脂质体、分散体和肠溶包衣替米考星体外释放和抑菌研究

发布时间：2018-11-08 14:34

【摘要】：作为大环内酯类，替米考星是在泰乐菌素的基础上通过化学半合成制备的抗菌药。该药具有较广的抗菌谱，临床上应用于治疗由革兰氏阴性菌和革兰氏阳性菌引起的畜禽呼吸道疾病。但是替米考星存在水溶解性差的问题，为了解决难溶性药物替米考星溶出效果差的缺陷，开发几种药物剂型，增加该药的临床应用。在本文研究中，分别使用脂质体、固体分散体和肠溶颗粒包衣技术来提高替米考星的溶出度和抑菌效果。对制备出来的三种制剂分别采用不同的表征方法进行检测，并且评价其优劣。本文研究内容和结果如下： ①建立紫外分光光度法对替米考星的测量及其标准曲线，探索替米考星脂质体包封率的测量方法。即分别使用SephadexG-25和SephadexG-50测定脂质体的洗脱曲线和回收率，并测定脂质体的包封率。然后采用纳米粒度及Zeta电位分析仪，测量按照不同处方以及不同方法制备的脂质体平均粒径和Zeta电位。经过比较优化后确认最佳工艺，结果表明：采用薄膜法制备的脂质体包封率达到51.28%，而硫酸铵梯度法、pH梯度法和逆向蒸发法制备脂质体，包封率分别为30.06%、41.65%和45.83%。薄膜法、硫酸铵梯度法、pH梯度法和逆向蒸发法制备脂质体粒径分别为103.7nm、78.21nm、81.66nm和248.6nm；Zeta电位则分别为-31.7mV、-19.3mV、-24.1mV和-5.28mV。 ②采用溶剂法和熔融法制备不同比例的替米考星固体分散体，并用DSC-TGA、X衍射和FTIR等手段共同对分散体进行了表征，结果均表明：替米考星与载体发生了一定的分子作用，替米考星均分散于载体中。 ③使用不同的配方和包衣材料，制备了替米考星肠溶包衣颗粒，获得了优化处方和工艺条件。并用紫外分光光度法测定三种处方及其各包衣增重比例的颗粒中替米考星含量，以及体外肠溶特征。 ④针对替米考星释药特征，1）完成了脂质体释放度实验，并且对薄膜法脂质体释放曲线进行拟合，获得其一级动力学方程:ln(100Q)0.2980t4.5087(r2=0.9739)。2）测试了肠溶包衣颗粒在胃液和肠液中的溶出度。3）固体分散体的溶出曲线显示：替米考星/聚乙二醇五个比例的固体分散体溶出速率均很快，在5min时即完全溶出，达到98%以上；而替米考星/聚乙烯吡咯烷酮-乙基纤维素则表现出一定的滞后溶出，，但是药物的积累溶出度也达到了85%以上。 ⑤体外抑菌实验表明：在原料药和三种制剂五个样品中，脂质体的抑菌能力略小于原料药；肠溶包衣颗粒的抑菌能力与原料药的无显著差别，菌种上的敏感度略有差别。替米考星/聚乙二醇固体分散体的抑菌效果最佳。替米考星/聚乙烯吡咯烷酮-乙基纤维素有一定的缓释作用，但在短时间内能实现替米考星的溶出，可抑制细菌的生长。通过体外溶出度实验和抑菌实验研究表明：经过三种方式处理后的替米考星溶出度得到了不同程度的改善，并且各制剂的体外抑菌效果与其体外溶出有一定的相关性。
[Abstract]:As macrolides, the tilmicosin is an antibacterial agent prepared by chemical and semi-synthesis on the basis of telosin. The composition has a wide antibacterial spectrum and is clinically applied to the treatment of livestock and poultry respiratory diseases caused by gram-negative bacteria and gram-positive bacteria. However, in order to solve the problem of poor water solubility of the tilmicosin, several kinds of drug dosage forms were developed to increase the clinical application of the drug. In this study, the solubility and the antibacterial effect of temetaka were improved by using liposome, solid dispersion and enteric coating technique, respectively. The three preparations were tested by different characterization methods, and their advantages and disadvantages were evaluated. The contents and results of this study are as follows: The measurement of tilmicosin and its standard curve by the method of ultraviolet spectrophotometry, and the measurement of the encapsulation rate of the tilmicosin liposome is explored. Methods: The elution profile and the recovery rate of the liposomes were determined by SephadexG-25 and Sephadex G-50, respectively. Sealing rate. The mean particle size and Zeta of the liposomes prepared according to different formulations and different methods were then measured using a nano-particle size and a Zeta potential analyzer. The results showed that the entrapment efficiency of the liposomes prepared by the thin film method was 51. 28%, and the liposome was prepared by the gradient method, the pH gradient method and the reverse evaporation method. The encapsulation rate was 30. 06%, 41. 65% and 45. 8, respectively. The particle size of the liposomes was 103.7nm, 782.21nm, 81.66nm and 248.6nm, respectively. The Zeta potential was -31.7 mV, -193.3mV, -24.1 mV and -5.28, respectively. In this paper, the solid dispersion of tilmicosin was prepared by solvent method and melting method, and the dispersion was characterized by DSC-TGA, X-ray diffraction and FTIR. In the carrier, different formulations and coating materials were used to prepare the tilmicosin enteric coated granules, which was excellent. the formula and the process conditions are defined, and the content of the tilmicosin in the particles of the three prescriptions and the weight-increasing proportion of each coating is determined by the ultraviolet spectrophotometry, and in-vitro enteric-soluble features. The present invention has completed the liposome release experiment for the tilmicosin release profile, and the film-method liposome release curve is fitted. The first-order kinetic equation was obtained: ln (100Q) 0. 2980t4. 5087 (r2 = 0.9739). 2) The solubility of the enteric coated granules in the gastric juice and the intestinal fluid was tested. The whole solution is more than 98%, and the tilmicosin/ polyethylene dialkanone-ethyl cellulose shows a certain hysteresis and dissolution, but the drug accumulation and dissolution In vitro antibacterial experiments show that the antibacterial ability of the liposome is slightly less than that of the drug substance in the five samples of the drug substance and the three preparations, and the antibacterial capacity of the enteric coated particles and the drug substance are not significant. The difference is that there is a slight difference in the sensitivity of the species. The antibacterial effect of the solid dispersion of the dialcohol is the best. The tilmicosin/ polyethylene dialkanone-ethyl cellulose has a certain slow-release effect, but it can be realized in a short time The dissolution of the test star can inhibit the growth of the bacteria, and the in vitro dissolution degree experiment and the bacteriostatic experimental study show that the solubility of the tilmicosin after three methods has been improved to a different degree, and the in vitro of each preparation
【学位授予单位】：重庆大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

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