US20120269896A1 - Magnetic iron oxide fine particles, and magnetic particle-containing water dispersion and process for producing the same - Google Patents
Magnetic iron oxide fine particles, and magnetic particle-containing water dispersion and process for producing the same Download PDFInfo
- Publication number
- US20120269896A1 US20120269896A1 US13/510,651 US201013510651A US2012269896A1 US 20120269896 A1 US20120269896 A1 US 20120269896A1 US 201013510651 A US201013510651 A US 201013510651A US 2012269896 A1 US2012269896 A1 US 2012269896A1
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- US
- United States
- Prior art keywords
- iron oxide
- magnetic
- water dispersion
- fine particles
- oxide fine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 239000006185 dispersion Substances 0.000 title claims abstract description 80
- 239000006249 magnetic particle Substances 0.000 title claims abstract description 64
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 title claims description 170
- 230000005291 magnetic effect Effects 0.000 title claims description 98
- 239000010419 fine particle Substances 0.000 title claims description 74
- 238000000034 method Methods 0.000 title claims description 29
- 239000007864 aqueous solution Substances 0.000 claims abstract description 56
- 229920000642 polymer Polymers 0.000 claims abstract description 38
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002244 precipitate Substances 0.000 claims abstract description 16
- 239000011163 secondary particle Substances 0.000 claims abstract description 16
- 239000011164 primary particle Substances 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000006228 supernatant Substances 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 238000000502 dialysis Methods 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 229920002125 Sokalan® Polymers 0.000 claims description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 13
- 239000004584 polyacrylic acid Substances 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 18
- 238000003745 diagnosis Methods 0.000 abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 abstract description 5
- 239000002245 particle Substances 0.000 description 103
- 230000005415 magnetization Effects 0.000 description 15
- 239000000084 colloidal system Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000002776 aggregation Effects 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 239000002131 composite material Substances 0.000 description 7
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 6
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 229910052596 spinel Inorganic materials 0.000 description 6
- 239000011029 spinel Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000002296 dynamic light scattering Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 238000000975 co-precipitation Methods 0.000 description 4
- 238000002591 computed tomography Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003302 ferromagnetic material Substances 0.000 description 4
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 238000002595 magnetic resonance imaging Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000015 thermotherapy Methods 0.000 description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000010908 decantation Methods 0.000 description 3
- 230000005294 ferromagnetic effect Effects 0.000 description 3
- 229960002089 ferrous chloride Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 229910021506 iron(II) hydroxide Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000011790 ferrous sulphate Substances 0.000 description 2
- 235000003891 ferrous sulphate Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000020169 heat generation Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 150000002505 iron Chemical class 0.000 description 2
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 2
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 2
- 239000000696 magnetic material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000011882 ultra-fine particle Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000004438 BET method Methods 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000005325 alkali earth metal hydroxides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052598 goethite Inorganic materials 0.000 description 1
- 239000011361 granulated particle Substances 0.000 description 1
- AEIXRCIKZIZYPM-UHFFFAOYSA-M hydroxy(oxo)iron Chemical compound [O][Fe]O AEIXRCIKZIZYPM-UHFFFAOYSA-M 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 229910006297 γ-Fe2O3 Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
- C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
- C09C1/22—Compounds of iron
- C09C1/24—Oxides of iron
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- 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
- A61K47/6927—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 solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
- A61K49/0423—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
- A61K49/0428—Surface-modified nanoparticles, e.g. immuno-nanoparticles
-
- 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
- A61K49/1821—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 coated or functionalised microparticles or nanoparticles
- A61K49/1824—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 coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—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 coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1851—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 coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1854—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 coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly(meth)acrylate, polyacrylamide, polyvinylpyrrolidone, polyvinylalcohol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G49/00—Compounds of iron
- C01G49/0018—Mixed oxides or hydroxides
- C01G49/0036—Mixed oxides or hydroxides containing one alkaline earth metal, magnesium or lead
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G49/00—Compounds of iron
- C01G49/02—Oxides; Hydroxides
- C01G49/08—Ferroso-ferric oxide [Fe3O4]
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/80—Particles consisting of a mixture of two or more inorganic phases
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/12—Surface area
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/42—Magnetic properties
Definitions
- the present invention relates to a raw drug for magnetic particle-containing drugs which are used in drug delivery systems (hereinafter referred to merely as “DDS”) as a method for delivering drugs, CT (computed tomography) diagnosis used for roentgen or MRI (magnetic resonance imaging system), and various therapies such as thermotherapy. More specifically, the present invention relates to a raw drug for magnetic particle-containing drugs which aims at improving delivery directivity of the magnetic particle-containing drugs to lesioned tissues and cells, contrast sensitivity in CT diagnosis and heat generation upon thermotherapy, etc.
- DDS drug delivery systems
- Patent Document 6 a method of coating a surface of the respective particles with a surface-treating agent such as surfactants
- a method of coating a surface of the respective particles with an inorganic material such as Al and Si Patent Document 7
- a method of coating a surface of the respective particles with an organic metal polymer Patent Document 4
- a method of preparing the monodisperse aqueous solution without using any dispersant Patent Document 8
- Patent Documents 9 to 11 it has been reported that in order to facilitate bonding between the magnetic iron oxide particles and vital molecules, the surface of the respective magnetic iron oxide particles is coated with a surface-modifying molecule having a functional group such as an amino group, a carboxyl group and a sulfone group.
- the aqueous sol is mixed with respective polymers or polysaccharides.
- the resulting magnetic particles have a large particle diameter owing to aggregation thereof, or these magnetic particles are merely weakly bonded to the surface-modifying molecule so that they tend to be readily dissociated from each other in blood and deteriorated in stability upon heat sterilization and stability with time.
- the fine magnetic iron oxide particles may hardly be uniformly dispersed in the biocompatible substance and supported thereon owing to occurrence of excessive magnetic aggregation between the iron oxide particles.
- the conventional magnetic iron oxide particles used for this purpose inevitably have a large particle diameter.
- the magnetic iron oxide particles having a large particle diameter remain in vivo after therapies.
- the magnetic iron oxide particles remaining in vivo may cause side reactions such as allergy reaction.
- the conventional magnetic iron oxide particles have failed to ensure a sufficient safety upon use thereof.
- Patent Document 1 Japanese Patent Application Laid-Open (KOKAI) No. 3-128331
- Patent Document 2 Japanese Patent Application Laid-Open (KOKAI) No. 4-52202
- Patent Document 3 Japanese Patent Application Laid-Open (KOKAI) No. 7-122410
- Patent Document 4 Japanese Patent Application Laid-Open (TOKUHYO) No. 8-500700
- Patent Document 5 Japanese Patent Application Laid-Open (KOKAI) No. 11-106391
- Patent Document 6 Japanese Patent Application Laid-Open (KOKAI) No. 1-4002
- Patent Document 7 Japanese Patent Application Laid-Open (KOKAI) No. 5-310429
- Patent Document 8 Japanese Patent Application Laid-Open (KOKAI) No. 2006-28032
- Patent Document 9 Japanese Patent Application Laid-Open (KOKAI) No. 2003-112925
- Patent Document 10 PCT Pamphlet WO 95/31220
- Patent Document 11 Japanese Patent No. 4079996
- the biocompatible substance and the magnetic iron oxide fine particles are uniformly dispersed and mixed.
- the magnetic iron oxide fine particles in the raw drug is present in the form of a monodisperse colloid aqueous solution comprising the magnetic iron oxide fine particles having a fine uniform particle diameter.
- the magnetic iron oxide fine particles have a good dispersion stability in a neutral pH range.
- the magnetic particles are provided on a surface thereof with a functional group to form a strong bond to vital molecules such as antibodies.
- a technical object of the present invention is to provide a dispersed colloid aqueous solution comprising magnetic iron oxide fine particles having a uniform particle size whose surface is modified with a carboxyl group-containing polymer, and the magnetic iron oxide fine particles which are capable of readily preparing the dispersed colloid aqueous solution.
- a magnetic particle-containing water dispersion comprising magnetic iron oxide fine particles which have a primary particle diameter of 5 to 15 nm and an average secondary particle diameter of 10 to 60 nm, a surface of the respective magnetic iron oxide fine particles being coated with a carboxyl group-containing polymer (Invention 1).
- the above magnetic particle-containing water dispersion wherein the water dispersion has a zeta potential of not more than ⁇ 20 mV when a pH value of the water dispersion lies within the range of 6 to 8 (Invention 2).
- the above magnetic particle-containing water dispersion wherein the carboxyl group-containing polymer is a polyacrylic acid having a molecular weight of 1500 to 10000 (Invention 3).
- the magnetic iron oxide fine particles according to the present invention can be readily dispersed in water to form a dispersed colloid of the magnetic iron oxide fine particles.
- the magnetic particle-containing water dispersion according to the present invention is in the form of a dispersed colloid aqueous solution comprising finely divided magnetic iron oxide fine particles, and further the surface of the respective magnetic iron oxide fine particles is coated with a carboxyl group-containing polymer. Therefore, it is possible to readily produce drugs comprising a composite material formed by uniformly dispersing the magnetic iron oxide fine particles in a biocompatible substance. In addition, since the raw drug comprises no liquid medium such as a surfactant, there is caused a less adverse influence on safety in living organisms.
- the finely divided magnetic particles are formed into an aggregated state thereof in a pharmaceutical drug granulating step, the obtained granulated particles are imparted with a function as a ferromagnetic material.
- the magnetic particles are in the form of ultrafine particles and therefore can be readily excreted from living organisms after dosage thereof.
- the primary particles of the magnetic iron oxide fine particles according to the present invention have an average particle diameter of 5 nm to 15 nm.
- the average particle diameter of the primary particles of the magnetic iron oxide fine particles is less than 5 nm, the resulting particles tend to be non-crystalline or amorphous.
- the average particle diameter of the primary particles of the magnetic iron oxide fine particles is more than 15 nm, the resulting particles tend to have an excessively large coercive force and suffer from excessive magnetic aggregation, so that secondary particles thereof have a particle diameter of not less than 200 nm.
- the average particle diameter of the primary particles of the magnetic iron oxide fine particles is preferably from 5 to 12 nm and more preferably not more than 10 nm since the particles can suitably exhibit a low coercive force.
- the secondary particles of the magnetic iron oxide fine particles according to the present invention have an average particle diameter of 10 nm to 60 nm.
- the average particle diameter of the secondary particles of the magnetic iron oxide fine particles is less than 10 nm, the resulting particles tend to be deteriorated in heat generation by an alternating magnetic field when used in thermotherapy for cancers.
- the average particle diameter of the secondary particles of the magnetic iron oxide fine particles is more than 60 nm, there tends to arise such a problem that the resulting particles are hardly excreted from living organisms after dosage thereof.
- the average particle diameter of the secondary particles of the magnetic iron oxide fine particles is preferably 10 nm to 30 nm.
- the magnetic iron oxide fine particles according to the present invention are in the form of a spinel type ferromagnetic material represented by the compositional formula: MO.Fe 2 O 3 wherein M is a divalent metal.
- M in the above formula is Fe
- the magnetic iron oxide fine particles have a compositional formula of xFeO.Fe 2 O 3 wherein x represents a content of the divalent iron.
- the compositional formula is FeO.Fe 2 O 3 , i.e., the magnetic particles are magnetite
- the compositional formula is ⁇ -Fe 2 O 3 , i.e., the magnetic particles are maghemite.
- the spinel type iron oxide is magnetic iron oxide.
- Mg may also be selected in addition to Fe. This is because Mg has a biocompatibility.
- the other divalent metals may also be selectively used according to the applications of the magnetic particles.
- the magnetic iron oxide fine particles according to the present invention are preferably in the form of a superparamagnetic material, and preferably have a coercive force of 0 to 6.0 kA/m.
- the coercive force of the magnetic iron oxide fine particles is more preferably 0.05 to 4.0 kA/m.
- the magnetic iron oxide fine particles according to the present invention have a saturation magnetization ( ⁇ s) of 5 to 90 Am 2 /kg.
- the saturation magnetization ( ⁇ s) of the magnetic iron oxide fine particles is less than 5 Am 2 /kg, the particles tend to have poor magnetic properties. Whereas, it may be difficult to obtain spinel type iron oxide particles having a magnetization value of more than 90 Am 2 /kg.
- the saturation magnetization (us) of the magnetic iron oxide fine particles is preferably 10 to 85 Am 2 /kg.
- Examples of the carboxyl group-containing polymer used in the present invention include many kinds of polymers such as polyacrylic acids, polymethacrylic acids and polyamino acids. Among these polymers, preferred are polyacrylic acids in view of a particle size and a particle size distribution of the resulting magnetic iron oxide fine particles.
- the carboxyl group-containing polymer preferably has a molecular weight of 1500 to 10000.
- the molecular weight of the carboxyl group-containing polymer is less than 1500, the resulting magnetic particles tend to have an excessively large primary particle diameter.
- the molecular weight of the carboxyl group-containing polymer is more than 10000, the magnetic particles tend to be aggregated together, so that the secondary particles thereof tend to have a large particle diameter.
- the magnetic particle-containing water dispersion according to the present invention has a zeta potential of not more than ⁇ 20 mV when a pH value of the water dispersion lies in the range of 6 to 8.
- a zeta potential of the water dispersion as measured when the pH value thereof lies within the range of 6 to 8 is more than ⁇ 20 mV, the resulting particles tend to have problems such as poor stability with time.
- the isoelectric point of the magnetic particle-containing water dispersion according to the present invention is preferably 2.0 to 3.0.
- the concentration of the magnetic iron oxide fine particles in the magnetic particle-containing water dispersion according to the present invention is preferably 5 to 50 mg/mL.
- concentration of the magnetic iron oxide fine particles in the water dispersion is more than 50 mg/mL, since a van der Waals force acting between the particles tends to become too large, the particles tend to be undesirably readily aggregated together.
- concentration of the magnetic iron oxide fine particles in the water dispersion is less than 5 mg/mL, such a thin water dispersion tends to be unpractical.
- the concentration of the magnetic iron oxide fine particles in the magnetic particle-containing water dispersion is more preferably 10 to 40 mg/mL.
- the magnetic iron oxide fine particles according to the present invention may be in the form of a composite material comprising, in addition to the magnetic particles, phospholipids, polysaccharides, proteins or dextrins.
- the magnetic iron oxide fine particles according to the present invention can be synthesized by an aqueous solution reaction (also referred to as a wet method) using an iron salt aqueous solution and an alkali aqueous solution.
- the aqueous solution reaction may be frequently carried out by a co-precipitation method and an oxidation reaction method.
- the co-precipitation method is the reaction in which when an alkali aqueous solution is added to a mixed aqueous solution comprising 1 mol of a ferrous (Fe(II)) salt aqueous solution and 2 mol of a ferric (Fe(III)) salt aqueous solution while stirring, the Fe(II) and 2Fe(III) are subjected to co-precipitation reaction therebetween to produce magnetite particles which are in the form of black spinel type magnetic iron oxide.
- Mg as the divalent metal other than Fe
- the size of the particles produced by the above reaction can be controlled by varying reaction conditions such as concentrations of the iron salts and a mixing temperature. Therefore, by using suitable combination of these reaction conditions, it is possible to produce magnetic iron oxide fine particles having a desired particle size.
- the oxidation reaction method is the reaction in which an alkali aqueous solution is added to a ferrous salt aqueous solution to produce a ferrous hydroxide colloid, and then an oxygen-containing gas such as air is passed through the ferrous hydroxide colloid-containing aqueous solution while heating and stirring to subject the ferrous hydroxide colloid to oxidation reaction, thereby producing magnetite particles as black magnetic iron oxide.
- an oxygen-containing gas such as air is passed through the ferrous hydroxide colloid-containing aqueous solution while heating and stirring to subject the ferrous hydroxide colloid to oxidation reaction, thereby producing magnetite particles as black magnetic iron oxide.
- the divalent metal other than Fe is added, spinel iron oxide particles comprising the metal added are obtained.
- the oxidation reaction of the above ferrous salt is carried out in the presence of a polyacrylic acid, even when a polyacrylic acid aqueous solution is added and reacted in the course of the above reaction, it is not possible to prepare the magnetic particle-containing water dispersion comprising the magnetic iron oxide fine particles having a particle size distribution as aimed by the present invention. Further, the oxidation reaction tends to proceed excessively in the course of the purification treatment, so that the color of the resulting particles is not black as a color of magnetite, but tends to be tinted with yellow to brown.
- an aqueous solution in which the carboxyl group-containing polymer such as a polyacrylic acid is dissolved is heated to a predetermined temperature, and then a mixed aqueous solution comprising the ferrous salt and the ferric salt and an alkali aqueous solution such as an aqueous ammonia solution are quickly added to the above solution to react with each other.
- a mixed aqueous solution comprising the ferrous salt and the ferric salt and an alkali aqueous solution such as an aqueous ammonia solution are quickly added to the above solution to react with each other.
- ferrous salt aqueous solution used in the present invention examples include a ferrous sulfate aqueous solution, a ferrous chloride aqueous solution and the like.
- ferric salt aqueous solution used in the present invention examples include a ferric sulfate aqueous solution, a ferric chloride aqueous solution and the like.
- alkali aqueous solution used in the present invention examples include an aqueous ammonia, aqueous solutions of alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and aqueous solutions of alkali earth metal hydroxides such as magnesium hydroxide and calcium hydroxide.
- the aqueous ammonia is preferably used.
- the alkali aqueous solution may be added in an equivalent amount based on the ferrous iron and the ferric iron.
- the carboxyl group-containing polymer such as a polyacrylic acid is previously dissolved in the reaction solution.
- the carboxyl group-containing polymer is allowed to be previously present in the reaction solution, the surface of the respective magnetite particles produced by the reaction is immediately coated with the polyacrylic acid, so that aggregation between the particles can be prevented.
- the concentration of the carboxyl group-containing polymer being present in the reaction solution may be adjusted such that a molar ratio of the polymer to whole iron (Fe) in the reaction solution is 0.3 to 3.0.
- concentration of the polymer is less than 0.3, the concentration of the polymer tends to be too dilute, so that the magnetic iron oxide fine particles may fail to be coated with the polymer to such an extent that aggregation between the particles can be prevented.
- concentration of the polymer is more than 3.0, the effect of addition of the polymer tends to be saturated, and the use of such a high concentration of the polymer is therefore meaningless.
- the concentration of the carboxyl group-containing polymer is preferably 0.8 to 2.5 in terms of a molar ratio to the whole Fe.
- the reaction temperature used in the present invention is preferably in the range of 90 to 100° C.
- the reaction temperature is lower than 90° C.
- goethite tends to be included in the resulting particles.
- magnetite particles may be produced, but such a high reaction temperature tends to need use of a special apparatus such as an autoclave, resulting in industrially disadvantageous process.
- the magnetic particle-containing water dispersion is washed with water in the following manner. That is, the solution obtained after the reaction is cooled to room temperature and then transferred into a beaker, etc., and an almost equal amount of ethanol is added to the reaction solution while stirring until producing a precipitate. After removing a supernatant liquid from the reaction solution, ion-exchanged water is added to the precipitate to disperse the precipitate therein. Ethanol is added again to the resulting dispersion, and then the dispersion is subjected to centrifugal separation to remove a supernatant liquid therefrom. The above procedure is repeated, and the finally obtained precipitate is dispersed in ion-exchanged water. If required, the resulting water dispersion is concentrated using an evaporator.
- the water dispersion is subjected to dialysis using a dialysis membrane in order to remove water-solubilized salts therefrom.
- a supernatant liquid is recovered using a centrifugal separator to remove the remaining aggregated particles therefrom.
- the magnetic particle-containing water dispersion recovered as the supernatant liquid is allowed to stand in a refrigerator maintained at a temperature of ⁇ 20° C. or lower for 5 hr or longer and thereby frozen, and the thus frozen product is freeze-dried under reduced pressure to obtain magnetic iron oxide fine particles according to the present invention.
- the above magnetic particle-containing water dispersion is further diluted to control a concentration thereof to 5 to 50 mg/mL, thereby obtaining a magnetic particle-containing water dispersion in which the magnetic iron oxide fine particles are dispersed in ion-exchanged water.
- the thus obtained magnetic iron oxide fine particles may also be combined with phospholipids, polysaccharides, proteins or dextrins to form a composite material thereof.
- the thus obtained composite material can be used in various applications.
- the composite material may be used in DDS as a method for delivering drugs, CT diagnosis used in roentgen and MRI (magnetic resonance imaging system), and various therapies such as thermotherapy.
- the magnetic particle-containing water dispersion comprising superparamagnetic iron oxide fine particles whose surface is coated with the carboxyl group-containing polymer can be stably dispersed under the specific conditions as described herein.
- a material capable of exhibiting a superparamagnetism is a ferromagnetic material having no coercive force (zero coercive force). That is, the large ferromagnetic particles even having a single domain structure will undergo occurrence of residual magnetization after applying an external magnetic field to magnetize the particles and then releasing the magnetic field therefrom. However, when the particle diameter of the ferromagnetic particles is reduced until ultrafine particles, the coercive force thereof is reduced and finally reaches zero. As a result, although the particles are magnetized when applying an external magnetic field thereto, any residual magnetization is not generated after releasing the magnetic field therefrom. This phenomenon is caused by thermal agitation effect, and the ferromagnetic fine particles having such an effect are called superparamagnetic particles.
- the magnetic particle-containing water dispersion according to the present invention is free from aggregation therebetween even when approaching to a permanent magnet having a surface magnetic flux of 10 mT (100 gauss), and is present in the form of a monodisperse colloid aqueous solution which can be stably maintained for a long period of time. It seems that such a phenomenon is contradictory to the fact that the magnetic iron oxide fine particles are in the form of a ferromagnetic material having a saturation magnetization as large as 50 to 90 Am 2 /kg. However, the saturation magnetization represents the magnetization value not per one particle but per unit weight as measured with respect to the magnetic iron oxide fine particles in the form of a powder. Therefore, the total number of particles per unit weight is increased as the particles becomes finer, so that the magnetization value per one particle becomes smaller.
- the reason why the magnetic iron oxide fine particles are used as the magnetic particles is that the iron oxide has a good biocompatibility, and the finer particles can be more readily excreted from living organisms.
- the particle size distribution was observed using a transmission electron microscope (TEM). Further, the average particle diameter of primary particles was determined by analysis using a digitizer.
- TEM transmission electron microscope
- the average particle diameter of secondary particles was measured by a dynamic light scattering method using a particle size distribution measuring device “FPAR-1000” manufactured by Otsuka Electronics Co., Ltd.
- the specific surface area was measured by BET method.
- the magnetic properties of the particles were measured using a vibration sample type magnetometer “VSM” by applying a magnetic field of 796 kA/m (10 kOe) thereto.
- the zeta potential and isoelectric point were measured using “ELS-6000” manufactured by Otsuka Electronics Co., Ltd.
- a 1000 mL reaction container equipped with a stirrer and a heater was used.
- raw iron salt materials and sodium hydroxide used therein both were guaranteed reagents, and ion-exchanged water was used as water.
- the reaction container was charged with 7.83 g of polyacrylic acid having a molecular weight of 5000 and 713.2 mL of ion-exchanged water, and while blowing a nitrogen gas into the reaction container, the contents of the reaction container were heated as such to 95° C.
- 10 mL of a 1.6 mmol/L ferrous sulfate aqueous solution and 10 mL of a 3.2 mmol/L ferric chloride aqueous solution were charged into the reaction container (COOH/Fe ratio: 2.27), and further 59.4 mL of a 14.8 mmol/L aqueous ammonia were added to the reaction container.
- the contents of the reaction container were reacted with each other for 2 hr while stirring.
- the resulting aqueous solution was cooled to 65° C.
- the obtained reaction solution was concentrated using an evaporator to reduce its volume to about 100 mL.
- the concentrated reaction solution was cooled to room temperature and then transferred to beaker, and ethanol was added in an almost equal amount thereto while stirring by a stirrer until producing a precipitate.
- ion-exchanged water was added to the remaining precipitate such that the total amount of the resulting mixture was about 100 g, and the mixture was dispersed while stirring.
- the resulting dispersion was treated using a centrifugal separator at 1000 rpm for 10 min. After removing a supernatant liquid from the obtained reaction solution, the above procedure was repeated again, and the finally obtained precipitate was dispersed in ion-exchanged water. Further, the resulting dispersion was concentrated using an evaporator to reduce its weight to about 40 g.
- a part of the thus obtained colloid aqueous solution was sampled and subjected to water-washing and filtration to obtain a paste.
- the thus obtained paste was freeze-dried to obtain particles.
- the particles had a BET specific surface area of 230 m 2 /g, an average primary particle diameter of 5 nm as measured by TEM, and an average secondary particle diameter of 17.3 nm as measured by a dynamic light scattering method.
- the obtained particles were magnetic iron oxide fine particles having magnetic properties including a saturation magnetization ( ⁇ s) of 13 Am 2 /kg and a coercive force (Hc) of 0.35 kA/m.
- the particles were purified using a dialysis membrane.
- the resulting dialyzate was concentrated using an evaporator to reduce its volume to 200 mL, and the concentrated solution was subjected to centrifugal separation at 12000 G for 30 min to recover a supernatant liquid therefrom. In the above procedure, aggregated particles were removed. Thus, the black colloid aqueous solution was purified.
- the concentration of the thus obtained magnetic particle-containing water dispersion was 10 mg/mL, and the pH value of the magnetic particle-containing water dispersion was 6.5. Further, it was confirmed that the zeta potential of the water dispersion was ⁇ 34 mV as measured at a pH of 7.0, and the isoelectric point thereof was 2.5.
- the reaction was conducted in the same manner as defined in Example 1 except for using a polyacrylic acid having a molecular weight of 1800, thereby obtaining a colloid solution.
- the particles had a BET specific surface area of 165 m 2 /g, an average primary particle diameter of 7 nm as measured by TEM, and an average secondary particle diameter of 56 nm as measured by a dynamic light scattering method. Further, it was confirmed that the obtained particles were magnetic iron oxide fine particles having magnetic properties including a saturation magnetization (us) of 32 Am 2 /kg and a coercive force (Hc) of 0.65 kA/m.
- the dispersed particles were subjected to purification step in the same manner as defined in Example 1, thereby obtaining a magnetic particle-containing water dispersion.
- the concentration of the thus obtained magnetic particle-containing water dispersion was 10 mg/mL, and the pH value of the magnetic particle-containing water dispersion was 6.5. Further, it was confirmed that the zeta potential of the water dispersion was ⁇ 31 mV as measured at a pH of 7.0, and the isoelectric point thereof was 2.6.
- a 1000 mL flask was charged with an aqueous solution previously prepared by mixing 60 g of a 13.9 mol/L NaOH aqueous solution with 530 g of ion-exchanged water and then heating the resulting mixture to 80° C. Then, 108.4 g of a 0.8 mmol/L ferrous chloride aqueous solution and 80 g of a 2.5 mmol/L ferric chloride aqueous solution were mixed with and added to the aqueous solution previously charged into the flask.
- the flask was charged with 60 g of an aqueous solution in which 12.1 g of a polyacrylic acid having a molecular weight of 5000 were dissolved, and the contents of the flask were reacted with each other at the same temperature for 1 hr. Thereafter, ion-exchanged water was added to the flask, and a supernatant liquid was removed by decantation from the reaction solution. This procedure was repeated to remove water-solubilized salts from the dispersion.
- a part of the thus obtained magnetic particle-containing dispersion was sampled and subjected to water-washing and filtration to obtain a paste.
- the thus obtained paste was freeze-dried to obtain particles.
- the particles had a BET specific surface area of 176 m 2 /g, an average primary particle diameter of 8 nm as measured by TEM, and an average secondary particle diameter of 120 nm as measured by a dynamic light scattering method.
- the obtained particles were apparently in the form of aggregated particles.
- the obtained particles had magnetic properties including a saturation magnetization ( ⁇ s) of 26.3 Am 2 /kg and a coercive force (Hc) of 0.92 kA/m.
- the dispersed particles were subjected to purification step in the same manner as defined in Example 1, thereby obtaining a magnetic particle-containing water dispersion.
- the concentration of the thus obtained magnetic particle-containing water dispersion was 10 mg/mL, and the pH value of the magnetic particle-containing water dispersion was 7.3. Further, it was confirmed that the zeta potential of the water dispersion was ⁇ 12 mV as measured at a pH of 7.0, and the isoelectric point thereof was 5.2.
- a 300 mL flask was charged with 50 mL of a 0.1 mol/L ferrous chloride aqueous solution and then with 0.09 g of a polyacrylic acid having a molecular weight of 1800.
- 11 mL of a 0.7 mol/L KOH aqueous solution was added to the flask to produce a precipitate of iron hydroxide.
- 50 mL of an aqueous solution comprising 0.035 mL of hydrogen peroxide was added to the flask at a rate of 33 mL/h.
- the contents of the flask were reacted with each other for 2 hr, and then ion-exchanged water was added thereto to subject the resulting dispersion to decantation.
- the above decantation was repeated to remove water-solubilized salts therefrom.
- a part of the thus obtained magnetic particle-containing dispersion was sampled and subjected to water-washing and filtration to obtain a paste.
- the thus obtained paste was freeze-dried to obtain particles.
- the particles had a BET specific surface area of 176 m 2 /g.
- the particles were in the form of a mixture of spherical particles and many acicular particles having an average primary particle diameter of 10 to 50 nm, and had an average secondary particle diameter of 120 nm as measured by a dynamic light scattering method.
- the obtained particles were apparently in the form of aggregated particles.
- the obtained particles had magnetic properties including a saturation magnetization (as) of 26.3 Am 2 /kg and a coercive force (Hc) of 0.92 kA/m.
- the dispersed particles were subjected to purification step in the same manner as defined in Example 1, thereby obtaining a magnetic particle-containing water dispersion.
- the concentration of the thus obtained magnetic particle-containing water dispersion was 10 mg/mL, and the pH value of the magnetic particle-containing water dispersion was 6.1. Further, it was confirmed that the zeta potential of the water dispersion was 3 mV as measured at a pH of 7.0, and the isoelectric point thereof was 6.2.
- the magnetic particle-containing water dispersion according to the present invention comprises magnetic fine particles whose surface is modified with a carboxyl group-containing polymer. Therefore, it is possible to readily produce a drug in the form of a composite material prepared by uniformly dispersing the magnetic fine particles in a biocompatible substance.
- the zeta potential of the water dispersion is not more than ⁇ 20 mV when the pH value of the water dispersion lies in a neutral range of from 6 to 8, the magnetic particles therein hardly suffer from aggregation therebetween even within living organisms and can exhibit a high stability with time.
- the magnetic fine particles of the present invention can be readily excreted from human body even after dosage thereto. Accordingly, it is possible to provide a raw drug which is free from any problems with respect to safety after dosage to human body as well as metabolism and excretion.
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JP2014156411A (ja) * | 2013-02-14 | 2014-08-28 | Toda Kogyo Corp | 複合磁性微粒子粉末、分散体 |
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2015
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US20150306246A1 (en) * | 2012-12-07 | 2015-10-29 | The Trustees Of Dartmouth College | Magnetic nanoparticles, composites, suspensions and colloids with high specific absorption rate (sar) |
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Also Published As
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JP5765520B2 (ja) | 2015-08-19 |
US20150164803A1 (en) | 2015-06-18 |
US9127168B2 (en) | 2015-09-08 |
WO2011062217A1 (ja) | 2011-05-26 |
CA2781329A1 (en) | 2011-05-26 |
EP2502882A4 (de) | 2016-01-20 |
CN102686518B (zh) | 2015-07-29 |
EP2502882B1 (de) | 2018-05-23 |
ES2675901T3 (es) | 2018-07-13 |
EP2502882A1 (de) | 2012-09-26 |
JP2011126876A (ja) | 2011-06-30 |
CN102686518A (zh) | 2012-09-19 |
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