be used.
  • the template particle can be easily produced by setting the conditions of the hydrothermal reaction to be mild conditions.
  • the magnetic particles according to Embodiment 1 have excellent merits that the particle diameter and hollow diameter of hollow magnetic particles can be controlled by controlling the particle diameter, particle diameter distribution, and particle shape of the template particles. Have Since it can be shaped according to needs, it can be expected to be applied and developed in various fields. Further, according to the magnetic particles according to the first embodiment, since the skeleton of the magnetic particles is formed of the metal material, there is an effect that the magnetic particles have excellent strength and heat resistance.
  • magnetic particle 1 which concerns on this Embodiment 1 demonstrated the example comprised only by the magnetic rod-like frame
  • other components and members such as a chemical
  • FIG. 3 is a conceptual diagram showing an example of the magnetic particle-containing preparation 7 according to the second embodiment.
  • the magnetic particle-containing preparation 7 according to Embodiment 2 has a configuration in which drug-encapsulated magnetic particles 6 are covered with a coating layer 40.
  • the drug-containing magnetic particle 6 is a generic term for the drug 30 containing the drug 30 in the hollow magnetic particle 1. From the viewpoint of increasing the loading amount of the medicine 30, a state in which the medicine 30 is filled in the hollow magnetic particles 1 is preferable.
  • the medicine 30 can be applied without particular limitation.
  • the drug 30 according to the second embodiment includes all substances applied for the purpose of treatment, diagnosis, prevention and the like in a broad sense, and is not particularly limited.
  • drugs include anticancer drugs, photosensitizers, gene therapy drugs and other narrowly defined therapeutic drugs, contrast agents and other narrowly defined diagnostic drugs, as well as peptides, proteins, nucleic acids (for example, DNA, RNA or these Analogs or derivatives (for example, peptide nucleic acids, phosphorothioate DNA, etc.), sugars, complexes thereof, and the like can be mentioned.
  • the nucleic acid is not particularly limited, such as linear or circular, regardless of whether it is single-stranded or double-stranded.
  • the drug 30 may contain a target substance (preservative, stabilizer, medium) other than the above.
  • the porosity is large in the range in which the magnetic rod-like skeleton 10 can maintain the skeleton.
  • the coating layer 40 covers at least a part of the drug-containing magnetic particles 6.
  • the material of the film constituting the main component of the coating layer 40 and the manufacturing method can be used without particular limitation.
  • the coating layer 40 may interact with the magnetic rod-like skeleton 10 or may interact with the drug 30 mounted inside the magnetic rod-like skeleton 10. It can be appropriately selected depending on the porosity of the magnetic rod-like skeleton 10 and the drug 30 mounted in the magnetic rod-like skeleton 10.
  • Suitable examples of the main component of the coating layer 40 include a lipid membrane or a polymer membrane.
  • Preferable examples include lipids, surfactants, polymers such as polyethylene glycol having an alkoxysilyl group, a chlorosilyl group, an isocyanatosilyl group, a mercapto group, and the like at the terminal.
  • biocompatible membrane For the purpose of in vivo use, it is preferable to apply a biocompatible membrane in order to avoid adverse events due to toxicity.
  • the biocompatible material is not particularly limited as long as it is a material that is compatible with the target living body as the name suggests, but it is preferable to use a lipid membrane, a biocompatible polymer, or the like.
  • lipid membranes include neutral lipids, positively charged lipids, and negatively charged lipids.
  • neutral lipids include diacylphosphatidylcholine, diacylphosphatidylethanolamine, cholesterol, ceramide, sphingomyelin, cephalin, and cerebroside.
  • positively charged lipids include DOTAP (1,2-dioleoyloxy-3-trimethylammonio propane), DC-6-14 (O, O'-ditetradecanoyl-N- ( ⁇ -trimethylammonioacetyl) diethanolamine chloride, DC-Chol (3beta).
  • -N- N, N, -dimethyl-aminoethane carbamol cholesterol
  • TMAG N- ( ⁇ -trimethylammonioacetyl) didodecyl-D-glutamate chloride
  • DOTMA N-2,3-di-oleyloxypropyl-N, N, N-trimethylammonium
  • DODAC dioctadecyldimethylammonium chloride
  • DDAB didodecyl-ammonium bromide
  • DOSPA 2,3-dioleyloxy-N- [2 (sperminecarboxamido) ethyl] -N, N-dimethyl-1-propanaminum trifluoroacetane
  • polymer film examples include block copolymers (styrene-isoprene-styrene, styrene-butanediene-styrene), albumin, docosahexaenoic acid, polyglutamic acid, polyethylene glycol / polyaspartic acid, polyethylene glycol / polyaspartic acid.
  • block copolymer in which one or both of a hydrophobic group and a hydrophilic group are modified in the side chain, polyethylene glycol poly (diethylenetriamine), and polyethylene glycol-poly ( ⁇ -benzyl aspartate).
  • Polylactide polyglycolide, polylactide copolymer, polyethylene oxide, polydioxanone, polycaprolactone, polyphosphazene, polyanhydride, polyamino acid, cellulose acetate butyrate, cellulose triacetate, polyacrylate, polyacrylamide, polyurethane, polysiloxane, polyvinyl pyrrolidone (PVP), and copolymers thereof.
  • PVP polyvinyl pyrrolidone
  • examples of the synthetic polymer used for the biocompatible polymer membrane include a polymer of a water-soluble monomer or a water-soluble polymer.
  • Preferable examples of the water-soluble monomer include n-isopropylacrylamide, acrylamide, acrylic acid, methacrylic acid, vinylpyrrolidone or a combination thereof.
  • polyvinyl alcohol (PVA) polyallylamine, polyvinylamine, aliphatic and aromatic diisocyanates, PVA in which an amino group is introduced by CNBr, or a combination thereof may be mentioned. it can.
  • PVA polyvinyl alcohol
  • PVA polyallylamine
  • polyvinylamine polyvinylamine
  • aliphatic and aromatic diisocyanates PVA in which an amino group is introduced by CNBr, or a combination thereof
  • FIG. 4A shows a partially enlarged cross-sectional view when a lipid membrane 41 made of an amphiphilic surfactant 50 is used as the membrane constituting the main component of the coating layer 40.
  • the lipid membrane 41 shown in FIG. 4A has a two-layer membrane structure in which the hydrophilic part 51 is arranged on the surface layer side and the hydrophobic part 52 side is arranged to face each other.
  • the amphiphilic surfactant 50 for example, a fatty-soluble unsaturated fatty acid having 18 carbon atoms such as oleic acid, linolenic acid, linolenic acid and the like is preferable. Among them, oleic acid having the smallest number of double bonds, that is, high oxidation resistance is preferable. In addition, oleylamine, thiol, and the like can be suitably used. However, as long as the above-described conditions of the coating layer are satisfied, the type of the surfactant can be used without any limitation. Moreover, it is also possible to mix and use 2 or more types of surfactant as needed.
  • FIG. 4B shows a partially enlarged conceptual diagram of the coating layer 40b in which the hydrophilic polymer 42 is modified on the surface of the lipid membrane 41.
  • the hydrophilic polymer 42 is modified on the surface of the lipid membrane 41.
  • the hydrophilic polymer 42 can be easily disposed on the surface by modifying at least a part of the lipid constituting the lipid membrane 41. For example, by reacting the functional group possessed by the lipid and the functional group possessed by the hydrophilic polymer 42, it can be bound via a covalent bond.
  • Examples of combinations of functional groups capable of forming a covalent bond include amino group / carboxyl group, amino group / acyl halide group, amino group / N-hydroxysuccinimide ester group, amino group / benzotriazole carbonate group, amino group / Examples include an aldehyde group, a thiol group / maleimide group, and a thiol group / vinylsulfone group.
  • the content of the hydrophilic polymer 42 with respect to the lipid membrane 41 is not particularly limited, but is 1 to 10% (molar ratio), preferably 7 to 10% (molar ratio).
  • the lipid modified with the hydrophilic polymer is preferably bonded to the end of the main chain of the hydrophilic polymer 42, but may be bonded to a side chain.
  • the kind of the hydrophilic polymer 42 is not particularly limited.
  • polyalkylene glycol for example, polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polyhexamethylene glycol
  • dextran pullulan
  • ficoll polyvinyl alcohol
  • styrene -Maleic anhydride alternating copolymer divinyl ether-maleic anhydride alternating copolymer
  • amylose, amylopectin, chitosan, mannan, cyclodextrin, pectin, carrageenan, etc. but polyalkylene glycol is preferred, polyethylene glycol is further preferable.
  • the molecular weight is usually 300 to 10,000, preferably 1000 to 5,000.
  • the hydrophilic polymer 42 includes alkyl groups (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group).
  • alkyl groups for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group).
  • alkoxy group for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, s-butoxy group, t-butoxy group, etc.
  • a substituent such as a hydroxyl group, a carbonyl group, an alkoxycarbonyl group, or a cyano group may be introduced.
  • FIG. 4C shows a partially enlarged cross-sectional view showing an example when the fat-soluble drug 31 is encapsulated in the coating layer 40c.
  • the fat-soluble drug 31 is encapsulated in the hydrophobic part 52 of the lipid film 41.
  • the fat-soluble drug 31 include chlorin e6 (hereinafter referred to as “Ce6”) ester, carmofur (fluorouracil-based anticancer agent), camptothecin, retinoic acid, paclitaxel, and the like.
  • Ce6 chlorin e6
  • camptothecin retinoic acid
  • the main component film constituting the coating layer 40 can be configured by the drug.
  • FIG. 4D is a partially enlarged cross-sectional view of the lipid membrane 41d constituting the coating layer 40d having a two-layer membrane structure in which the hydrophobic portion 52 is disposed on the surface layer side and the hydrophilic portion 51 side is disposed so as to face each other. Indicates. It is possible to extend the residence time in the blood vessel by modifying the hydrophobic portion 52 with the hydrophilic polymer 42d.
  • FIG. 4E illustrates an example in which phospholipid 60 is used as the lipid membrane 41e constituting the coating layer 40e.
  • the lipid membrane 41e shown in FIG. 4E has a two-layer membrane structure in which the hydrophilic part 61 is arranged on the surface layer side and the hydrophobic part 62 side is arranged to face each other.
  • Examples of the phospholipid used in the present invention include egg yolk lecithin, soybean lecithin, cardiolipin, sphingomyelin, phosphatidic acid, phosphatidylserine, phosphatidylinositol, phosphatidylcholine (for example, dioleoylphosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, Palmitoylphosphatidylcholine, distearoylphosphatidylcholine, etc.), phosphatidylglycerol (eg dioleoylphosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, etc.), phosphatidylethanola Down (e.
  • Phospholipids are usually used alone, but two or more phospholipids may be used in combination.
  • medical agent to be used is a phospholipid
  • the coating layer 40 can be comprised with a chemical
  • glycolipids examples include, for example, glycosphingolipid (eg, ganglioside, galactosyl cerebroside, lactosyl cerebroside, etc.), glyceroglycolipid (eg, sulfoxyribosyl glyceride, diglycosyl diglyceride, digalactosyl diglyceride, galactosyl diglyceride, glycosyl diglyceride Etc.).
  • glycosphingolipid eg, ganglioside, galactosyl cerebroside, lactosyl cerebroside, etc.
  • glyceroglycolipid eg, sulfoxyribosyl glyceride, diglycosyl diglyceride, digalactosyl diglyceride, galactosyl diglyceride, glycosyl diglyceride Etc.
  • cholesterol examples include, for example, animal-derived sterols (eg, cholesterol, cholesterol succinic acid, lanosterol, dihydrolanosterol, desmosterol, dihydrocholesterol, etc.), plant-derived sterols (phytosterols) (eg, stigmasterol, sitosterol, campesterol) , Brush casterol, etc.), microorganism-derived sterols (eg, timosterol, ergosterol, etc.) and the like.
  • animal-derived sterols eg, cholesterol, cholesterol succinic acid, lanosterol, dihydrolanosterol, desmosterol, dihydrocholesterol, etc.
  • plant-derived sterols eg, stigmasterol, sitosterol, campesterol
  • Brush casterol etc.
  • microorganism-derived sterols eg, timosterol, ergosterol, etc.
  • saturated or unsaturated fatty acids include unsaturated or saturated fatty acids having 12 to 20 carbon atoms such as palmitic acid, oleic acid, stearic acid, arachidonic acid, myristic acid and the like.
  • the coating layer 40 is not limited to the lipid membrane as described above, and various materials can be applied as long as the above conditions are satisfied.
  • physiologically functional substances such as antibodies or antitumor active substances may be bound.
  • the coating layer is not limited to a single-layer film, and may have a multilayer film structure such as a two-layer film.
  • the particle size of the magnetic particle-containing preparation 7 according to the present invention can be arbitrarily set according to the target site and purpose.
  • the average particle size of the magnetic particle-containing preparation 7 is not particularly limited, but is preferably 5 nm or more and 3000 nm or less.
  • the size is such that it can pass through capillaries (minimum of about 5 ⁇ m)
  • the particle size is micro-sized, there is a problem that precipitation easily occurs during the manufacturing process.
  • the magnetic particle containing formulation 7 is a nanoparticle. From the viewpoint of long-term blood retention, it is preferably 500 nm or less, and from the viewpoint of preventing renal excretion, it is preferably 2 nm or more.
  • the film thickness of the coating layer 40 is not particularly limited, but in the case of a bimolecular film, it is usually about 5 nm or more and 30 nm or less.
  • a method for producing the magnetic particle-containing preparation 7 of the present invention will be described.
  • an example in which a lipid membrane is applied as the coating layer 40 will be described.
  • hollow magnetic particles 1 serving as a skeleton are manufactured.
  • the manufacturing method can be manufactured, for example, by the method described in the first embodiment.
  • drug-encapsulated magnetic particles 6 are prepared by encapsulating drug 30 in hollow magnetic particles 1.
  • the drug-containing magnetic particles 6 are coated with the coating layer 40.
  • the drug When using a water-soluble drug, the drug is dissolved in a solvent such as water or an aqueous solution. And after adding a hollow magnetic particle to this and making it disperse
  • a magnetic particle-containing preparation having a good accumulation property When used in a magnetic induction drug transmission system, a magnetic particle-containing preparation having a good accumulation property may be collected in advance by bringing a magnet exhibiting a predetermined magnetic field close to a dispersed aqueous solution and redispersed in physiological saline or the like.
  • the drug 30 When using a drug that is soluble in an organic solvent, the drug 30 is dissolved in the organic solvent. And after adding the hollow magnetic particle 1 to this and disperse
  • the surface of the hollow magnetic particles may be modified in advance with molecules or polymers having excellent biocompatibility, and the drug may be added as described above. In this case, it is not necessary to add a molecule or a polymer that forms a lipid membrane.
  • the magnetic particle-containing preparation 7 containing the drug in the hollow magnetic particles or at least one of the coating layers can be obtained.
  • the coating layer 40 can be formed, for example, according to the methods of Non-Patent Document 3 and Patent Document 5 proposed by Namiki et al.
  • the above manufacturing method is an example, and various methods can be applied without departing from the gist of the present invention.
  • a polymer film is used as the film constituting the main component of the coating layer 40, it can be manufactured through a process of coating the drug-containing magnetic particles 6.
  • Water-soluble drugs include buffer salts (for example, phosphate buffer salts, citrate buffer salts, acetate buffer salts, etc.), sugars, polyhydric alcohols, water-soluble polymers, nonionic surfactants, antioxidants. Hydration accelerators, pH adjusters, and the like can be used as appropriate. Similarly, in a fat-soluble drug, a regulator, a preservative, and the like can be appropriately used.
  • buffer salts for example, phosphate buffer salts, citrate buffer salts, acetate buffer salts, etc.
  • sugars for example, phosphate buffer salts, citrate buffer salts, acetate buffer salts, etc.
  • polyhydric alcohols for example, polyhydric alcohols, water-soluble polymers, nonionic surfactants, antioxidants. Hydration accelerators, pH adjusters, and the like can be used as appropriate.
  • a regulator, a preservative, and the like can be appropriately used.
  • the drug introduction rate can be determined, for example, by thermogravimetric analysis of the magnetic particle-containing preparation. More specifically, the drug introduction rate can be determined by determining the amount of weight loss below the decomposition temperature of the coating layer such as lipid.
  • a fluorescent dye a water-soluble fluorescent dye for a water-soluble drug, a fat-soluble fluorescent dye for a fat-soluble drug
  • the magnetic particle-containing preparation is purified and dispersed. Alternatively, it may be quantified indirectly by irradiating with excitation wavelength light and measuring the fluorescence intensity.
  • a method of labeling a drug using a radioisotope may be used.
  • Non-Patent Document 3 for the quantification of the lipid membrane outer layer, in the case of phospholipid, malachite green reagent (BIOMOL GREEN Reagent: BIOMOL Research laboratories, PA, USA) decomposes phospholipid into phosphoric acid. And can be quantified. In the case of cholesterol, it can be quantified using a cholesterol quantification kit (Calbiochem, Darmstadt, Germany).
  • FIG. 5 is a schematic conceptual diagram of an association-type magnetic particle-containing preparation 8 composed of the magnetic particle-containing preparation 7 of FIG. 3A and a composite formed body 70 capable of self-association by electrostatic interaction or the like.
  • the composite formed body 70 is expressed as a transparent body so as to visualize the inside.
  • the composite formed body 70 can be provided outside the magnetic particle-containing preparation 7.
  • the composite formed body 70 can enclose a drug inside.
  • the composite formed body 70 itself may be a drug. It is also possible to mount the drug only on the composite formed body 70 without providing the drug in the magnetic particle-containing preparation 7. Further, it is possible to provide the composite formed body 70 with another function without mounting the medicine.
  • the membrane constituting the main component of the coating layer 40 is constituted by a positively charged lipid, and the nucleic acid having a negative charge is used as the complex formed body 70.
  • an association-type magnetic particle-containing preparation 8 composed of the magnetic particle-containing preparation 7 and a nucleic acid can be formed (see Patent Document 5).
  • the drug is also included in the magnetic particle-containing preparation 7, the amount of the drug loaded can be significantly increased.
  • medical agent of FIG. 5 is an example, Comprising: It is not limited to this.
  • the magnetic particle-containing preparation 7 and the association-type magnetic particle-containing preparation 8 are examples, and various modifications can be made without departing from the spirit of the present invention.
  • the drug can be contained in the drug-containing magnetic particles 6 and the coating layer 40.
  • the drug contained in the coating layer 40 may be included in the molecules constituting the main component, or may be the molecules constituting the main component itself.
  • the magnetic particle-containing preparation 7 configured as described above can be applied to treatment or diagnosis in vivo using a known magnetic delivery system.
  • the magnetic particle-containing preparation 7 can be delivered into a living body using an external magnetic field as in Patent Document 4 above.
  • a magnetic irradiation device 82 is installed in the stomach 81 or the like, which is an affected part of the subject 80, and a medicine 84 containing the magnetic particle-containing preparation 7 is injected into the blood by an injection 83.
  • This method can be adopted.
  • the magnetic drug injected into the blood is accumulated in the affected area by the magnetic force of the magnetic irradiation device 82.
  • techniques such as the above-mentioned Patent Document 5 proposed by the inventor Namiki et al. And Japanese Patent Application No. 2008-304288 can be suitably applied.
  • the biological species from which the target cells to which the magnetic particle-containing preparation 7 is to be delivered is not particularly limited, for example, animals, plants, microorganisms, etc., but is preferably derived from animals, such as humans, monkeys, More preferred are mammals such as cattle, sheep, goats, horses, pigs, rabbits, dogs, cats, mice, rats, guinea pigs and the like.
  • the type of the target cell is not particularly limited, for example, somatic cells, germ cells, stem cells, or cultured cells thereof.
  • the magnetic particle-containing preparation 7 can be used both in vivo and in vitro.
  • administration routes include, for example, intravenous, intraarterial, portal vein, parenchymal organ (eg, brain, eyes, thyroid, mammary gland, heart, lung, liver, pancreas, kidney, adrenal gland, Ovary, testis, etc.), luminal organs (eg, esophagus, stomach, duodenum, jejunum, ileum, large intestine, gallbladder, ureter, intravesical, etc.), cerebrospinal cavity, intrathoracic, intraperitoneal, muscle It is not particularly limited, such as internal, intra-articular, subcutaneous, intradermal.
  • Substances that can bind to receptors on the surface of cell membranes eg, antibodies or fragments thereof (eg, Fab fragments, F (ab) '2 fragments, single chain antibodies, etc.), insulin, transferrin, folic acid, hyaluronic acid, sugar chains , Apolipoprotein (eg, apo A-1, apo B-48, apo B-100, apo E, etc.), growth factor (eg, epidermal growth factor, hepatocyte growth factor, fibroblast growth factor, insulin-like growth factor) It is possible to bind to the surface of the magnetic particle-containing preparation 7 without particular limitation.
  • the magnetic response efficiency can be increased as compared with the case where the magnetic nanoparticles are arranged in the center of the dosage form or evenly dispersed in the dosage form. Further, as the magnetic response efficiency is improved, it is possible to reduce the required amount of the magnetic metal element to be contained in the dosage form. As a result, it is possible to increase the loading amount of the medicine.
  • the film constituting the main component of the coating layer 40 is made of a medicine, the amount of medicine loaded can be further improved.
  • the drug contained in the drug-containing magnetic particles 6 and the drug contained in the coating layer 40 can be designed separately and independently, it is also suitable for applications where a plurality of drugs are desired to be contained. .
  • ADVANTAGE OF THE INVENTION According to this invention, it has the outstanding effect that a chemical
  • the phospholipid and the amphiphilic surfactant suitable as the main raw material can easily avoid toxicity. Moreover, since there are an infinite number of selectable lipids, it is easy to improve the performance of the drug delivery system by selecting the type, combination and ratio of lipids. Furthermore, there are also merits that there are many drug delivery systems using nanoparticles mainly composed of lipids and clinical trials of gene therapy.
  • an association-type magnetic particle-containing preparation 8 composed of a magnetic particle-containing preparation 7 and a composite containing a drug
  • the types of drugs that can be used in a drug delivery system using magnetic properties are further increased. I can expect that.
  • the drug is also included in the magnetic particle-containing preparation 7, the amount of drug loaded can be significantly increased.
  • the drug can be directly and efficiently delivered and accumulated by administering the magnetic particle-containing preparation 7 to blood or the like and placing the affected part, which is a lesion, in a magnetic field environment. .
  • the affected part which is a lesion
  • a dramatic improvement in the effect of treatment can be expected.
  • the magnetic particle-containing preparation according to Embodiment 2 is particularly useful for treatments that are highly toxic, have a very narrow therapeutic area, and have to limit the administration of the drug due to side effects.
  • Embodiment 3 Next, an example of a magnetic particle-containing preparation different from that in Embodiment 2 will be described.
  • the magnetic particle-containing preparation 7 according to the second embodiment at least the drug component is encapsulated in the hollow magnetic particle 1, but the magnetic particle-containing preparation according to the third embodiment includes at least the drug in the coating layer. Is different in that
  • FIG. 7 shows a partially enlarged view of the coating layer 40m of the magnetic particle-containing preparation 7m according to the third embodiment.
  • an antitumor active substance 45 is bonded to a lipid film 41m.
  • the magnetic particle-containing preparation 7m according to Embodiment 3 is not only delivered to the tumor site for detection, but can specifically act on the tumor tissue. Therefore, it can be used as a contrast agent with excellent tumor tissue detection ability.
  • the temperature of the tumor tissue can be locally increased by thermotherapy using energy irradiation such as alternating magnetic field irradiation or ultrasonic irradiation.
  • a therapeutic agent in the magnetic particles or in the coating layer it can be used as a therapeutic agent that acts on the tumor tissue. These can be used together arbitrarily.
  • the inside of the magnetic particle-containing preparation 7m may contain a therapeutic agent as described above, or may be filled with a substance that promotes the formation of the coating layer 40m or may be hollow. Further, as the magnetic particles to be used, instead of the hollow magnetic particles 1, it is also possible to apply adhesion-type magnetic particles 2 and fusion-type magnetic particles 3.
  • the antitumor active substance 45 is bound to the coating layer 40m.
  • a pharmacologically active substance a gene transfer mediator, an immune enhancing substance, a physiologically functional substance, a cell fusion substance, and the like. It is also possible to bind selected physiologically active substances, therapeutic agents and the like to the lipid membrane 41m and the like.
  • Magnetic particles according to the present invention (hollow magnetic particles 1, adhesion-type magnetic particles 2, fusion-type magnetic particles 3) and magnetic-particle-containing preparations (magnetic particle-containing preparation 7, in addition to drug-containing magnetic particles 6
  • the association type magnetic particle-containing preparation 8 is also an example, and various modifications are possible without departing from the spirit of the present invention. Further, the present invention can be widely applied not only in the medical field but also in the electronic material field, the chemical field, and the like.
  • Example 1 Synthesis of Adhesive Magnetic Particle 2A
  • Template particles having a positive zeta potential were prepared by the following method. First, silica particles as pre-template particles (Sea Catalyst KE-P30 manufactured by Nippon Shokubai Co., Ltd., 0.64 g) and 80 ml of deionized water were placed in a 100 ml beaker and dispersed with a homogenizer for 10 minutes to obtain silica particles. An aqueous dispersion was obtained.
  • PDDA poly (diallyldimethylammonium chloride)
  • This aqueous dispersion was added to a 10 mmol / dm 3 NaCl aqueous solution, and the zeta potential of the PDDA-coated silica particles was measured at 25 ° C. with a zeta potentiometer (ELS8000) manufactured by Otsuka Electronics.
  • the zeta potential was +60 mV, and it was confirmed that the potential was reversed from the zeta potential of -30 mV of unmodified silica particles. That is, it was confirmed that the silica particles were coated with the cationic polymer PDDA.
  • the PDDA-coated silica particles prepared in this way are referred to as “PDDA / SiO 2 —OH”.
  • the contents of the flask were transferred to a 100 ml three-necked flask, 0.086 g (0.45 mmol) of iron (III) ethoxide (Alfa Aesar), 0.196 g of acetylacetonatoplatinum (II) (Sigma-Aldrich) (0.500 mmol) was added, and the mixture was placed in a nitrogen gas atmosphere, and then stirred at room temperature for 24 hours. While stirring at a rotation speed of 200 rpm in a nitrogen gas atmosphere, the temperature was raised from room temperature to 230 ° C. at 10 ° C. per minute and heated at 230 ° C. for 2 hours.
  • FIG. 8A shows a transmission electron microscope image of FePt nanoparticle-adsorbed PDDA-coated silica particles (adhesive magnetic particles).
  • Example 2 When synthesizing FePt nanoparticle-adsorbed PDDA-coated silica particles (adhesive magnetic particles), the amount of PDDA / SiO 2 —OH aqueous dispersion added was 10 ml (content of SiO 2 calculated by calculation; An aqueous dispersion of FePt nanoparticle-adsorbed PDDA-coated silica particles was prepared in the same manner as in Example 1 except that the amount was changed to 0.08 g). The yield of FePt nanoparticle-adsorbed PDDA-coated silica particles was 0.056 g.
  • FIG. 8B shows a transmission electron microscope image of the FePt nanoparticle-adsorbed PDDA-coated silica particles obtained in Example 2.
  • Example 3 When synthesizing FePt nanoparticle-adsorbed PDDA-coated silica particles (adhesive magnetic particles), the amount of PDDA / SiO 2 —OH aqueous dispersion added was 25 ml (content of SiO 2 calculated by calculation; An aqueous dispersion of FePt nanoparticle-adsorbed PDDA-coated silica particles was prepared in the same manner as in Example 1 except that the amount was changed to 0.2 g). The yield of FePt nanoparticle-adsorbed PDDA-coated silica particles was 0.082 g.
  • FIG. 8C shows a transmission electron microscope image of the FePt nanoparticle-adsorbed PDDA-coated silica particles obtained in Example 3.
  • Example 4 When synthesizing FePt nanoparticle-adsorbed PDDA-coated silica particles (adhesive magnetic particles), the amount of PDDA / SiO 2 —OH aqueous dispersion added was 2.5 ml (contained by calculation of SiO 2 content) An aqueous dispersion of FePt nanoparticle-adsorbed PDDA-coated silica particles was prepared in the same manner as in Example 1 except that the amount was changed to 0.02 g). The yield of FePt nanoparticle-adsorbed PDDA-coated silica particles was 0.044 g.
  • FIG. 8D shows a transmission electron microscope image of the FePt nanoparticle-adsorbed PDDA-coated silica particles obtained in Example 4.
  • Example 5 When synthesizing FePt nanoparticle-adsorbed PDDA-coated silica particles (adhesive magnetic particles), the amount of PDDA / SiO 2 —OH aqueous dispersion added was 1 ml (content of SiO 2 calculated by calculation; An aqueous dispersion of FePt nanoparticle-adsorbed PDDA-coated silica particles was prepared in the same manner as in Example 1 except that the amount was changed to 0.008 g). The yield of FePt nanoparticle-adsorbed PDDA-coated silica particles was 0.032 g.
  • FIG. 8E shows a transmission electron microscope image of the FePt nanoparticle-adsorbed PDDA-coated silica particles obtained in Example 5.
  • Example 6 1.6g silica particles (Nippon Shokubai Co., Ltd. Seahoster KE-P30, diameter 0.28 ⁇ m) and 80ml ethanol are placed in a 100ml beaker and dispersed with a homogenizer for 10 minutes.
  • APTE 3-aminopropyltriethoxysilane
  • FIG. 8F shows a transmission electron microscope image of the FePt nanoparticle-adsorbed APTE-coated silica particles obtained in Example 6.
  • Example 1 (Comparative Example 1) Instead of adding 5 ml of the PDDA / SiO 2 —OH aqueous dispersion in Example 1 (content of SiO 2 calculated by calculation; 0.04 g), silica particles (Seahoster KE-P30 manufactured by Nippon Shokubai Co., Ltd.) The aqueous dispersion of the FePt nanoparticle adsorbed APTE-coated silica particles was prepared in the same manner as in Example 1 except for 5 ml of the aqueous dispersion of 5) (content of SiO 2 obtained by calculation; 0.04 g).
  • FIG. 17A shows a transmission electron microscope image of the silica particles obtained in Comparative Example 1.
  • FIG. This shows that FePt nanoparticles are not adsorbed on the surface of silica fine particles exhibiting a negative zeta potential, and adhesion-type magnetic particles cannot be obtained.
  • Example 2 The same method as in Example 6, except that 100 mg of 3-mercaptopropyltriethoxysilane (hereinafter abbreviated as "MPTE") was used instead of 3-aminopropyltriethoxysilane in Example 6.
  • MPTE 3-mercaptopropyltriethoxysilane-coated silica particles
  • the zeta potential was ⁇ 20 mV.
  • an aqueous dispersion of FePt nanoparticle-adsorbed MPTE-coated silica particles was prepared by the same method as in Example 1.
  • FIG. 17B shows a transmission electron microscope image of the FePt nanoparticle-adsorbed MPTE-coated silica particles obtained in Comparative Example 2.
  • Example 1 it can be seen that the black FePt nanoparticles are adsorbed on the silica particles of the pre-template particles as the core material.
  • Comparative Example 1 it can be seen that the FePt nanoparticles are not attached to the silica particles. This indicates that the template particles and the metal-based nanoparticles need to have different polarities.
  • Comparative Example 2 it turns out that the FePt nanoparticle has not adhered to the thiol modification silica particle. In the case of thiol modification with a negative zeta potential, it can be seen that adhesion-type magnetic particles cannot be obtained.
  • Example 7 Synthesis of Hollow Magnetic Particle 1A
  • the aqueous dispersion of FePt nanoparticle-adsorbed PDDA-coated silica particles (adhesive magnetic particles) obtained in Example 1 was redispersed under ultrasonic waves using an ultrasonic cleaner. 5 ml out of 20 ml was placed in a sealed supercritical reaction vessel TSC-0011 (volume 11 ml) manufactured by Pressure Glass Industrial Co., Ltd. and sealed with a torque wrench.
  • the sealed reaction vessel was placed in an electric furnace preheated to 400 ° C. and subjected to heat treatment for 3 hours under the condition of a pressure of about 37 MPa.
  • the reaction vessel was placed in a water bath and quenched. After opening the stopper of the reaction vessel and applying ultrasonic treatment, an aqueous dispersion of FePt-hollow magnetic particles (magnetic particles 1A) was obtained.
  • FIG. 9A shows a 100 keV transmission electron microscope (Hitachi H7100 transmission electron microscope) image of FePt-hollow magnetic particles (magnetic particles 1A). From the figure, it can be seen that the silica particles of the core material are dissolved and removed. It can also be seen that the FePt nanoparticles are fused together to form a magnetic cage skeleton 10A having voids on the surface.
  • the transmission electron microscope image of FIG. 9B is an image obtained by projecting hollow magnetic particles onto a two-dimensional plane. This was subjected to image processing with a 100 keV transmission electron microscope (Hitachi H7100 transmission electron microscope) and binarized into black and white. At this time, the lowest brightness and the highest brightness are standardized, and those whose brightness is 80% or more are defined as white, and the electron beam transmission part (the above-described black and white binarization) with respect to the area of the outline (circular) shape The percentage of the area of the area determined to be white was calculated. As a result, the total area in the outline of the hollow magnetic particles was 179,206 pixels, the transmission part was 4977 pixels, and the porosity was calculated to be 2.78%.
  • Example 3 An aqueous dispersion of FePt nanoparticle-adsorbed PDDA-coated silica particles (adhesive magnetic particles) obtained in Example 3 was prepared, and FePt-hollow magnetic particles (magnetic particles 1B) were prepared in the same manner as in Example 7. An aqueous dispersion was obtained.
  • FIG. 10A shows a 100 keV transmission electron microscope image of FePt-hollow magnetic particles (magnetic particles 1A). From the figure, it can be seen that the silica particles of the core material are dissolved and removed. It can also be seen that the FePt nanoparticles are fused together to form a magnetic cage skeleton 10B having voids on the surface.
  • the transmission electron microscope image in FIG. 10B is an image obtained by projecting hollow magnetic particles onto a two-dimensional plane.
  • the porosity of the magnetic particles was calculated by the same method as in Example 7. As a result, the total area in the outline of the hollow magnetic particles was 170349 pixels, the transmission part was 17367 pixels, and the porosity was calculated to be 10.2%.
  • Example 9 Preparation of magnetic particle-containing preparation
  • Various anticancer agents were enclosed in the FePt-hollow magnetic particles (magnetic particles 1A) obtained in Example 7 above, and the magnetic rod-like skeleton was sealed with a lipid membrane to prepare ferromagnetic nanoparticles for cancer treatment.
  • the hydrothermally treated FePt-hollow magnetic particle dispersion was dialyzed and purified using distilled water. After adding various anticancer agents to the obtained FePt-hollow magnetic particle dispersion, a chloroform solution in which phosphatidylcholine as a phospholipid was dissolved was further added.
  • a ferromagnetic nanoparticle for cancer treatment (magnetic particle-containing preparation 7A) having a magnetic rod-shaped skeleton covered with phospholipid and having an anticancer agent inside the skeleton was prepared.
  • FIG. 11A shows a transmission electron microscope image of a magnetic particle-containing preparation 7A, which is a nanoparticle for cancer treatment, in which an anticancer drug doxorubicin is sealed in an FePt-hollow magnetic particle (magnetic particle 1A), and FIG. An enlarged transmission electron microscope image near the coating layer 40A made of a lipid membrane is shown.
  • the scale bar in these figures corresponds to 20 nm.
  • the average outer diameter was 352 nm
  • the average lipid film thickness was 8 nm
  • the magnetic skeleton thickness was 18 nm
  • the average inner diameter was 300 nm.
  • the volume inside the magnetic rod-like skeleton 10A was determined to be 61.9% with respect to the volume of the magnetic particle-containing preparation 7A.
  • the drug loading rate was 61.9%.
  • the porosity of the magnetic rod-like skeleton 10A was calculated as 0%. Therefore, it is considered that the drug loading rate is actually higher than that described above.
  • the results of magnetic induction of the magnetic particle-containing preparation 7A which is the above-mentioned cancer treatment nanoparticle, will be described.
  • a well (A) of a 96-well plate 200 ⁇ l of a nanoparticle dispersion for cancer treatment was placed, a 500 mT neodymium magnet was placed on the bottom of the well (A), and after 5 minutes, 100 ⁇ l of the supernatant was transferred to the well (B).
  • the magnetic accumulation characteristics of the magnetic particle-containing preparation 7A in the well (A) were confirmed by observing the plate at an excitation wavelength of 480 nm and a fluorescence wavelength of 580 nm of doxorubicin (see FIG. 12).
  • FePt-hollow magnetic particles (magnetic particles 1A) obtained in Example 7 were dialyzed and purified using distilled water, washed with ethanol and freeze-dried.
  • an aqueous solution of anticancer drug doxorubicin 100 ⁇ g / ml
  • the air inside the hollow magnetic particles was completely replaced with an aqueous doxorubicin solution.
  • a chloroform solution in which phosphatidylcholine, which is a phospholipid, was dissolved was added.
  • a ferromagnetic nanoparticle for cancer treatment (magnetic particle-containing preparation 7A) having a magnetic rod-shaped skeleton covered with phospholipid and having an anticancer agent inside the skeleton was prepared. Furthermore, the ferromagnetic nanoparticles for cancer treatment covered with phospholipids were accumulated by magnetic force, and the liposomes consisting only of phospholipids without the magnetic rod-like skeleton were removed and purified.
  • the containing cancer nanoparticle dispersion for cancer treatment was added to the cells. The concentration was adjusted by dilution with 10% fetal bovine serum / cell culture medium RPMI 1640. Next, gastric cancer cell line MKN-45 and this cancer therapeutic ferromagnetic nanoparticle were incubated for 15 minutes.
  • a neodymium magnet was installed on the bottom of the container. After 15 minutes, the magnet was removed, and the cells were washed with the culture medium, and then replaced with the culture medium and cultured. The total time for incubation and culture was 4 days.
  • Example 3 The method and conditions were the same as in Example 10 except that no neodymium magnet was installed on the bottom of the container.
  • Example 4 The same as Example 10 except that the anticancer agent doxorubicin was not added to the FePt-hollow magnetic particle dispersion.
  • Comparative Example 5 The method and conditions were the same as in Comparative Example 4 except that no neodymium magnet was installed on the bottom of the container.
  • FIG. 13A shows a graph of the average value and standard deviation of the cell survival rate% when the experiments of Example 10 and Comparative Examples 3 to 5 were performed 6 times, respectively. From FIG. 13A, in Example 10, the cell survival rate was 25.7%, while in Comparative Examples 3 to 5, the cell survival rate was 90% or more. That is, in Example 10, it was found that an excellent antitumor effect was exhibited against the gastric cancer cell line MKN-45. In Comparative Example 3, the cell viability was high although it was the same as Example 10 except that no neodymium magnet was installed. From these results, the efficient accumulation effect and the excellent antitumor effect by the excellent magnetic accumulation property of the ferromagnetic nanoparticles for cancer treatment according to Example 10 are clear.
  • Example 6 A reference solution without using anticancer drug doxorubicin without using ferromagnetic nanoparticles for cancer treatment was incubated with gastric cancer cell line MNK-45. Incubation time was 4 days. Moreover, the neodymium magnet was not installed in the bottom face of the container. Other methods and conditions were the same as in Example 10 above.
  • FIG. 13B shows a graph of the average value and standard deviation of the cell viability% when the experiment of each of the samples of Example 10 and Comparative Examples 6 to 10 was performed six times.
  • the cell viability of the reference of Comparative Example 6 was about 100%.
  • the cell survival rate was 90% or more.
  • Comparative Example 7 the cell survival rate was 90% or more.
  • Comparative Example 8 and 9 an antitumor effect is observed.
  • Comparative Example 10 it can be seen from Comparative Example 10 that even when the doxorubicin content is the same as that in Example 10, an antitumor effect can be observed by increasing the incubation time.
  • the method of increasing the drug dose and the method of extending the drug administration time have a large burden on the living body.
  • the ferromagnetic nanoparticles for cancer treatment of Example 10 according to the present invention the cell viability can be reduced in a short time with a small amount of drug by utilizing the magnetic accumulation characteristics.
  • the magnetic particles of the present invention are applied to biotechnology fields such as gene introduction into cells and animal tissues by holding a drug by inclusion, etc., and treatment of diseases by delivering genes / drugs to affected areas. be able to.
  • the magnetic particle of this invention can be utilized suitably for the treatment of the disease by the thermotherapy by an alternating magnetic field.
  • the magnetic particles of the present invention contain a radioisotope or a contrast agent accumulated in the affected area, which is detected by the micro magnetic detection device of the particle accumulated in the affected area, or detected by magnetic resonance imaging (MRI). It can also be used for diagnosis of diseases by detecting magnetic particles.
  • the magnetic particles of the present invention include a test agent for influenza, a diagnostic agent carrier, a bacterial separation simple substance, a cell separation carrier, a nucleic acid separation and purification carrier, a protein separation and purification carrier, an immobilized enzyme carrier, a magnetic toner, a magnetic ink, and a magnetic paint. Further, it can be applied to catalyst carriers, catalysts, fuel cells and the like.

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Abstract

La présente invention concerne des particules magnétiques d'une structure nouvelle et un procédé de production desdites particules magnétiques. L'invention concerne également une préparation médicinale d'une structure nouvelle, ladite préparation contenant lesdites particules magnétiques. La préparation médicinale contenant les particules magnétiques (7) comprend : des particules magnétiques (1) qui sont creuses à l'intérieur et constituées d'un squelette en forme de cage magnétique composé d'un objet fritté obtenu à partir de nanoparticules magnétiques y compris des nanoparticules métalliques comprenant l'un quelconque de Fe, Co et Ni et dans lesquelles la porosité obtenue par projection de l'objet fritté sur un plan bidimensionnel, traitement de l'image projetée en termes de transmission d'images par microscope électronique, et détermination de la proportion des parties transparentes par rapport à la surface totale à l'intérieur du contour de l'objet fritté représente 1 à 50 % ; et une couche d'enrobage (40) avec laquelle au moins une partie de la couche de surface de chaque particule magnétique (1) est enrobée. La préparation médicinale contient un médicament (30) au sein du squelette en forme de cage magnétique (10) et/ou dans la couche d'enrobage (40).
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JP2015092464A (ja) * 2013-10-04 2015-05-14 国立大学法人東京工業大学 ガス拡散電極用触媒層、その製造方法、膜電極接合体および燃料電池
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CN103076415A (zh) * 2011-11-15 2013-05-01 南昌大学 一种富集水产品中天然四环素类抗生素的方法
JP2015530561A (ja) * 2012-07-09 2015-10-15 財團法人國家衛生研究院Ｎａｔｉｏｎａｌ Ｈｅａｌｔｈ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅｓ 透過型電子顕微鏡のための標本調製
JP2015092464A (ja) * 2013-10-04 2015-05-14 国立大学法人東京工業大学 ガス拡散電極用触媒層、その製造方法、膜電極接合体および燃料電池
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JP2018514754A (ja) * 2015-03-18 2018-06-07 フォルシュングスツェントルム・ユーリッヒ・ゲゼルシャ タンパク質ミスフォールディング病のタンパク質凝集体を検出するための標準体の製造方法ならびに標準体およびその使用
CN106623974A (zh) * 2016-12-19 2017-05-10 天津大学 一种具有类漆酶活性的铂纳米颗粒及制备方法及用途
CN108325553A (zh) * 2018-02-02 2018-07-27 河南科技大学 一种具有包覆磁芯结构的氮化钛微球催化剂的制备方法
JP2019153478A (ja) * 2018-03-05 2019-09-12 地方独立行政法人神奈川県立産業技術総合研究所 ナノ粒子連結触媒およびその製造方法、ガス拡散電極用触媒層、膜電極接合体並びに燃料電池
JP7113422B2 (ja) 2018-03-05 2022-08-05 地方独立行政法人神奈川県立産業技術総合研究所 ナノ粒子連結触媒の製造方法
CN109796019A (zh) * 2019-02-21 2019-05-24 华中科技大学 一种空心二氧化硅纳米球及其制备方法和应用
CN112426980A (zh) * 2020-11-18 2021-03-02 四川大学 磁响应二维材料气凝胶微球及其制备方法
JP2022113151A (ja) * 2021-01-22 2022-08-03 ウルトラ ヴイ カンパニー リミテッド フィラー用生分解性高分子微粒子、その製造方法及びこれを含む凍結乾燥体並びにフィラー用注射剤
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