WO2009137964A1 - Preparation of superparamagnetic composite microparticles from cyclodextrin - Google Patents

Preparation of superparamagnetic composite microparticles from cyclodextrin Download PDF

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WO2009137964A1
WO2009137964A1 PCT/CN2008/002149 CN2008002149W WO2009137964A1 WO 2009137964 A1 WO2009137964 A1 WO 2009137964A1 CN 2008002149 W CN2008002149 W CN 2008002149W WO 2009137964 A1 WO2009137964 A1 WO 2009137964A1
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cyclodextrin
magnetic
superparamagnetic
water
cyclodextrin composite
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French (fr)
Chinese (zh)
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彭明丽
崔亚丽
陈超
刘艳红
张华�
张彩权
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陕西北美基因股份有限公司
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    • 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
    • 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
    • A61K47/6949—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
    • H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
    • H01F1/0018—Diamagnetic or paramagnetic materials, i.e. materials with low susceptibility and no hysteresis
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
    • H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
    • H01F1/42—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of organic or organo-metallic materials, e.g. graphene

Definitions

  • the invention belongs to the field of material synthesis, and particularly relates to a preparation method for synthesizing superparamagnetic cyclodextrin composite microparticles without using a coupling reagent by utilizing active groups of superparamagnetic nanoparticles and cyclodextrin itself.
  • Cyclodextrins have significantly different properties relative to other linear biocompatible polymers, such as dextran, starch. It is composed of 6, 7 or 8 D-glucopyranose units connected by ot-1, 4 glycosidic bonds, having a conical cylindrical cavity structure with a diameter of 0.5-0.8 nm, all 6- The primary hydroxyl group is at the small end of the cylindrical cavity, that is, the first side, and all of the 2,3-position secondary hydroxyl groups are at the large end of the cylindrical cavity, that is, the second side.
  • the inside of the cavity is composed of 3, 5 hydrogen atoms and glycosidic oxygen atoms, which are hydrophobic, and the entire cavity is hydrophilic due to the presence of hydroxyl groups.
  • This internal hydrophobic and external hydrophilic nature of cyclodextrins makes them widely used in supramolecular chemistry.
  • Research on the introduction of cyclodextrin into magnetic nanomaterials to prepare magnetic cyclodextrin composite microparticles is on the rise. For example, Berlin Heart Co., Ltd.
  • the magnetic nanoparticles are precipitated by metal salt ions under strong alkali conditions, the substance cannot be stably existed under acidic conditions, and therefore modification under acidic conditions has a destructive effect on the stability of the magnetic nanoparticles.
  • the oleic acid-stabilized iron oxide nanoparticles are dissolved in an aqueous solution of ⁇ -cyclodextrin at room temperature. After stirring for 20 hours, a water dispersion stabilizing system (Nano Lett., 2003, 3, 1555) was obtained.
  • the inner cavity of the cyclodextrin in the magnetic composite particles obtained by the method is occupied by oleic acid, and it is difficult to further utilize the properties of the cyclodextrin.
  • NDS dissolves ⁇ -cyclodextrin in ammonia water, slowly adds the solid magnetic nano-Fe 3 0 4 obtained by coprecipitation at 40 °C, maintaining the temperature at 40-50 °C until the pH of the reaction system is Neutral, an inclusion complex of ⁇ -cyclodextrin-Fe 3 0 4 was obtained (J. Mag. Mag. Mater. 2004 (272-276) 2395-2397; J. Braz. Chem. Soc., 2003 ( 14) 6, 936-941).
  • the method for preparing the superparamagnetic cyclodextrin composite microparticles of the present invention is obtained by using a super-paramagnetic nanoparticle and a reactive group monohydroxy group of the cyclodextrin itself under alkaline conditions by means of ultrasonic dispersion, and obtaining a magnetic nano-core and A superparamagnetic cyclodextrin composite particle composed of a cyclodextrin shell.
  • a method for preparing superparamagnetic cyclodextrin composite particles comprising the steps of:
  • the above-mentioned magnetic nanoparticle mixed system containing a small amount of water means a slurry mixture in which water is separated and discarded.
  • the above alkaline solution means NaOH or KOH or hydrazine hydrate or ammonia water.
  • the ratio of the mass ratio of the above magnetic nanoparticles to cyclodextrin ranges from 0.25 to 10.
  • the above magnetic nanoparticles have a particle size ranging from 5 to 30 nm.
  • the mass percentage of the above alkali solution NaOH or KOH or hydrazine hydrate or ammonia water is 10 to 30%.
  • the above dispersion time by ultrasonication is 5-30 minutes.
  • the above magnetic nanoparticles have the following chemical composition (Fe 2 O 3 MFe 3 0 4 ) or MFe 2 0 4 , where r is 0 to 1 , and M is Zn, Mn or Co.
  • Nanoparticles having a hydroxyl group on the surface and capable of being dispersed in water or in a water-miscible system with a particle size ranging from 5 to 30 nm can be synthesized by a common method such as chemical coprecipitation or microemulsion method.
  • the present invention relates to a cyclodextrin which is a cyclic oligosaccharide which is formed by linking 6,7 or 8 or more D-glucopyranose units via aI,4 glycosidic bonds, and its chemical composition is (Cst ⁇ O ⁇ H ⁇ R ⁇
  • n 6, 7, 8, ...
  • R is a group in which a hydrogen atom is substituted on the hydroxyl group of the D-glucopyranose unit, and is CH 2 CH(OH)CH 3 , C 3 ⁇ 4, (CH 2 ) 4 S0 3 Na, (CH 2 ) 4 S0 3 H.
  • the present invention relates to raising the temperature of the reaction system to mean any temperature at which the temperature of the reaction system is raised from room temperature to between 30 and 80 °C.
  • the invention utilizes super-paramagnetic nanoparticles and a reactive group monohydroxy group of the cyclodextrin itself, and can obtain superparamagnetic cyclodextrin composite particles under alkaline conditions without coupling reagents, the method is simple and convenient, and does not need to be added.
  • the coupling reagent is simple in post-treatment and high in yield.
  • Figure 2 Schematic diagram of the structure of magnetic cyclodextrin composite particles.
  • Fig. 4 FTIR spectrum of the magnetic cyclodextrin composite fine particles obtained in Example 2 of the present invention.

Abstract

The preparation of superparamagnetic composite microparticles from cyclodextrin comprises: first, preparing the fluids of magnetic microparticles incluing little water, then adding the cyclodextrin powder to the fluids, and making pH of the fluids above 10 by hydroxide solution. The cyclodextrin in the fluids is dissolved by ultrasonic dispersion for 5-30 minutes. The above mixture is heated up to 40-80°C under stirring and reacts for 3-20 hours, then magnetic cyclodextrin composite microparticles are obtained by magnetically separation or centrifugation or dialysis until the mixture is neutral. The method purposes to prepare the magnetic composite microparticles directly using the active groups in the cyclodextrin and magnetic nanoparticles without adding linking reagents. The magnetic composite microparticles produced by the methods as above have good biocompatibility and high magnetic intensity and can be used to release a variety of drugs slowly.

Description

超顺磁性环糊精复合微粒的制备方法 技术领域  Method for preparing superparamagnetic cyclodextrin composite particles
本发明属于材料合成领域， 特别涉及一种利用超顺磁性纳米颗粒和环糊 精本身的活性基团， 不需偶联试剂合成超顺磁性环糊精复合微粒的制备方法。 背景技术  The invention belongs to the field of material synthesis, and particularly relates to a preparation method for synthesizing superparamagnetic cyclodextrin composite microparticles without using a coupling reagent by utilizing active groups of superparamagnetic nanoparticles and cyclodextrin itself. Background technique
随着磁性纳米材料技术的发展， 磁性复合微粒在生物方面的应用也越来 越多。 相对于其他线性的生物相容性高分子， 如葡聚糖， 淀粉而言， 环糊精 具有明显不同的性质。 它是由 6, 7, 8或更多 D-吡喃葡萄糖单元通过 ot-1, 4糖 苷键连接而成的， 具有直径在 0.5-0.8纳米的锥形圆筒空腔结构， 所有的 6-位 伯羟基在圆筒空腔的小口端， 即第一面， 所有的 2, 3-位仲羟基在圆筒空腔的 大口端， 即第二面。 空腔内部由 3， 5位氢原子和糖苷氧原子组成， 具有疏水 性， 而腔外由于羟基的存在， 使整个分子具有亲水性。 环糊精的这种内部疏 水和外部亲水的特性使其在超分子化学中有着广泛的应用。 将环糊精引入磁 性纳米材料， 制备磁性环糊精复合微粒的研究正在兴起。 如德国的柏林心脏 有限公司利用共沉淀法得到的磁性纳米颗粒，再利用 pH = 1-2的酸性条件下加 入修饰后的环糊精得到含有环糊精的磁性纳米分散体系， 再利用 1-乙基 -3- (二 甲基氨基丙基)碳二亚胺 （EDC) 等将有生物活性的物质如青霉素、 胰岛素等 连接在复合颗粒上（中国专利公开号： CN1607963A, 欧洲专利： EP1439860)。 但由于磁性纳米颗粒是在强碱条件下由金属盐离子沉淀得到的， 该物质在酸 性条件下不能够稳定存在， 因此在酸性条件下对其进行修饰存在着对磁性纳 米颗粒稳定性的破坏。 美国罗切斯特大学的 Yang, H.利用 a-环糊精的内空腔亲 脂性和外空腔亲水性，将油酸稳定的氧化铁纳米颗粒溶解在 α-环糊精的水溶液 中，在室温中搅拌 20小时后得到了水分散稳定体系（Nano lett., 2003, 3, 1555 )。 该方法得到的磁性复合颗粒中环糊精的内空腔被油酸占据， 很难进一步利用 环糊精的性质。 巴西的 Mohallem, N. D. S.将 β-环糊精溶解于氨水中， 在 40 °C 下将共沉淀得到的固体磁性纳米 Fe304缓慢加入， 保持温度在 40-50 °C至反应 体系的 pH为中性， 得到了 β-环糊精 -Fe304的包结复合物 （J. Mag. Mag. Mater. 2004 (272-276) 2395-2397; J. Braz. Chem. Soc., 2003 (14) 6, 936-941 ) 。 作者通 过红外光谱的分析认为该反应条件下固体磁性纳米 Fe304颗粒被装入 β-环糊精 内疏水空腔， 形成 β-环糊精 -Fe304的包结复合物。 但 β-环糊精的内部空腔大小 仅为 6.0-6.5人， 而纳米 Fe304颗粒的大小在 2-10纳米， 两者有着数量级的差别。 With the development of magnetic nanomaterial technology, the application of magnetic composite particles in biological applications is also increasing. Cyclodextrins have significantly different properties relative to other linear biocompatible polymers, such as dextran, starch. It is composed of 6, 7 or 8 D-glucopyranose units connected by ot-1, 4 glycosidic bonds, having a conical cylindrical cavity structure with a diameter of 0.5-0.8 nm, all 6- The primary hydroxyl group is at the small end of the cylindrical cavity, that is, the first side, and all of the 2,3-position secondary hydroxyl groups are at the large end of the cylindrical cavity, that is, the second side. The inside of the cavity is composed of 3, 5 hydrogen atoms and glycosidic oxygen atoms, which are hydrophobic, and the entire cavity is hydrophilic due to the presence of hydroxyl groups. This internal hydrophobic and external hydrophilic nature of cyclodextrins makes them widely used in supramolecular chemistry. Research on the introduction of cyclodextrin into magnetic nanomaterials to prepare magnetic cyclodextrin composite microparticles is on the rise. For example, Berlin Heart Co., Ltd. in Germany uses the magnetic nanoparticles obtained by the co-precipitation method, and then adds the modified cyclodextrin to the cyclodextrin-containing magnetic nano-dispersion system under the acidic condition of pH = 1-2, and then uses 1- Ethyl-3-(dimethylaminopropyl)carbodiimide (EDC), etc., is attached to a composite particle by a biologically active substance such as penicillin, insulin, etc. (Chinese Patent Publication No.: CN1607963A, European Patent: EP1439860) . However, since the magnetic nanoparticles are precipitated by metal salt ions under strong alkali conditions, the substance cannot be stably existed under acidic conditions, and therefore modification under acidic conditions has a destructive effect on the stability of the magnetic nanoparticles. Yang, H., of the University of Rochester, USA. Using the inner cavity lipophilicity of the a-cyclodextrin and the hydrophilicity of the outer cavity, the oleic acid-stabilized iron oxide nanoparticles are dissolved in an aqueous solution of α-cyclodextrin at room temperature. After stirring for 20 hours, a water dispersion stabilizing system (Nano Lett., 2003, 3, 1555) was obtained. The inner cavity of the cyclodextrin in the magnetic composite particles obtained by the method is occupied by oleic acid, and it is difficult to further utilize the properties of the cyclodextrin. Mohallem, Brazil, NDS dissolves β-cyclodextrin in ammonia water, slowly adds the solid magnetic nano-Fe 3 0 4 obtained by coprecipitation at 40 °C, maintaining the temperature at 40-50 °C until the pH of the reaction system is Neutral, an inclusion complex of β-cyclodextrin-Fe 3 0 4 was obtained (J. Mag. Mag. Mater. 2004 (272-276) 2395-2397; J. Braz. Chem. Soc., 2003 ( 14) 6, 936-941). The authors analyzed by infrared spectroscopy that the solid magnetic nano-Fe 3 0 4 particles were loaded into the hydrophobic cavity of β-cyclodextrin under the reaction conditions to form an inclusion complex of β-cyclodextrin-Fe 3 0 4 . However, the internal cavity size of β-cyclodextrin is only 6.0-6.5, while the size of nano-Fe 3 0 4 particles is 2-10 nm, which has an order of magnitude difference.
确认本 因此纳米 Fe304颗粒不可能形成文中所述结构。 该方法虽然没有形成作者认为 的 β-环糊精 -Fe304的包结复合物， 且反应时间长等缺点， 但该反应在碱性条件 下进行有一定的借鉴意义。 湘潭大学的刘峥等以乳化剂修饰的 Fe304为核， 环 氧氯丙烷为交联剂， 釆用分散聚合法， 合成了平均粒径在 3.2微米磁性交联 β- 环糊精聚合物微球（化工新型材料， 2006， 34 (1), 20; 桂林工学院学报 2005, 8, 5 (4), 543 ) ， 但该方法得到的 β-环糊精聚合物微球粒径较大， 粒度分布较宽， 分散体系的稳定性差。 2007年新加坡国立大学的 Xia， H.-B.报道了在非离子型 表面活性剂高分子和 β-环糊精存在下，利用共沉淀法合成了水溶性的环糊精复 合纳米颗粒（Chem. Mater. 2007， 19, 4087) 。但该方法引入了非离子型表面活 性剂高分子 NP-5 (聚乙二醇 （5 ) 壬基苯基醚） ， 使其很难用于生物体系中。 台湾的 Chen, D.-H.报道了利用碳二亚胺将柠檬酸修饰后的 β-环糊精键合在阿 拉伯糖胶磁性纳米颗粒上， 得到含有环糊精的复合纳米颗粒 （Chem. Mater. 2007, 19, 6345 ) 。 但该方法比较复杂， 步骤繁琐， 合成难度较大。 Confirmation Therefore, nano-Fe 3 0 4 particles are unlikely to form the structures described herein. Although this method does not form the inclusion complex of β-cyclodextrin-Fe 3 0 4 which the author thinks, and has a short reaction time, the reaction has certain reference significance under alkaline conditions. Liu Wei, from Xiangtan University, used emulsifier-modified Fe 3 0 4 as the core and epichlorohydrin as the cross-linking agent to synthesize the average particle size of 3.2 μm magnetically cross-linked β-cyclodextrin. Microspheres (New Chemical Materials, 2006, 34 (1), 20; Journal of Guilin University of Technology 2005, 8, 5 (4), 543), but the β-cyclodextrin polymer microspheres obtained by this method have larger particle diameters. Large, wide particle size distribution, poor stability of the dispersion system. In 2007, Xia, H.-B. of the National University of Singapore reported the synthesis of water-soluble cyclodextrin composite nanoparticles by coprecipitation in the presence of nonionic surfactant polymers and β-cyclodextrin. Mater. 2007, 19, 4087). However, this method introduces the nonionic surfactant polymer NP-5 (polyethylene glycol (5) nonylphenyl ether), making it difficult to use in biological systems. Chen, D.-H. of Taiwan reported that citric acid modified β-cyclodextrin was bonded to arabinose magnetic nanoparticles by carbodiimide to obtain cyclodextrin-containing composite nanoparticles (Chem. Mater. 2007, 19, 6345 ). However, the method is complicated, the steps are cumbersome, and the synthesis is difficult.
以上综述可以看出目前已有的合成磁性环糊精复合微粒的方法均存在一 定的缺陷。  As can be seen from the above review, the existing methods for synthesizing magnetic cyclodextrin composite microparticles have certain drawbacks.
发明内容 Summary of the invention
本发明的超顺磁性环糊精复合微粒的制备方法， 是在碱性条件下， 借助 超声分散， 利用超顺磁性纳米颗粒和环糊精本身的活性基团一羟基， 得到由 磁性纳米核心和环糊精壳层组成的超顺磁性环糊精复合微粒。  The method for preparing the superparamagnetic cyclodextrin composite microparticles of the present invention is obtained by using a super-paramagnetic nanoparticle and a reactive group monohydroxy group of the cyclodextrin itself under alkaline conditions by means of ultrasonic dispersion, and obtaining a magnetic nano-core and A superparamagnetic cyclodextrin composite particle composed of a cyclodextrin shell.
本发明的技术解决方案是：  The technical solution of the present invention is:
一种超顺磁性环糊精复合微粒的制备方法， 该方法包括以下步骤： A method for preparing superparamagnetic cyclodextrin composite particles, the method comprising the steps of:
1 ) 制备磁性纳米颗粒混合体系： 1) Preparation of a magnetic nanoparticle mixing system:
将分散在水中的磁性纳米颗粒或分散在与水互溶的体系中的磁性纳米颗 粒， 通过磁性分离或 /和离心， 得到含有少量水的磁性纳米颗粒混合体系； Dispersing magnetic nanoparticles dispersed in water or magnetic nanoparticles dispersed in a water-miscible system by magnetic separation or/and centrifugation to obtain a magnetic nanoparticle mixed system containing a small amount of water;
2) 加入环糊精粉末： 2) Add cyclodextrin powder:
向含有少量水的磁性纳米颗粒混合体系中加入环糊精粉末， 并且通过碱 溶液调整磁性纳米颗粒混合体系的 pH， 使 pH值大于 10， 然后超声分散， 使 磁性纳米颗粒混合体系中的环糊精溶解；  Adding a cyclodextrin powder to a magnetic nanoparticle mixed system containing a small amount of water, and adjusting the pH of the magnetic nanoparticle mixing system by an alkali solution to have a pH greater than 10, and then ultrasonically dispersing, thereby making the cyclodazole in the magnetic nanoparticle mixed system Finely dissolved
3 ) 复合得到超顺磁性环糊精复合微粒  3) Composite super-paramagnetic cyclodextrin composite particles
一边升高步骤 2)的反应体系温度至 40〜80 °C， 一边充分搅拌， 当温度达 到最佳温度时， 幵始计时 3~20小时， 结束反应 （搅拌伴随整个过程）， 通过 磁性分离、 离心或透析使体系到达中性， 得到磁性环糊精复合微粒。 上述含有少量水的磁性纳米颗粒混合体系是指将水分离并弃去后的泥浆 状混合物。 While raising the temperature of the reaction system of step 2) to 40~80 °C, stir well, when the temperature reaches the optimal temperature, start the reaction for 3~20 hours, end the reaction (stirring with the whole process), pass the magnetic separation, Centrifugation or dialysis allows the system to reach neutrality, resulting in magnetic cyclodextrin composite particles. The above-mentioned magnetic nanoparticle mixed system containing a small amount of water means a slurry mixture in which water is separated and discarded.
上述碱溶液是指 NaOH或 KOH或水合肼或氨水。  The above alkaline solution means NaOH or KOH or hydrazine hydrate or ammonia water.
上述磁性纳米颗粒和环糊精的质量比的比值范围为 0.25~10。  The ratio of the mass ratio of the above magnetic nanoparticles to cyclodextrin ranges from 0.25 to 10.
上述磁性纳米颗粒的粒径范围在 5〜30纳米。  The above magnetic nanoparticles have a particle size ranging from 5 to 30 nm.
上述碱溶液 NaOH或 KOH或水合肼或氨水的质量百分比为 10〜30%。 上述利用超声分散的时间为 5-30分钟。  The mass percentage of the above alkali solution NaOH or KOH or hydrazine hydrate or ammonia water is 10 to 30%. The above dispersion time by ultrasonication is 5-30 minutes.
上述磁性纳米颗粒具有以下化学组成 (Fe203MFe304) 或者 MFe204，其中 r为 0〜1， M为 Zn, Mn或 Co。 可通过化学共沉淀或微乳液法等常用方法合成 表面含有羟基， 能够分散在水中或与水互溶体系中， 粒径范围在 5-30纳米范 围纳米颗粒。 The above magnetic nanoparticles have the following chemical composition (Fe 2 O 3 MFe 3 0 4 ) or MFe 2 0 4 , where r is 0 to 1 , and M is Zn, Mn or Co. Nanoparticles having a hydroxyl group on the surface and capable of being dispersed in water or in a water-miscible system with a particle size ranging from 5 to 30 nm can be synthesized by a common method such as chemical coprecipitation or microemulsion method.
本发明涉及环糊精是指由 6, 7, 8或更多 D-吡喃葡萄糖单元通过 a-I, 4糖 苷键连接而成的环状寡糖， 其化学组成为 (Cst^O ^H ^R^^  The present invention relates to a cyclodextrin which is a cyclic oligosaccharide which is formed by linking 6,7 or 8 or more D-glucopyranose units via aI,4 glycosidic bonds, and its chemical composition is (Cst^O ^H ^R ^^
其中 n为 D-吡喃葡萄糖单元的个数， n = 6, 7, 8， ......12。  Where n is the number of D-glucopyranose units, n = 6, 7, 8, ....
R,为 D-吡喃葡萄糖单元羟基上取代氢原子的基团， 为 CH2CH(OH)CH3, C¾, (CH2)4S03Na, (CH2)4S03H。 R is a group in which a hydrogen atom is substituted on the hydroxyl group of the D-glucopyranose unit, and is CH 2 CH(OH)CH 3 , C 3⁄4, (CH 2 ) 4 S0 3 Na, (CH 2 ) 4 S0 3 H.
DS为取代氢原子的基团的取代度， DS = 0-3。  DS is the degree of substitution of a group replacing a hydrogen atom, DS = 0-3.
本发明涉及升高反应体系温度是指使反应体系温度从室温升高至 30-80°C 之间的任何温度。  The present invention relates to raising the temperature of the reaction system to mean any temperature at which the temperature of the reaction system is raised from room temperature to between 30 and 80 °C.
本发明利用超顺磁性纳米颗粒和环糊精本身的活性基团一羟基， 不需偶 联试剂即可在碱性条件下得到超顺磁性环糊精复合微粒， 该方法简单方便， 不需要外加的偶联试剂， 后处理简单， 产量较高。  The invention utilizes super-paramagnetic nanoparticles and a reactive group monohydroxy group of the cyclodextrin itself, and can obtain superparamagnetic cyclodextrin composite particles under alkaline conditions without coupling reagents, the method is simple and convenient, and does not need to be added. The coupling reagent is simple in post-treatment and high in yield.
附图说明 DRAWINGS
图 1. 取代度 DS = 1的 β-环糊精的结构图。  Figure 1. Structure of the β-cyclodextrin with degree of substitution DS = 1.
图 2. 磁性环糊精复合微粒的结构示意图。  Figure 2. Schematic diagram of the structure of magnetic cyclodextrin composite particles.
图 3. 本发明实施例 1中得到的磁性环糊精复合微粒的 ΤΕΜ照片。  Fig. 3. Fig. 3 of the magnetic cyclodextrin composite fine particles obtained in Example 1 of the present invention.
图 4. 本发明实施例 2中得到的磁性环糊精复合微粒的 FTIR图谱。  Fig. 4. FTIR spectrum of the magnetic cyclodextrin composite fine particles obtained in Example 2 of the present invention.
图 5. 本发明实施例 2中得到的磁性环糊精复合微粒磁化曲线。  Fig. 5. Magnetization curve of the magnetic cyclodextrin composite fine particles obtained in Example 2 of the present invention.
具体实施方式 detailed description
下面以具体实施例来对本发明进行详细说明， 但并不是对本发明的具体 限制。  The invention is described in detail below by way of specific examples, but not by way of limitation.
实施例 1. 向盛有共沉淀法得到磁性四氧化三铁固体粉末 0.2104克的 50毫升圆底烧瓶中 加入 3毫升蒸馏水， 得到含有少量水的磁性纳米颗粒混合体系。 在该混合体系 中加入 a-环糊精 0.7009克， 氨水溶液 1.6毫升后， 用 100瓦超声分散 5分钟后， 得 到 pH = 12的均匀分散体系， 升高反应体系温度至 40 °C， 并在该温度下保持 3 小时。 反应结束后， 利用磁性分离， 离心或透析等方法反复洗涤至溶液呈中 性， 即得到超顺磁性 α-环糊精复合微粒。 Example 1. To a 50 ml round bottom flask containing 0.2104 g of a magnetic ferroferric oxide solid powder by a coprecipitation method, 3 ml of distilled water was added to obtain a magnetic nanoparticle mixed system containing a small amount of water. 0.7009 g of a-cyclodextrin and 1.6 ml of aqueous ammonia solution were added to the mixed system, and after ultrasonic dispersion for 5 minutes with 100 watts, a uniform dispersion system of pH = 12 was obtained, and the temperature of the reaction system was raised to 40 ° C, and Hold at this temperature for 3 hours. After the completion of the reaction, the solution is neutralized by magnetic separation, centrifugation or dialysis until the solution is neutral, that is, superparamagnetic α-cyclodextrin composite fine particles are obtained.
实施例 2. Example 2.
移取磁性四氧化三铁水溶液 300毫克， 磁分离后弃去上清， 加入 2.7毫升 水和 581.2毫克的羟丙基 -β-环糊精和 1.2毫升的氨水溶液，用 100瓦超声分散 20分钟后， 得到 ρΗ = 13的均匀分散体系， 升高反应体系温度至 50°C， 并在 该温度下保持 6 小时。 反应结束后， 利用磁性分离， 离心或透析等方法反复 洗涤至溶液呈中性， 即得到超顺磁性羟丙基 -β-环糊精复合微粒。  Pipette 300 mg of magnetic ferroferric oxide aqueous solution, discard the supernatant after magnetic separation, add 2.7 ml of water and 581.2 mg of hydroxypropyl-β-cyclodextrin and 1.2 ml of aqueous ammonia solution, and disperse with 100 watts for 20 minutes. Thereafter, a homogeneous dispersion system of ρ Η = 13 was obtained, and the temperature of the reaction system was raised to 50 ° C and maintained at this temperature for 6 hours. After the completion of the reaction, the mixture is repeatedly washed by magnetic separation, centrifugation or dialysis until the solution is neutral, that is, superparamagnetic hydroxypropyl-β-cyclodextrin composite fine particles are obtained.
实施例 3. Example 3.
移取共沉淀法得到磁性四氧化三铁流体 5.53毫升（固体物含量 36.2毫克 /毫升）于 50毫升圆底烧瓶中， 置于磁铁上分离至上层澄清， 并弃去上层水溶 液。 再加入 γ-环糊精 1.9393毫克， 水 2.0毫升。 利用 1 M NaOH， 调节体系 pH = 10, 用 100瓦超声分散 5分钟后， 升高反应体系温度至 70 °C， 并在该温 度下保持 5 小时。 反应结束后， 利用磁性分离， 离心或透析等已知方法得到 超顺磁性 γ-环糊精复合微粒。  The coprecipitation method was carried out to obtain 5.53 ml of a magnetic ferroferric oxide fluid (solid content 36.2 mg/ml) in a 50 ml round bottom flask, placed on a magnet to separate the upper layer to be clarified, and the upper aqueous solution was discarded. Then add γ-cyclodextrin 1.9393 mg, water 2.0 ml. Using 1 M NaOH, adjust the system pH = 10, and after ultrasonic dispersion for 5 minutes with 100 watts, raise the temperature of the reaction system to 70 °C and keep it at this temperature for 5 hours. After the completion of the reaction, superparamagnetic γ-cyclodextrin composite fine particles are obtained by a known method such as magnetic separation, centrifugation or dialysis.
实施例 4. Example 4.
向盛有磁性纳米 y-Fe203固体粉末 0.4200克的 50毫升圆底烧瓶中加入 3 毫升蒸馏水， 得到含有少量水的磁性纳米颗粒混合体系。 在该混合体系中加 入羟丙基 -β-环糊精 0.7004克， 氨水溶液 1.6毫升后， 用 100瓦超声分散 15分 钟， 得到 ρΗ = 14的均匀分散体系。 升高反应体系温度至 80°C， 并在该温度 下保持 20小时。 反应结束后， 利用磁性分离， 离心或透析等已知方法得到分 散在水中超顺磁性环糊精复合微粒。 To a 50 ml round bottom flask containing 0.4200 g of a magnetic nano-y-Fe 2 0 3 solid powder, 3 ml of distilled water was added to obtain a magnetic nanoparticle mixed system containing a small amount of water. 0.7004 g of hydroxypropyl-β-cyclodextrin and 1.6 ml of an aqueous ammonia solution were added to the mixed system, and then dispersed by ultrasonication at 100 watts for 15 minutes to obtain a uniform dispersion system of ρ Η = 14. The temperature of the reaction system was raised to 80 ° C and maintained at this temperature for 20 hours. After the completion of the reaction, superparamagnetic cyclodextrin composite fine particles dispersed in water are obtained by a known method such as magnetic separation, centrifugation or dialysis.

Claims

权利要求书 Claim
1. 一种超顺磁性环糊精复合微粒的制备方法， 该方法包括以下步骤： A method for preparing a superparamagnetic cyclodextrin composite microparticle, the method comprising the steps of:
1 ) 制备磁性纳米颗粒混合体系： 1) Preparation of a magnetic nanoparticle mixing system:
将分散在水中的磁性纳米颗粒或分散在与水互溶的体系中的磁性纳米颗 粒， 通过磁性分离或 /和离心， 得到含有少量水的磁性纳米颗粒混合体系； Dispersing magnetic nanoparticles dispersed in water or magnetic nanoparticles dispersed in a water-miscible system by magnetic separation or/and centrifugation to obtain a magnetic nanoparticle mixed system containing a small amount of water;
2) 加入环糊精粉末： 2) Add cyclodextrin powder:
向含有少量水的磁性纳米颗粒混合体系中加入环糊精粉末， 并且通过碱 溶液调整磁性纳米颗粒混合体系的 pH， 使 pH值大于 10， 然后超声分散， 使 磁性纳米颗粒混合体系中的环糊精溶解；  Adding a cyclodextrin powder to a magnetic nanoparticle mixed system containing a small amount of water, and adjusting the pH of the magnetic nanoparticle mixing system by an alkali solution to have a pH greater than 10, and then ultrasonically dispersing, thereby making the cyclodazole in the magnetic nanoparticle mixed system Finely dissolved
3 ) 复合得到超顺磁性环糊精复合微粒  3) Composite super-paramagnetic cyclodextrin composite particles
一边升高步骤 2) 的反应体系温度至 40~80 °C， 一边充分搅拌， 当温度达 到最佳温度时， 开始计时 3〜20小时， 结束反应 （搅拌伴随整个过程）， 通过 磁性分离、 离心或透析使体系到达中性， 得到磁性环糊精复合微粒。  While raising the temperature of the reaction system of step 2) to 40~80 °C, stir well, when the temperature reaches the optimal temperature, start counting for 3~20 hours, end the reaction (stirring with the whole process), pass magnetic separation, centrifuge Or dialysis to bring the system to neutral, and magnetic cyclodextrin composite particles are obtained.
2. 根据权利要求 1所述的超顺磁性环糊精复合微粒的制备方法， 其特征 在于： 所述含有少量水的磁性纳米颗粒混合体系是指将水分离并弃去后的泥 浆状混合物。  The method for producing superparamagnetic cyclodextrin composite fine particles according to claim 1, wherein the magnetic nanoparticle mixed system containing a small amount of water refers to a slurry mixture obtained by separating and discarding water.
3. 根据权利要求 1所述的超顺磁性环糊精复合微粒的制备方法， 其特征 在于： 所述碱溶液是指 NaOH或 KOH或水合肼或氨水。  The method for producing superparamagnetic cyclodextrin composite fine particles according to claim 1, wherein the alkali solution means NaOH or KOH or hydrazine hydrate or ammonia water.
4. 根据权利要求 1所述的超顺磁性环糊精复合微粒的制备方法， 其特征 在于： 所述磁性纳米颗粒和环糊精的质量比的比值范围为 0.25~10。  The method for preparing superparamagnetic cyclodextrin composite microparticles according to claim 1, wherein the ratio of the mass ratio of the magnetic nanoparticles to the cyclodextrin ranges from 0.25 to 10.
5. 根据权利要求 1~4任一所述的超顺磁性环糊精复合微粒的制备方法， 其特征在于： 所述磁性纳米颗粒的粒径范围在 5~30纳米。  The method for preparing superparamagnetic cyclodextrin composite microparticles according to any one of claims 1 to 4, wherein the magnetic nanoparticles have a particle diameter ranging from 5 to 30 nm.
6. 根据权利要求 5所述的超顺磁性环糊精复合微粒的制备方法， 其特征 在于： 所述碱溶液 NaOH或 KOH或水合肼或氨水的质量百分比为 10~30%。  The method for preparing superparamagnetic cyclodextrin composite microparticles according to claim 5, wherein the alkali solution NaOH or KOH or hydrazine hydrate or ammonia water has a mass percentage of 10 to 30%.
7. 根据权利要求 6所述的超顺磁性环糊精复合微粒的制备方法， 其特征 在于： 所述利用超声分散的时间为 5-30分钟。  The method for producing superparamagnetic cyclodextrin composite fine particles according to claim 6, wherein the time for dispersion by ultrasonication is 5 to 30 minutes.
8. 根据权利要求 7所述的超顺磁性环糊精复合微粒的制备方法， 其特征在 于： 所述磁性纳米颗粒具有以下化学组成 (F O^F^O 或者 MFe204， 其中 r为 0〜1， M为 Ζη, Μη或 Co。 The method for preparing superparamagnetic cyclodextrin composite microparticles according to claim 7, wherein the magnetic nanoparticles have the following chemical composition (FO^F^O or MFe 2 0 4 , wherein r is 0 〜1, M is Ζη, Μη or Co.
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