药物/环糊精超分子体系的构筑及其性能应用研究
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摘要
近年来,环糊精(CDs)在国内外已广泛应用于医药、化工、农业、日用消费品及生物技术等领域中。环糊精经化学修饰后可以得到各种各样的衍生物,不仅可以扩展其原有的分子键合能力,而且可以改变其分子选择性,环糊精及其衍生物的分子识别和组装研究已经成为超分子化学的一个热点领域。为了进一步研究其分子识别机理和在药物传输领域的潜在应用价值,本文首先做了紫苏子油与β-环糊精的包合及脱包研究,并利用红外光谱,热分析等对包合物进行了验证,其次选择难溶性的活性药物分子蒿甲醚制备了蒿甲醚羟丙基β-环糊精包合物,并利用高效液相色谱技术对包合物进行了分析检测,然后合成了5种化学修饰环糊精,最后利用合成的环糊精衍生物作为中间体,设计并合成出环糊精及其环糊精衍生物与灯盏花乙素的键接复合物,研究了其水溶性。论文具体内容主要包括以下几个部分：
(1)简要介绍了超分子化学及环糊精及其衍生物和天然药物的分子识别包合及作为药物载体的研究进展和重要成果。
(2)用正己烷提取紫苏子油,利用溶液法制备了β-环糊精与紫苏子油固体包合物,以红外光谱分析(IR)、热分析(TGA-DSC)方法对固体包合物进行了验证,TGA曲线和DSC曲线证明了包合物的生成,显示经过包合后热稳定性增强；脱包曲线显示包合物脱包速率降低,稳定性增强。结果表明,紫苏子油和β-环糊精形成1：1包结复合物,用索氏提取器对包合物进行了脱包实验,得到脱包曲线,进一步证明整个包合实验过程是可行的,成功得到了紫苏子油-β-环糊精包合物。
(3)制备了天然萜类药物蒿甲醚和羟丙基β-环糊精包合物,并利用高效液相色谱技术对包合物做了部分分析检测工作。研究结果表明,包合物中的蒿甲醚含量完全达到实验要求。
(4)合成了5种p-环糊精衍生物中间体,利用核磁、IR等手段对合成的化合物进行了结构表征研究。结果表明,合成方法是正确的,成功的合成出目标中间体。
(5)利用已经制备出的环糊精衍生物作为中间体,运用三种不同的方法合成出灯盏花乙素的环糊精键接复合物,利用核磁、IR等手段对合成的化合物进行了结构表征。并对合成出的灯盏花乙素环糊精键接物做了水溶性实验。结果显示：环糊精键接复合物具有作为前药的前景。
Recently, cyclodextrins (CDs) have been widely used in pharmaceutical, chemical industry, agriculture, consumer goods and bio-technology and other fields around home and abroad. Cyclodextrins can be chemically modified to give us a variety of derivatives, not only to expand its original molecular binding ability, but also to change its molecular selectivity. The molecular recognition and assembly of chemical modified cyclodextrins have become the significant topic of supramolecular chemistry. In order to reveal mechanism of the molecular recognition and their potential application in drug delivery system, firstly, complex and de-clathration of perilla frufescens seed oil-β-cyclodextrin was carried out. The infrared spectroscopy (IR), thermal analysis (TGA-DSC) method were used to verify the solid inclusion complex. Secondly, the inclusion complexes of artemether and hydroxypropyl P-cyclodextrin was prepared by the the insoluble and active drug artemether and hydroxypropylβ-cyclodextrin. High-Performance Liquid Chromatography was used to detected the inclusion complex. And then, five kinds of modified cyclodextrins were synthetized. The synthetized cyclodextrins derivatives were used to design and synthesis the binding complexes of scutellarin and cyclodextrin. The water solubility of the binding complexes was studied, as well as. The paper included the following sections.
(1) A brief description of research progress and important achievements of supramolecular chemistry, molecular recognition of cyclodextrin and its derivatives with natural medicines, drug carrier of cyclodextrin conjugations.
(2) Solid inclusion complexes of theβ-cyclodextrin with perilla seed oil which was extracted with hexane, was prepared by solution method. The complexes was verified by IR and TGA-DSC. TGA curves and DSC curves proved that inclusion complex was formed and the thermal stability was enhanced. De-clathration curves showed that the De-clathration rate of inclusion complex reduced, and the stability was enhancement. The results showed that perilla seed oil andβ-CD formed 1:1 inclusion complexes. The De-clathration was carried out by soxhlet extraction, as a result the De-clathration was got, which proved the feasibility of the De-clathration. Perilla seed oil-β-cyclodextrin inclusion was prepared in this way. The inclusion of artemether and hydroxypropyl (3-cyclodextrin was prepared. The inclusion was verified by High-Performance Liquid Chromato-graphy. The results showed that the content of artemethe in inclusion fully meet the requirement of experiment.
(4) Five kinds ofβ-cyclodextrin derivatives which structural charcterization were verified by NMR, IR and so on, were synthesized. The results showed that the synthesis method was correct. And the target intermediate could be synthesized in this way.
(5) In three different ways, the conjugations of scutellarin and cyclodextrins was synthesized, using the prepared derivatives of cyclodextrin as the intermediate. The structural characterization of the compound we synthesized was verified by NMR and IR. And the water solubility of the compound was studied, as well. The results showed that conjugations of scutellarin and cyclodextrins had prospects of prodrug.
(1)简要介绍了超分子化学及环糊精及其衍生物和天然药物的分子识别包合及作为药物载体的研究进展和重要成果。
(2)用正己烷提取紫苏子油,利用溶液法制备了β-环糊精与紫苏子油固体包合物,以红外光谱分析(IR)、热分析(TGA-DSC)方法对固体包合物进行了验证,TGA曲线和DSC曲线证明了包合物的生成,显示经过包合后热稳定性增强；脱包曲线显示包合物脱包速率降低,稳定性增强。结果表明,紫苏子油和β-环糊精形成1：1包结复合物,用索氏提取器对包合物进行了脱包实验,得到脱包曲线,进一步证明整个包合实验过程是可行的,成功得到了紫苏子油-β-环糊精包合物。
(3)制备了天然萜类药物蒿甲醚和羟丙基β-环糊精包合物,并利用高效液相色谱技术对包合物做了部分分析检测工作。研究结果表明,包合物中的蒿甲醚含量完全达到实验要求。
(4)合成了5种p-环糊精衍生物中间体,利用核磁、IR等手段对合成的化合物进行了结构表征研究。结果表明,合成方法是正确的,成功的合成出目标中间体。
(5)利用已经制备出的环糊精衍生物作为中间体,运用三种不同的方法合成出灯盏花乙素的环糊精键接复合物,利用核磁、IR等手段对合成的化合物进行了结构表征。并对合成出的灯盏花乙素环糊精键接物做了水溶性实验。结果显示：环糊精键接复合物具有作为前药的前景。
Recently, cyclodextrins (CDs) have been widely used in pharmaceutical, chemical industry, agriculture, consumer goods and bio-technology and other fields around home and abroad. Cyclodextrins can be chemically modified to give us a variety of derivatives, not only to expand its original molecular binding ability, but also to change its molecular selectivity. The molecular recognition and assembly of chemical modified cyclodextrins have become the significant topic of supramolecular chemistry. In order to reveal mechanism of the molecular recognition and their potential application in drug delivery system, firstly, complex and de-clathration of perilla frufescens seed oil-β-cyclodextrin was carried out. The infrared spectroscopy (IR), thermal analysis (TGA-DSC) method were used to verify the solid inclusion complex. Secondly, the inclusion complexes of artemether and hydroxypropyl P-cyclodextrin was prepared by the the insoluble and active drug artemether and hydroxypropylβ-cyclodextrin. High-Performance Liquid Chromatography was used to detected the inclusion complex. And then, five kinds of modified cyclodextrins were synthetized. The synthetized cyclodextrins derivatives were used to design and synthesis the binding complexes of scutellarin and cyclodextrin. The water solubility of the binding complexes was studied, as well as. The paper included the following sections.
(1) A brief description of research progress and important achievements of supramolecular chemistry, molecular recognition of cyclodextrin and its derivatives with natural medicines, drug carrier of cyclodextrin conjugations.
(2) Solid inclusion complexes of theβ-cyclodextrin with perilla seed oil which was extracted with hexane, was prepared by solution method. The complexes was verified by IR and TGA-DSC. TGA curves and DSC curves proved that inclusion complex was formed and the thermal stability was enhanced. De-clathration curves showed that the De-clathration rate of inclusion complex reduced, and the stability was enhancement. The results showed that perilla seed oil andβ-CD formed 1:1 inclusion complexes. The De-clathration was carried out by soxhlet extraction, as a result the De-clathration was got, which proved the feasibility of the De-clathration. Perilla seed oil-β-cyclodextrin inclusion was prepared in this way. The inclusion of artemether and hydroxypropyl (3-cyclodextrin was prepared. The inclusion was verified by High-Performance Liquid Chromato-graphy. The results showed that the content of artemethe in inclusion fully meet the requirement of experiment.
(4) Five kinds ofβ-cyclodextrin derivatives which structural charcterization were verified by NMR, IR and so on, were synthesized. The results showed that the synthesis method was correct. And the target intermediate could be synthesized in this way.
(5) In three different ways, the conjugations of scutellarin and cyclodextrins was synthesized, using the prepared derivatives of cyclodextrin as the intermediate. The structural characterization of the compound we synthesized was verified by NMR and IR. And the water solubility of the compound was studied, as well. The results showed that conjugations of scutellarin and cyclodextrins had prospects of prodrug.
引文
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