CN102686518B - 磁性氧化铁微粒粉末、含有磁性颗粒的水分散体及其制造方法 - Google Patents
磁性氧化铁微粒粉末、含有磁性颗粒的水分散体及其制造方法 Download PDFInfo
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- CN102686518B CN102686518B CN201080051477.2A CN201080051477A CN102686518B CN 102686518 B CN102686518 B CN 102686518B CN 201080051477 A CN201080051477 A CN 201080051477A CN 102686518 B CN102686518 B CN 102686518B
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- containing magnetic
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 239000006249 magnetic particle Substances 0.000 title claims abstract description 60
- 239000006185 dispersion Substances 0.000 title claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims description 37
- 239000000843 powder Substances 0.000 title claims description 11
- 239000010419 fine particle Substances 0.000 title claims description 7
- 239000002245 particle Substances 0.000 claims abstract description 60
- 239000007864 aqueous solution Substances 0.000 claims abstract description 46
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 30
- 229920000642 polymer Polymers 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011164 primary particle Substances 0.000 claims abstract description 14
- 239000006228 supernatant Substances 0.000 claims abstract description 12
- 150000002505 iron Chemical class 0.000 claims abstract description 6
- 239000012670 alkaline solution Substances 0.000 claims abstract description 4
- 239000007789 gas Substances 0.000 claims abstract description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 4
- 239000012266 salt solution Substances 0.000 claims abstract description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 92
- 230000005291 magnetic effect Effects 0.000 claims description 67
- 229910052742 iron Inorganic materials 0.000 claims description 41
- 239000008187 granular material Substances 0.000 claims description 38
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- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 229910052596 spinel Inorganic materials 0.000 claims description 8
- 239000011029 spinel Substances 0.000 claims description 8
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 22
- 150000002500 ions Chemical group 0.000 description 10
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000005415 magnetization Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000006978 adaptation Effects 0.000 description 7
- 239000000084 colloidal system 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
- 239000003513 alkali Substances 0.000 description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 6
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- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 4
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- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 3
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- 229960002089 ferrous chloride Drugs 0.000 description 3
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- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 3
- 229910021506 iron(II) hydroxide Inorganic materials 0.000 description 3
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000004523 agglutinating effect Effects 0.000 description 2
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- 125000000524 functional group Chemical group 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
- 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 2
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 2
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 238000004438 BET method Methods 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910001566 austenite Inorganic materials 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000012267 brine Substances 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
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 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
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
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- 230000001575 pathological effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
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- 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
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- 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
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- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G49/00—Compounds of iron
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- C01G49/08—Ferroso-ferric oxide [Fe3O4]
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- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
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- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
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Abstract
本发明提供一种含有磁性颗粒的水分散体,其中,磁性颗粒的一次颗粒的平均粒径为5~15nm,二次颗粒的平均粒径为10~60nm,该含有磁性颗粒的水分散体在pH6~8范围内的ζ电压为-20mV以下,关于该含有磁性粉末的表面以具有羧基的聚合物包覆的含有磁性颗粒的水分散体,该含有磁性颗粒的水分散体能够通过在氮气气氛气中,将溶解有具有羧基的聚合物水溶液升温到90~100℃,添加2价和3价的铁盐溶液和碱溶液,以相同温度进行反应,通过添加乙醇进行沉淀后,除去上清液并向水溶解,进行透析来制造,作为能够再现性良好地生成含有能够发挥均一的功能性的诊断用、治疗用等的磁性颗粒的医药的含有磁性颗粒的水分散体有用。
Description
技术领域
本发明涉及在医疗技术领域中,在作为药物传输法的药物传输系统(以下记为DDS)、可以在伦琴射线和MRI(核磁共振)等中使用的CT(计算断层像法)诊断和温热治疗法等的治疗用的含有磁性颗粒的医药中使用的原药。详细而言,本发明涉及以提高上述含有磁性颗粒的医药向病变组织、细胞的传输指向性、以CT诊断时的造影敏感度和温热治疗时的产热性等性能为目的的含有磁性颗粒的医药用原药。
背景技术
近年,作为磁性体,研究了使用磁性氧化铁微粒,与磷脂质、蛋白质和水溶性聚合物等机体适应性物质复合化的含有磁性颗粒的医药(专利文献1~5等)。
另外,为了制备磁性氧化铁微粒的单分散水溶液,已知有以表面活性剂等表面处理剂包覆颗粒表面的方法(专利文献6)、包覆Al、Si等无机物的方法(专利文献7)、或者以有机金属聚合物包覆的方法(专利文献4)、或者不使用一切分散剂等制备单分散水溶液的方法(专利文献8)等。
另外,为了使与机体分子的结合变得容易,报道了在磁性氧化铁颗粒表面包覆具有氨基、羧基、磺酸基等官能团的表面修饰分子(专利文献9~11)。
这些均在暂时制备氧化铁的水溶胶后,分别与高分子、多糖类混合进行制备。因此,磁性颗粒的粒径由于凝集而变大,或磁性颗粒与这些表面修饰分子的结合弱,在血液中容易解离,加热灭菌时的稳定性和经时稳定性差。
特别是由于氧化铁颗粒的过度磁凝集而不容易在机体适应性物质中使微细的磁性氧化铁颗粒均匀分散、载持,至此使用着大颗粒尺寸的磁性氧化铁颗粒。
另外,颗粒尺寸大的磁性氧化铁颗粒,在治疗后,氧化铁颗粒在体内残留的可能性高,另外,有时形成过敏反应等副作用的原因。难以说能够充分确保使用上的安全性。
因此,考虑血中稳定性、血中滞留性优异,再考虑肿瘤集聚性,要求开发能够再现性良好地生成对特定靶分子形成特异亲和性结合那样的诊断用和治疗用含有磁性颗粒的医药的含有磁性颗粒的医药用原药。
现有技术文献
专利文献
专利文献1:日本特开平3-128331号公报
专利文献2:日本特开平4-52202号公报
专利文献3:日本特开平7-122410号公报
专利文献4:日本特表平8-500700号公报
专利文献5:日本特开平11-106391号公报
专利文献6:日本特开平1-4002号公报
专利文献7:日本特开平5-310429号公报
专利文献8:日本特开2006-28032号公报
专利文献9:日本特开2003-112925号公报
专利文献10:国际公开第95/31220号小册子
专利文献11:专利4079996号公报
发明内容
发明所要解决的课题
如上所述,为了再现性良好地得到具有均一特性的含有磁性体的医药,在含有磁性体的医药制药时,使机体适应性物质和氧化铁微粒均匀分散混合是不可缺少的条件,因此,原药中的磁性氧化铁微粒必须是由微细、粒度均匀的磁性氧化铁微粒构成的单分散胶体水溶液。
另外,为了保持在血液中的稳定性,在中性pH区域的分散稳定性是必要的。
另外,在磁性颗粒表面必须具有官能团,使其与抗体等机体分子形成强结合。
另外,要求是耐氧化性强、在必要时能够再分散为必要浓度的磁性氧化铁微粒粉末(干燥粉末)。
本发明是鉴于上述现有的问题形成的发明,以提供具有羧基的聚合物修饰颗粒表面、由均匀粒度得到的磁性氧化铁微粒的分散胶体水溶液和能够容易地制备该分散胶体水溶液为技术性课题。
用于解决课题的方法
即,本发明是一种磁性氧化铁微粒粉末,其特征在于:磁性氧化铁微粒的一次粒径为5~15nm,二次颗粒的平均粒径为10~60nm,该颗粒表面以具有羧基的聚合物包覆(本发明1)。
另外,本发明是pH6~8范围内的ζ电压为-20mV以下的上述含有磁性颗粒的水分散体(本发明2)。
另外,本发明是具有羧基的聚合物是分子量为1500~10000的聚丙烯酸的上述含有磁性颗粒的水分散体(本发明3)。
另外,本发明是上述任一项所述的含有磁性颗粒的水分散体的制造方法,其特征在于:在氮气气氛气中,将溶解有具有羧基的聚合物水溶液升温到90~100℃,添加2价和3价的铁盐溶液和碱溶液,以相同温度进行反应,冷却到室温后,通过添加乙醇进行沉淀后,通过除去上清液并向水分散、透析,得到以含有羧基的聚合物包覆的磁性氧化铁微粒的水分散体(本发明4)。
另外,本发明是反应时的羧基COOH相对于全部铁Fe的摩尔比例(COOH/Fe)为0.3~3的上述含有磁性颗粒的水分散体的制造方法(本发明5)。
发明的效果
本发明的磁性氧化铁微粒粉末,能够容易地在水中分散,得到磁性氧化铁微粒的分散胶体。
本发明的含有磁性颗粒的水分散体是微细的磁性氧化铁微粒的分散胶体水溶液,而且,颗粒表面以具有羧基的聚合物包覆,因此,能够容易地合成含有使磁性氧化铁微粒均一地分散在机体适应性物质中的复合物的医药。而且,由于是液体介质不含表面活性剂的原药,因此,对机体安全性影响极小。
另外,微细的磁性颗粒能够在制药造粒工序中通过制备微粒的集合状态,对造粒颗粒赋予强磁性体的功能。
另外,由于是超微粒,给药后能够容易地从体内排出。
具体实施方式
如下所述更详细地说明本发明的构成。
本发明中的磁性氧化铁微粒的一次颗粒的平均粒径为5nm~15nm。一次颗粒的平均粒径小于5nm时,是非晶体,大于15nm时,顽磁力变大,容易产生过度的磁凝集,二次粒径成为200nm以上。一次颗粒的平均粒径优选为5~12nm,更优选为顽磁力小的10nm以下。
本发明中的磁性氧化铁微粒的二次颗粒的平均粒径为10~60nm。二次颗粒的平均粒径小于10nm时,在癌症的温热疗法中使用时,由交替磁场产生的产热性变低,另一方面,如果二次颗粒的平均粒径大于60nm,则给药后从体内排出时产生问题。优选的二次颗粒的平均粒径优选为10nm~30nm。
本发明中的磁性氧化铁微粒是尖晶石型强磁性体MO·Fe2O3(M是2价金属),M是Fe时的组成为xFeO·Fe2O3,该组成式的x表示2价铁的含量,x=1是FeO·Fe2O3,是磁铁矿,x=0是γ-Fe2O3,是磁赤铁矿,其中间(x=0~1)也是尖晶石型氧化铁,是磁性氧化铁,可以使用这些超顺磁性氧化铁颗粒。
作为本发明中的磁性氧化铁微粒的组成MO·Fe2O3(M是2价金属)的M,除了Fe以外,可以选择Mg。这是由于Mg具有机体适应性,但也能够根据目的选择使用其它2价金属。
本发明中的磁性氧化铁微粒优选是超顺磁性体,优选顽磁力为0~6.0kA/m。大于6.0kA/m的高顽磁力时,产生残留磁化,容易磁凝集。更优选顽磁力为0.05~4.0kA/m。磁性氧化铁微粒的饱和磁化值σs为5~90Am2/kg。在小于5Am2/kg的饱和磁化值时,磁性不足,在尖晶石型氧化铁颗粒中难以得到大于90Am2/kg的磁化值。更优选饱和磁化值σs为10~85Am2/kg。
作为具有本发明中所使用的羧基的聚合物,存在聚丙烯酸、聚甲基丙烯酸、聚氨基酸等多个种类。其中,从磁性氧化铁微粒的粒度和粒度分布方面出发优选使用聚丙烯酸。
另外,具有羧基的聚合物的分子量优选为1500~10000。具有羧基的聚合物的分子量小于1500时,磁性颗粒的一次粒径变大。另一方面,关于分子量大于10000的聚合物,磁性颗粒之间的凝集多,二次粒径变大。
本发明的含有磁性颗粒的水分散体在pH6~8范围内的ζ电压为-20mV以下。考虑机体适应性,如果pH6~8范围内的ζ电压是大于-20mV的值,在经时稳定性中形成问题。
本发明的含有磁性颗粒的水分散体的等电点优选为2.0~3.0。
本发明的含有磁性颗粒的水分散体的磁性氧化铁微粒的浓度优选为5~50mg/ml。在大于50mg/ml时,在颗粒之间发生作用的范德华力的影响变大,容易发生凝集,故而不优选。小于5mg/ml时,浓度过稀而不实用。优选的浓度为10~40mg/ml。
本发明的磁性氧化铁微粒能够制成与磷脂质、多糖类、蛋白质或糊精类的复合体。
接着,叙述本发明的含有磁性颗粒的水分散体的制造方法。
本发明的磁性氧化铁微粒能够以使用铁盐水溶液和碱水溶液的水溶液反应(称为湿法)合成。
一般而言,在水溶液反应中,通常使用共沉淀法和氧化反应法。
共沉淀法是指在1摩尔亚铁盐水溶液Fe(II)和2摩尔铁盐水溶液Fe(III)的混合水溶液中边搅拌边加入碱水溶液,发生Fe(II)和2Fe(III)的共沉淀反应,生成黑色尖晶石型磁性氧化铁的磁铁矿颗粒的反应。在该反应中,添加Fe以外的2价金属、例如添加Mg时,可以得到含有Mg的尖晶石型磁性氧化铁微粒。另外,能够通过铁盐浓度、混合温度等反应条件控制生成颗粒的大小,因此,通过组合这些反应条件,合成磁性氧化铁微粒。
在该反应中途,即使添加聚丙烯酸水溶液进行反应,也不能制备含有具有本发明目的的粒度分布的磁性颗粒的水分散体。
另一方面,氧化反应法是指在亚铁盐水溶液中添加碱水溶液,生成氢氧化亚铁胶体,边加热搅拌含有该氢氧化亚铁胶体的水溶液边通入空气等含氧气体,通过氢氧化亚铁胶体的氧化反应生成黑色磁性氧化铁的磁铁矿颗粒的反应。与上述共沉淀法同样,在添加Fe以外的2价金属时,可以得到含有添加金属的尖晶石型氧化铁微粒。另外,能够通过组合控制该反应条件,合成磁性氧化铁微粒。
但是,如果在聚丙烯酸的共存下进行上述亚铁盐的氧化反应法,即使在该反应中途添加聚丙烯酸水溶液进行反应,也不能制备含有具有本发明目的的粒度分布的磁性颗粒的水分散体。另外,在精制中途氧化反应过度进行,大部分不是磁铁矿的黑色,变为黄色~褐色。
因此,本发明的发明人进行深入研究,从而发现如下所述的反应条件。
即,将溶解有具有聚丙烯酸等羧基的聚合物的水溶液加热到规定的温度,在其中迅速添加亚铁盐和铁盐的混合水溶液以及氨水溶液等的碱水溶液,使之反应。通过上述反应液制作磁性氧化铁微粒,可以认为聚丙烯酸直接包覆通过反应生成的磁铁矿颗粒的颗粒表面,能够抑制颗粒之间的凝集。
作为本发明中的亚铁盐水溶液,能够使用硫酸亚铁水溶液或氯化亚铁水溶液等。作为本发明中的铁盐水溶液,能够使用硫酸铁水溶液或氯化铁水溶液等。
作为本发明中的碱水溶液,能够使用氨水、氢氧化钠、氢氧化钾等碱金属氢氧化物的水溶液、氢氧化镁、氢氧化钙等碱土类金属氢氧化物的水溶液。更优选为氨水。
在本发明中,添加相对于亚铁和铁为当量的量的碱水溶液。
在本发明中,在进行磁性氧化铁微粒的反应时,在反应溶液中预先溶解聚丙烯酸等具有羧基的聚合物是重要的。通过在反应溶液中事前存在具有羧基的聚合物,由反应生成的磁铁矿颗粒的颗粒表面直接由聚丙烯酸酯包覆,能够抑制颗粒之间的凝集。
反应溶液中的具有羧基的聚合物的浓度,以相对于反应溶液中的全部铁(Fe)的摩尔比计,存在0.3~3.0的量。聚合物浓度小于0.3时,由于浓度稀,不能以能够抑制磁性氧化铁微粒凝集程度包覆聚合物。聚合物浓度大于3.0时,由于效果饱和,没有需要以该浓度以上存在的意义。更优选的聚合物浓度为0.8~2.5。通过使反应溶液中的具有羧基的聚合物浓度为上述范围,能够使ζ电压为-20mV以下。
本发明中的反应温度优选为90~100℃。小于90℃时,针铁矿混合存在。大于100℃时,也生成磁铁矿,但由于需要具有高压釜等装置,在工业上不容易。
本发明中,含有磁性颗粒的水分散体的水洗如下地进行。即,将冷却到室温的反应后的溶液转移到烧杯等中,边用搅拌器搅拌边添加几乎等量乙醇直到沉淀生成。弃去上清液,添加离子交换水使之分散。再次添加乙醇,以离心分离除去上清液。再次反复该操作,使最终得到的沉淀物在离子交换水中分散,根据需要用蒸发器进行浓缩。
接着,为了除去在水中可溶的盐类,使用透析膜进行透析。用蒸发器进行浓缩后,用离心分离机回收上清液,除去残留的凝集颗粒。
接着,通过将上清液的含有磁性颗粒的水分散体在-20℃以下的冰箱内放置5小时以上,使其冻结,进行减压下的冷冻干燥,由此能够得到本发明的含有磁性氧化铁微粒。
然后,将含有磁性颗粒的水分散体的浓度稀释调整为5~50mg/ml,能够得到磁性氧化铁微粒在离子交换水中分散的含有磁性颗粒的水分散体。
另外,能够以得到的磁性氧化铁微粒与磷脂质、多糖类、蛋白质或糊精类的复合体形式应用于各种用途中,例如,药物传输法的DDS、伦琴射线、MRI(磁共振)等中使用的CT诊断和温热治疗法等的治疗用等。
<作用>
本发明的发明人反复深入研究,结果发现,含有以具有羧基的聚合物包覆磁性颗粒表面的超顺磁性氧化铁微粒的含有磁性颗粒的水分散体的分散稳定条件。
表现超顺磁性的是顽磁力为零的强磁性体。即,强磁性体的颗粒即使是单极磁区结构,在大颗粒时,施加外部磁场磁化后,向外部磁场开放,产生残留磁化,但如果颗粒极其微细,顽磁力减少,最终为零,如果施加外部磁场磁化,向外部磁场开放后,不产生残留磁化。该现象是由热扰动作用引起的,将这样的强磁性微粒称为超顺磁性。
本发明的含有磁性颗粒的水分散体,即使靠近表面磁束10mT(100高斯)的永磁铁也不凝集,是长期稳定的单分散胶体水溶液。可以认为这是与磁性氧化铁微粒的饱和磁化值为50~90Am2/kg的强磁性体矛盾的现象,但如果将饱和磁化值表示为以粉末状测定磁性氧化铁微粒时的每单位重量的磁化值,将其换算为每1个颗粒的磁化值,则越是微粒程度,每单位重量的总颗粒个数越多,每1个的磁化值越小。
另外,作为磁性颗粒使用磁性氧化铁颗粒,是由于氧化铁具有机体适应性的缘故,越是微粒,从机体内排出越容易。
实施例
本发明的代表性实施方式如下。另外,本发明不受以下的实施例限定。
另外,在生成物的结构解析中使用X线衍射装置。
粒度分布用透过型电子显微镜TEM观察。另外,通过数字化仪分析,求出一次颗粒的平均粒径。
二次颗粒的平均粒径通过动态光散射法,利用粒度分布计FPAR-1000(大塚电子生产)测定。
比表面积值通过BET法测定。
磁特性的测定使用振动试样磁力计VSM、以796kA/m(10kOe)的磁场测定。
ζ电压和等电点利用ELS-6000(大塚电子生产)测定。
实施例1
使用具备搅拌装置和加热装置的1000ml的反应容器,原料铁盐和苛性钠使用特级试剂,另外,水使用离子交换水。
(1)磁性氧化铁微粒的合成工序
在反应器中加入7.83g分子量为5000的聚丙烯酸和713.2ml离子交换水,吹入氮气,直接使之升温到95℃。接着,在反应器中加入10ml1.6mmol/l的硫酸亚铁水溶液和10ml 3.2mmol/l的硫酸铁水溶液(COOH/Fe比例=2.27),再添加59.4ml 14.8mmol/l的氨水,搅拌2小时使之反应。使水溶液冷却到65℃。在蒸发器中将反应液浓缩到约100ml。冷却到室温后,将浓缩液移入烧杯,边搅拌浆料边添加几乎等量的乙醇直至生成沉淀。弃去上清液,添加离子交换水,使得总量为100g左右,边搅拌边使之分散。再次加入等量乙醇,以1000rpm离心分离机10分钟进行处理。除去上清液,再次反复该操作,使最终得到的沉淀物分散在离子交换水中。再以蒸发器浓缩到40g左右。
收集这里所得到的一部分胶体水溶液,将水洗过滤的浆料冷冻干燥,得到粉末,对其进行分析的结果为,BET比表面积为230m2/g,由TEM测得的一次颗粒的平均粒径为5nm,由动态光散射法测得的二次颗粒平均粒径为17.3nm。另外,是磁特性为饱和磁化值σs为13Am2/kg、顽磁力Hc为0.35kA/m的磁性氧化铁微粒。
(2)分散颗粒的精制工序
使用透析膜进行精制。以蒸发器将所得到的透析液浓缩到200ml,以12000G进行30分钟离心分离,回收上清液。通过该操作除去凝集颗粒。这样操作,精制黑色的胶体水溶液。
所得到的含有磁性颗粒的水分散体浓度为10mg/ml,含有磁性颗粒的水分散体的pH为6.5。另外,在pH7.0的ζ电压为-34mV。等电点为2.5。
实施例2
除了使用分子量1800的聚丙烯酸以外,与实施例1同样地进行反应,得到胶体溶液。同样地对粉末分析的结果为,BET比表面积为165m2/g、由TEM测得的一次颗粒的平均粒径为7nm、由动态光散射法测得的二次颗粒平均粒径为56nm。另外,是磁特性为饱和磁化值σs为32Am2/kg、顽磁力Hc为0.65kA/m的磁性氧化铁微粒。
接着,与实施例1同样操作,进行分散颗粒的精制工序,得到含有磁性颗粒的水分散体。
所得到的含有磁性颗粒的水分散体浓度为10mg/ml,含有磁性颗粒的水分散体的pH为6.5。另外,在pH7.0的ζ电压为-31mV。等电点为2.6。
比较例1
在1000ml烧瓶中,在预先混合有60g 13.9mol/l的NaOH水溶液和530g离子交换水、加温到80℃的水溶液中,混合添加108.4g 0.8mmol/l的氯化亚铁水溶液和80g 2.5mmol/l的氯化铁水溶液。接着,添加60g溶解有12.1g分子量为5000的聚丙烯酸的水溶液,以同样温度使之反应1小时后,添加离子交换水进行倾析,除去上清液。重复该操作,除去在水中可溶的盐类。
收集这样操作得到的一部分含有磁性颗粒的分散体,将水洗过滤的浆料冷冻干燥,得到粉末,对其进行分析的结果为,BET比表面积为176m2/g,由TEM测得的一次颗粒的平均粒径为8nm,由动态光散射法测得的二次颗粒平均粒径为120nm,明显是凝集物。另外,磁特性是饱和磁化值σs为26.3Am2/kg、顽磁力为0.92kA/m。
接着,与实施例1同样操作,进行分散颗粒的精制工序,得到含有磁性颗粒的水分散体。
所得到的含有磁性颗粒的水分散体浓度为10mg/ml,含有磁性颗粒的水分散体的pH为7.3。另外,在pH7.0的ζ电压为-12mV。等电点为5.2。
比较例2
在300ml烧瓶中制备50ml 0.1mol/l的氯化亚铁水溶液,在其中添加0.09g分子量为1800的聚丙烯酸。接着,添加11ml 0.7mol/l的KOH水溶液。接着,以33ml/h的速度添加50ml含有0.035ml过氧化氢的水溶液。使之反应2小时后,添加离子交换水反复进行倾析,除去在水中可溶的盐类。
收集这样操作得到的一部分含有磁性颗粒的分散体,将水洗过滤的浆料冷冻干燥,得到粉末,对其进行分析的结果为,BET比表面积为176m2/g,另一方面,由TEM观察到一次颗粒的平均粒径为10~50nm的球状颗粒和大量针状颗粒的混合物,由动态光散射法测得的二次颗粒平均粒径为120nm,明显是凝集物。另外,磁特性是饱和磁化值σs为26.3Am2/kg、顽磁力为0.92kA/m。
接着,与实施例1同样操作,进行分散颗粒的精制工序,得到含有磁性颗粒的水分散体。
所得到的含有磁性颗粒的水分散体浓度为10mg/ml,含有磁性颗粒的水分散体的pH为6.1。另外,在pH7.0的ζ电压为3mV。等电点为6.2。工业上的可利用性
本发明的含有磁性体的水分散体以含有羧基的聚合物修饰表面,因此,能够容易合成含有使磁性体微粒在机体适合性物质中均匀分散的复合物的医药,而且,由于在pH6~8中性区域的ζ电压为-20mV以下,即使在机体中,颗粒之间难以发生凝集,经时稳定。另外,由于一次粒径和二次粒径非常小,因此,即使以抗体等修饰颗粒表面,最终的粒度也不变大,对人体给药后,也容易地从体内排出,因此,能够提供关于对人体给药后的安全性和代谢、排出不产生任何问题的原药。
Claims (5)
1.一种磁性氧化铁微粒粉末的制造方法,其特征在于:
在氮气气氛气中,将溶解有具有羧基的聚合物水溶液升温到90~100℃,添加2价和3价的铁盐溶液和碱溶液,以相同温度进行反应,通过添加乙醇进行沉淀后,通过除去上清液并向水分散、透析而得到以含有羧基的聚合物包覆的磁性氧化铁微粒的水分散体后,通过冷冻干燥而得到磁性氧化铁微粒粉末,
所述磁性氧化铁微粒的使用透过型电子显微镜决定的一次颗粒的平均粒径为5~15nm,由动态光散射法测得的二次颗粒的平均粒径为10~60nm,该颗粒表面以具有羧基的聚合物包覆,该磁性氧化铁微粒是尖晶石型磁性体MO·Fe2O3,其中,M是2价金属。
2.一种含有磁性颗粒的水分散体的制造方法,其特征在于:
在氮气气氛气中,将溶解有具有羧基的聚合物的水溶液升温到90~100℃,添加2价和3价的铁盐溶液和碱溶液,以相同温度进行反应,冷却到室温后,通过添加乙醇进行沉淀后,通过除去上清液并向水分散、透析,得到以含有羧基的聚合物包覆的磁性氧化铁微粒的水分散体,
所述含有磁性颗粒的水分散体是在水中分散有磁性氧化铁微粒的含有磁性颗粒的水分散体,所述磁性氧化铁微粒的使用透过型电子显微镜决定的一次颗粒的平均粒径为5~15nm,由动态光散射法测得的二次颗粒的平均粒径为10~60nm,该颗粒表面以具有羧基的聚合物包覆,该磁性氧化铁微粒是尖晶石型磁性体MO·Fe2O3,其中,M是2价金属。
3.如权利要求2所述的含有磁性颗粒的水分散体的制造方法,其特征在于:所述含有磁性颗粒的水分散体在pH6~8范围内的ζ电压为-20mV以下。
4.如权利要求2所述的含有磁性颗粒的水分散体的制造方法,其特征在于:所述具有羧基的聚合物是分子量为1500~10000的聚丙烯酸。
5.如权利要求2~4中任一项所述的含有磁性颗粒的水分散体的制造方法,其特征在于:
反应时的羧基COOH相对于全部铁Fe的摩尔比例(COOH/Fe)为0.3~3。
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