文档介绍：万古霉素提取工艺优化及高纯度万古霉素的制备
摘要
万古霉素(ycin)是从东方链霉菌(Streptomyces orientalis)中分离得到的糖肽类抗生素,是目前治疗青霉素耐药菌感染者和对β-内酰***类抗生素过敏者的首选药。万古霉素的分离纯化工艺开发已经有几十年的历史,国内于 90 年代末首次开发成功,由于价格优势及国内 GMP 管理水平的提高,万古霉素原料药全球市场基本被中国占领,但随着国内竞争的日益加剧,万古霉素工艺水平的提高和高品质万古霉素的制备成为各药企的主要研究内容。
本研究主要对万古霉素提取工艺进行了优化,并开发了高纯度万古霉素的制备方法。
(1)优化了万古霉素发酵液的预处理 pH 值,从而使万古霉素发酵液效价提高,确保了过滤速度并提高了过滤收率。
(2)优化了万古霉素发酵液陶瓷膜微滤工艺,通过对浓缩体积和滤速的研究,对加水倍数和过滤收率的研究,得到了最优的陶瓷膜过滤工艺参数,从而在保证过滤速度的同时提高了过滤收率。
(3)优化了万古霉素解吸液脱色工艺,通过对万古霉素解吸液在不同活性炭加量、起始
pH 值及搅拌时间的研究,确定了相关的工艺参数,然后通过正交实验得到了优化的活性炭脱色方案,从而在确保脱色效果的同时提高了脱色收率。
(4)以色谱纯度为 95%左右的万古霉素浓缩液为上柱液,利用 C18 硅胶做填料,通过中低压色谱制备柱,使用添加 %***化铵的甲醇水溶液作为洗脱剂,解吸得到高纯度万古霉素后,经过浓缩冻干,制备得到色谱纯度大于 99%的高纯度万古霉素冻干粉。从而开发了一条简单、高效,并适用于工业化生产的制备高纯度万古霉素的工艺路线。
关键词:万古霉素;提取;工艺优化;高纯度;制备
Purification Process Optimization of ycin and the Preparation of High Purity ycin
ABSTRACT
ycin is a glycopeptide antibiotic which obtained from the broth of Streptomyces orientalis. In those infected with Penicillin-resistant bacteria and patients hypersensitive to β-lactamase antibiotics, ycin is the first choice currently. The separation and purification technology of ycin has been developed for several decades, since its first development in the late 1990s, the global market for ycin API is mainly occupied by China due to price advantage and the increasing of domestic GMP management level. But with the deepening of petition, the improvement on ycin process and its high quality preparation e the major subject for panies.
This study is mainly concentrated on process optimization of ycin extraction and developed a preparation method for high purity ycin.
Optimized the preprocessing pH of ycin fermentation broth, thus improved its potency, ensured filtrating speed and yield.
Optimized the ceramic membrane microfiltration process, by studying of dosage, filtrating speed, multiples of adding water, filtrating yield, we get the most optimal process parameters, thus increasing filtrating yield and ensure filtrating speed at the same time.
Optimized the