1、摘 要-环糊精及其衍生物具有独特的筒状结构，可以选择性键合药物分子形成包合物，药物分子被包容于筒状结构的疏水空腔内，具有很好的分散度。同时，由于 -环糊精及其衍生物外部的亲水性，使形成的包合物具有良好的可润湿性。随着对具有不同性能的新型 -环糊精衍生物开发和利用的深入，-环糊精及其衍生物包合技术在药物制剂方面的应用日益广泛。本论文从对 -环糊精的修饰出发，合成了一系列 -环糊精衍生物，探讨了羟丙基-环糊精(HP-CD)的取代度对大豆苷元包合作用的影响；其次，以法莫替丁为客体模型药物，研究了 HP-CD 对法莫替丁的包合作用。本论文的主要工作包括四部分：第一章：首先，对 -环糊精衍生物的种类、合
2、成意义以及修饰方法进行了较为全面地阐述。其次，分别从 -环糊精及其衍生物包合物的应用、制备方法、表征方法、分子间的结合方式以及化学计量试验方法等方面，全面综述了 -环 糊精及其衍生物包合技术在药物制剂中的研究与进展。 第二章：通过改变原料配比和催化剂的用量，制备了一系列不同取代度的 HP-CD，分别对其进行了结构表征。并运用核磁共振法( 1H NMR)测定了 8 种 HP-CD 的取代度。另外，参照文献提供的方法合成了羧甲基化的 -环糊精(CM-CD) 和 3 种磺酸基- 环糊精(SO3-CD)，分别对产品结构进行了表征。确定了 CM-CD 的取代度和 3 种 SO3-CD 的磺化趋势。第三章
3、：实验采用溶液搅拌法制备了 6 种不同取代度(DS) 的 HP-CD 与大豆苷元的包合物，通过红外光谱法(IR)，X 射线衍射法(XRD)，紫外光谱法(UV)及热分析法对 6 种包合物进行了物相鉴定，并对表征图谱进行了分析比较。结果表明，不同取代度的 HP-CD 对大豆苷元均产生了包合作用，DS=7.8 的包合物的图谱差异较为明显，包合效果较好。通过对其中 4 种取代度的 HP-CD 与大豆苷元相溶解度的考察，判断包合类型并计算表观稳定常数(K c)，实验结果表明， 4 种取代度的 HP-CD 均可与大豆苷元形成摩尔比为1:1 的包合物，其包合类型均为 AL 型；当 DS=7.8 时，HP-C
4、D/ 大豆苷元包合物表观稳定常数最大( K1:1=21.63 Lmol-1)，包合物更稳定。第四章：以法莫替丁为客体模型药物，分别采用溶液搅拌法和回流法制备了 HP-CD与法莫替丁的包合物，并用 IR 光谱法，XRD 法，UV 光谱法及热分析法对其进行了定性、定量的分析表征。在此基础上，考察了 HP-CD 与法莫替丁的相溶解度，绘制出了相溶解度图。实验结果显示，包合物中法莫替丁分子进入 HP-CD 分子中形成包合物超分子体系，该包合物不同于简单的物理混合物。该超分子体系中，包合类型为 AL 型，主客体分子以 1:1摩尔比稳定包合，表观稳定常数 K1:1 为 146 Lmol-1，达到了药典规定
5、的药用要求范围。关键词：羟丙基-环糊精，大豆苷元，包合作用，法莫替丁，表观稳定常数Abstract-cyclodextrin and its derivatives are a series of cyclic oligosaccharides shaped like truncated cone, which can selectively bind drug molecules local in their special cavity due to their unique structures of interior hydrophobic cavity. Meanwhile, bec
6、ause of their exterior hydrophilic surface, the inclusion complexes with good wettability can be obtained. As many new -cyclodextrin derivatives with excellent performance are synthesized and used widely, the inclusion technology of -cyclodextrin and its derivatives has been widely applied to pharma
7、ceutical preparations. In this work, several water-soluble -cyclodextrin derivatives were synthesized firstly, and the effects of the substitution degree of hydroxypropyl-cyclodextrin (HP-CD) on preparation of the inclusion complex of HP-CD/daidzein were investigated. Secondly, the inclusion role of
8、 HP-CD on the famotidine was studied carefully using famotidine as model drug.This thesis is constituted by four chapters:In chapter 1, a review on types, synthesic significance and modification methods of -cyclodextrin derivatives was disscussed comprehensively. In addition, The Research and progre
9、ss of the inclusion technology of -cyclodextrin and its derivatives in pharmaceutical preparations were overviewed overallly based on the application, preparation methods，characterization methods, the combination of molecular and chemical methods of measurement tests of inclusion compound. In chapte
10、r 2, the HP-CDs with different substitution degrees (DS) have been synthesized by changing the amount of alkali and the ratio of raw materials. Meanwhile, the DS of the HP-CDs were calculated by 1H-NMR, respectively. In addition, Carboxymethyl-cyclodextrin (CM-CD) and three sulfonated -cyclodextrin
11、(SO3-CD) were synthesized and characterized based on literature methods. The DS of CM-CD and sulfonation trend of SO3-CD were determined.In chapter 3, six inclusion complexes of daidzein and HP-CD were prepared by the solution stirring method. The complexes were characterized by infrared spectrophot
12、ometry (IR), X-ray diffractometry (XRD), and ultra-violet spectrophotometry (UV) and thermal analysis method. the results indicate that the inclusion complexes were produced and the characterization spectrum differences of DS=7.8 HP-CD/daidzein was more obvious.In addition, the phase-solubility prof
13、iles of daidzein with the four HP-CD were investigated to determine the inclusion types and calculate the apparent stability constants (Kc). It concludes that all inclusion complexes followed AL type which suggested the presence of inclusion complexes of daidzein and cyclodextrins with molar ratio o
14、f 1:1. When the DS of HP-CD was 7.8, the K1;1 of the inclusion complexes was larger than others, which suggested that DS=7.8 HP-CD/daidzein was more stable. In chapter 4, the inclusion complexes of famotidine with HP-CD were prepared by the solution stirring method and reflux method. The two inclusi
15、on complexes were characterized by IR, XRD, UV，DSC and TG. In addition, the phase-solubility study of famotidine with HP-CD was investigated to determine the inclusion type and calculate the apparent stability constant. The results indicate that the inclusion type of famotine with HP-CD was AL. In this inclusion complex supramolecular system, the host and guest bonded at 1:1 molecules ratio, and the apparent stability constant was 146 Lmol-1. Key words: hydroxypropyl-cyclodextrin, daidzein, inclusion effect, famotidine, the apparent stability constant
