JP2013541509A - 酸化鉄ナノカプセル、その製造方法およびそれを含む磁気共鳴画像診断造影剤 - Google Patents
酸化鉄ナノカプセル、その製造方法およびそれを含む磁気共鳴画像診断造影剤 Download PDFInfo
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- JP2013541509A JP2013541509A JP2013525847A JP2013525847A JP2013541509A JP 2013541509 A JP2013541509 A JP 2013541509A JP 2013525847 A JP2013525847 A JP 2013525847A JP 2013525847 A JP2013525847 A JP 2013525847A JP 2013541509 A JP2013541509 A JP 2013541509A
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- Prior art keywords
- iron oxide
- solution
- dextran
- mixed
- dodecylamine
- 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.)
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 title claims abstract description 144
- 239000002088 nanocapsule Substances 0.000 title claims abstract description 52
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 42
- 239000002872 contrast media Substances 0.000 title claims abstract description 23
- 238000002595 magnetic resonance imaging Methods 0.000 title description 14
- 229940031182 nanoparticles iron oxide Drugs 0.000 claims abstract description 100
- 239000002775 capsule Substances 0.000 claims abstract description 80
- 239000000463 material Substances 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 16
- 239000003446 ligand Substances 0.000 claims abstract description 16
- 229910052742 iron Inorganic materials 0.000 claims abstract description 9
- 150000004698 iron complex Chemical class 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 72
- 229920002307 Dextran Polymers 0.000 claims description 37
- 239000002105 nanoparticle Substances 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 29
- 239000000126 substance Substances 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 22
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 22
- 239000006185 dispersion Substances 0.000 claims description 21
- 239000011259 mixed solution Substances 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 15
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 claims description 14
- 235000020778 linoleic acid Nutrition 0.000 claims description 14
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 claims description 14
- 210000004185 liver Anatomy 0.000 claims description 14
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 11
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 9
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 7
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 9
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- 238000002347 injection Methods 0.000 description 5
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- HOIQWTMREPWSJY-GNOQXXQHSA-K iron(3+);(z)-octadec-9-enoate Chemical compound [Fe+3].CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O HOIQWTMREPWSJY-GNOQXXQHSA-K 0.000 description 5
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- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
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- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
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- CCCMONHAUSKTEQ-UHFFFAOYSA-N octadecene Natural products CCCCCCCCCCCCCCCCC=C CCCMONHAUSKTEQ-UHFFFAOYSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 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 1
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Classifications
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- 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
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Abstract
【選択図】図5
Description
Claims (20)
- 鉄錯体を熱分解して、疏水性配位子が結合された酸化鉄ナノ粒子を製造するステップ、および
カルボキシメチルデキストラン−ドデシルアミンコンジュゲートまたはデキストラン−リノール酸コンジュゲートのカプセル物質に前記疏水性配位子が結合された酸化鉄ナノ粒子を封入して酸化鉄ナノカプセルを製造するステップ、
を含むことを特徴とする酸化鉄ナノカプセルの製造方法。 - a)下記の化学式1のカルボキシメチルデキストラン−ドデシルアミンコンジュゲートまたは下記の化学式2のデキストラン−リノール酸コンジュゲートであるカプセル物質を製造するステップと、
b)鉄を中心原子とし、C4〜C25を含む疎水性有機酸基が配位子として結合している鉄錯体を熱分解して、疏水性配位子が結合された酸化鉄ナノ粒子を製造するステップと、
c)前記カプセル物質を緩衝溶液に溶解してカプセル物質水溶液を製造し、前記酸化鉄ナノ粒子を非極性有機溶媒に分散させてナノ粒子分散液を製造するステップと、
d)前記カプセル物質水溶液に前記ナノ粒子分散液を滴下し攪拌して、複数個の酸化鉄ナノ粒子がカプセル物質に封入された酸化鉄ナノカプセル分散液を製造するステップ、および
e)揮発を利用して、前記d)ステップの酸化鉄ナノカプセル分散液に含まれた非極性有機溶媒を除去して、酸化鉄ナノカプセル水分散液を製造するステップ、
を含むことを特徴とする、請求項1に記載の酸化鉄ナノカプセルの製造方法。
(化学式1)
(化学式2)
(前記化学式1中、前記RはHまたはCH2COOHであり、前記nは1〜5000の整数であり、前記化学式2中、前記xは1〜1000の整数であり、前記yは1〜1000の整数である。) - カプセル物質は、カルボキシメチルデキストラン−ドデシルアミンコンジュゲートであり、a)ステップは、下記のステップを含んで行われることを特徴とする、請求項2に記載の酸化鉄ナノカプセルの製造方法。
a1−1)カルボキシメチルデキストラン溶液とドデシルアミン溶液を混合して、第1混合溶液を製造するステップと、
a1−2)前記第1混合溶液に、EDC(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)およびNHS(n-hydroxysuccinicimide)を添加して、第2混合溶液を製造するステップ、および
a1−3)前記第2混合溶液を透析および凍結乾燥するステップ。 - カプセル物質は、デキストラン−リノール酸コンジュゲートであり、a)ステップは、下記のステップを含んで行われることを特徴とする、請求項2に記載の酸化鉄ナノカプセルの製造方法。
a2−1)デキストラン溶液とリノール酸溶液を混合して、第1混合溶液を製造するステップと、
a2−2)前記第1混合溶液に、DCC(n,n’-dicyclohexylcarbodiimide)およびDMAP(dimethylaminopyridine)を添加して、第2混合溶液を製造するステップ、および
a2−3)前記第2混合溶液を透析および凍結乾燥するステップ。 - カルボキシメチルデキストランの重量平均分子量は、500〜1,000,000Daであることを特徴とする、請求項3に記載の酸化鉄ナノカプセルの製造方法。
- カルボキシメチルデキストラン溶液は、カルボキシメチルデキストラン:水が1:3〜5の重量比で混合されたカルボキシメチルデキストラン水溶液に、前記カルボキシメチルデキストラン水溶液の水の重量を基準に10〜15倍のDMSO(dimethyl sulfoxide)が添加されて製造されることを特徴とする、請求項3に記載の酸化鉄ナノカプセルの製造方法。
- ドデシルアミン溶液は、ドデシルアミン:クロロホルム:DMSO(dimethyl sulfoxide)が1:8〜12:25〜35の重量比で混合されることを特徴とする、請求項6に記載の酸化鉄ナノカプセルの製造方法。
- ドデシルアミン:カルボキシメチルデキストランが1:1〜10の重量比になるように、カルボキシメチルデキストラン溶液とドデシルアミン溶液が混合されることを特徴とする、請求項7に記載の酸化鉄ナノカプセルの製造方法。
- ドデシルアミン:EDC:NHSが1:0.3〜0.7:0.1〜0.4になるように、前記EDCおよびNHSが添加されることを特徴とする、請求項7に記載の酸化鉄ナノカプセルの製造方法。
- デキストランの重量平均分子量は、100〜150,000Daであることを特徴とする、請求項4に記載の酸化鉄ナノカプセルの製造方法。
- デキストラン溶液は、デキストラン:DMSO(dimethyl sulfoxide)が1:50〜80の重量比で混合された溶液であり、リノール酸溶液は、リノール酸:DMSO(dimethyl sulfoxide)が1:8〜14の重量比で混合された溶液であることを特徴とする、請求項4に記載の酸化鉄ナノカプセルの製造方法。
- デキストラン:リノール酸が1:2〜5の重量比になるように、デキストラン溶液とリノール酸溶液が混合されることを特徴とする、請求項11に記載の酸化鉄ナノカプセルの製造方法。
- デキストラン:DCC:DMAPが1:1.5〜2:0.3〜0.8の重量比になるように、前記DCCおよびDMAPが添加されることを特徴とする、請求項12に記載の酸化鉄ナノカプセルの製造方法。
- c)ステップの緩衝溶液はリン酸緩衝生理食塩水であり、非極性有機溶媒はクロロホルムであることを特徴とする、請求項2に記載の酸化鉄ナノカプセルの製造方法。
- d)ステップにおいて、カプセル物質:酸化鉄ナノ粒子が1:0.05の重量比となる酸化鉄分散液がカプセル物質水溶液に滴下されることを特徴とする、請求項14に記載の酸化鉄ナノカプセルの製造方法。
- d)ステップの滴下は、0.1〜3ml/min速度で行われることを特徴とする、請求項15に記載の酸化鉄ナノカプセルの製造方法。
- カプセル物質水溶液は、カプセル物質:緩衝溶液が1:50〜500の重量比で混合された溶液であり、前記ナノ粒子分散液は、酸化鉄ナノ粒子:非極性有機溶媒が1:10〜100の重量比で混合された溶液であることを特徴とする、請求項15に記載の酸化鉄ナノカプセルの製造方法。
- d)ステップの攪拌は、20000〜30000rpmであることを特徴とする、請求項16に記載の酸化鉄ナノカプセルの製造方法。
- 請求項1〜18から選択された何れか一項の製造方法により製造された酸化鉄ナノカプセル。
- 請求項1〜18から選択された何れか一項の製造方法により製造された酸化鉄ナノカプセルを含有するMRI肝臓造影剤。
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