和厚朴酚环糊精包合物的制备及评价

发布时间：2018-07-12 14:58

本文选题：和厚朴酚 + 羟丙基-β-环糊精　；参考：《重庆医科大学》2014年硕士论文

【摘要】：和厚朴酚（Honokiol, HNK）是从我国传统中药木兰科植物厚朴（Magnolia officinalis Rehd. et Wils）或凹叶厚朴（Magnolia officinalisRehd. et Wils. var. biloba Rehd. et Wils）的干燥干皮、根皮及枝皮中提取的具有生物活性的化学物质。研究发现和厚朴酚具有明显的抗肿瘤、抗炎、抗氧化、抗辐射及心血管保护作用等药理活性。和厚朴酚易氧化，在水中几乎不溶，生物利用度低的特点限制了其进一步研究和应用。本文采用环糊精包合技术，率先采用羟丙基-β-环糊精（hydroxy-propyl-β-cyclodextrin, HPCD）和磺丁基-β-环糊精（sulfobutylether-β-cyclodextrin，SBECD）作为包合材料，利用溶液搅拌法制备和厚朴酚羟丙基-β-环糊精包合物（HNK-HPCD）与和厚朴酚磺丁基-β-环糊精包合物（HNK-SBECD），增加HNK的表观溶解度，改善其生物利用度，为其进一步研究及应用奠定基础。本实验的主要内容包括：1.建立HNK含量测定方法，考察HPCD对HNK的增溶情况；2.筛选HNK-HPCD包合物制备方法和工艺优化；3. HNK-HPCD包合物验证及体外释放行为研究；4. HNK-HPCD大鼠体内药动学研究；5. HNK-SBECD制备工艺研究；6. HNK-SBECD包合物验证及体外释放行为考察；7. HNK-SBECD大鼠体内初步药动学研究。建立HNK含量测定的紫外分光光度方法。采用相溶解度实验，考察HPCD不同温度下，对HNK的增溶情况。从溶液搅拌法、超声法和研磨法中筛选制备HNK-HPCD包合物的方法，考虑到超声法和研磨法不利于工业化生产，，而溶液搅拌法的稳定性和可重复性较好，最终选择溶液搅拌法制备包合物。通过单因素考察和三因素五水平星点设计-效应面法对制备工艺进行优化。采用溶液搅拌法制备HNK-HPCD和HNK-SBECD包合物溶液，通过冷冻干燥，获得固态的包合物。通过X-射线衍射法（XPD）、差示扫描量热法(DSC)和红外光谱法（FT-IR）等方法对包合物进行验证；采用透析袋法考察了HNK-HPCD与HNK-SBECD的体外释药行为。本文以SD大鼠为实验动物，考察HNK-HPCD与HNK-SEBCD在大鼠体内的药动学行为。溶解搅拌法制备HNK-HPCD和HNK-SBECD包合物溶液，分别灌胃给予HNK-HPCD和HNK-SBECD包合物溶液，考察其药动学；同时制备HNK的混悬剂（0.5%CMC-Na），灌胃给药，作为包合物溶液的对照；本研究还考察了HNK-HPCD和HNK-SBECD包合物溶液尾静脉注射给药的药动学行为。建立了以吴茱萸碱为内标的反相高效液相色谱测定HNK血药浓度的方法，采用非房室模型（统计矩）对血药浓度时间数据进行分析。结果表明，将HNK制备成HNK-HPCD和HNK-SBECD后，与口服HNK混悬剂相比，相对生物利用度分别是HNK混悬剂的2.13倍和1.58倍。系列实验表明，本文选择的制备方法简单方便有效。将HNK制备成HNK-HPCD和HNK-SBECD后，HNK的表观溶解度显著提高，同时也改善了其相对生物利用度。
[Abstract]:Magnolia officinalis Rehd. et Wils or Magnolia officinalis Rehd. et Wils. Et Wils. var. biloba Rehd. et Wils are bioactive chemicals extracted from dried bark, root skin and branch bark of Magnolia officinalis Rehd. et Wils. It was found that honokiol had obvious pharmacological activities such as anti-tumor, anti-inflammatory, anti-oxidation, anti-radiation and cardiovascular protection. And honokiol is easy to be oxidized, almost insoluble in water, and its low bioavailability limits its further research and application. The inclusion materials of hydroxy-propyl- 尾 -cyclodextrin (HPCD) and sulfobutylether- 尾 -cyclodextrin (SBECD) were used as inclusion materials. HNK-HPCD and honokiol sulfoxypropyl- 尾 -cyclodextrin inclusion complex (HNK-SBECD) were prepared by solution stirring method. The apparent solubility of honokiol hydroxypropyl 尾 -cyclodextrin (HNK-SBECD) was increased and its bioavailability was improved. The main contents of this experiment include: 1. To establish a method to determine the content of HNK and to investigate the solubilization of HNK by HPCD. The preparation method and process optimization of HNK-HPCD inclusion complex were selected. Identification of HNK-HPCD inclusion complex and in vitro release behavior of HNK-HPCD Pharmacokinetics of HNK-HPCD rats in vivo. Study on preparation process of HNK-SBECD. Identification of HNK-SBECD inclusion complex and in vitro release behavior of HNK-SBECD. Preliminary pharmacokinetic study of HNK-SBECD rats in vivo. A UV spectrophotometric method for the determination of HNK was established. The solubilization of HNK at different temperatures of HPCD was investigated by phase solubility experiment. The method of preparing HNK-HPCD inclusion compound was screened from solution stirring method, ultrasonic method and grinding method. Considering that ultrasonic method and grinding method are not good for industrial production, the solution stirring method has better stability and repeatability. Finally, the inclusion compound was prepared by solution stirring method. The preparation process was optimized by single factor investigation and three factor and five level star design-effect surface method. The solution of HNK-HPCD and HNK-SBECD inclusion compound was prepared by solution agitation, and the solid inclusion compound was obtained by freeze-drying. The inclusion complex was verified by X-ray diffraction (XPD), differential scanning calorimetry (DSC) and infrared spectroscopy (FT-IR), and the in vitro release behavior of HNK-HPCD and HNK-SBECD was investigated by dialysis bag method. The pharmacokinetics of HNK-HPCD and HNK-SEBCD in SD rats was investigated. HNK-HPCD and HNK-SBECD inclusion complex solution were prepared by dissolving and stirring method. HNK-HPCD and HNK-SBECD inclusion complex solution were administered intragastrically to investigate the pharmacokinetics of HNK-HPCD and HNK-SBECD inclusion complex solution. The pharmacokinetics of HNK-HPCD and HNK-SBECD inclusion complex solution was also investigated. A method for determination of HNK concentration by reversed-phase high performance liquid chromatography (RP-HPLC) with rutaecarpine as internal standard was established. The time data of blood drug concentration were analyzed by non-atrioventricular model (statistical moments). The results showed that the relative bioavailability of HNK prepared into HNK-HPCD and HNK-SBECD was 2.13 and 1.58 times higher than that of oral HNK suspension respectively. A series of experiments show that the method chosen in this paper is simple, convenient and effective. The apparent solubility and relative bioavailability of HNK in HNK-HPCD and HNK-SBECD were significantly improved after the preparation of HNK into HNK-HPCD and HNK-SBECD.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

【共引文献】