论文总字数：20744字

摘 要

2003年底，注射用达托霉素在美国FDA首次以商品名Cubicin上市，规格为350mg和500mg。我国CFDA于2009年批准同意该品种进口，商品名为克必信，规格为500mg。达托霉素对革兰氏阳性菌具有较广的抗菌谱。这些细菌包括耐药菌，如耐万古霉素的肠球菌，耐甲氧西林的金葡菌，糖肽类敏感的金葡菌，凝固酶阴性的葡萄球菌和耐青霉素的肺炎链球菌。目前，临床上对于这些耐药菌可选择的抗生素很少，而达托霉素在临床上有着明显的优势，其临床耐药菌株的出现率非常低，产生的不良反应也在可以接受的范围内，应用前景十分广阔。因此，开发该产品有着极其重要的临床意义。临床主要用于治疗感染性内膜炎、复杂性皮肤及皮肤软组织感染。不过达托霉素对温度、pH值特别敏感，其制剂仿制难度较高，本课题在仿制国外进口品种克必信（CUBICIN）的基础上研制开发了注射用达托霉素。

根据达托霉素的理化特性，通过前期文献调研，对达托霉素注射剂的处方及制备工艺进行了系统的筛选，得到了符合USP标准的注射用达托霉素。

达托霉素的处方筛选与工艺研究以达托霉素的有关物质为主要考察指标，确定其最佳处方和制备工艺。达托霉素热稳定性较差，参照原研资料（EMEA 《Scientific Discussion》），本品原料药本身具有很好的骨架结构，处方中不需添加赋形剂；本品主要采取无菌操作结合过滤除菌的无菌保障工艺。本品原料药为冷冻冻干粉，生产工艺步骤包括配液、pH值调节和浓度调整、无菌过滤、灌装、冷冻干燥、充氮压塞，轧盖，灯检，包装制成。为避免达托霉素在生产过程的降解，采用了低温配液条件；并且，冻干成品充氮气保护。中间体pH控制在4.5~5.0。灌装时过量5%以保证在临床用药过程中复溶后可取用足够的给药剂量。制得的中试样品水分、酸度、有关物质及含量测定等各项质量考察指标均与国外市售品克必信（CUBICIN）一致，无明显差异。研究结果表明，该处方设计合理，制备工艺稳定，产品质量可控。

关键词 注射用达托霉素 处方工艺研究 处方筛选 分析方法验证

ABSTRACT

Daptomycin can be resistant to gram positive bacteria in vitro．These bacteria includsdrug-resistant bacteria，such asvancomycin-resistant enterococcus，Methicillin-resi-stant staphylococcus aureus，glycopeptide-sensitive Staphylococcus aureus，coagulase negative Staphylococcus and penicillin-resistant Streptococcus pneumoniae．At present，few antibiotics are available for these resistant strains in clinic．Daptomycin for injection has obvious advantages in clinic，the occurrence rate of clinical resistance strains is very low，the advantage of fighting against drug-resistant bacteria will become more significant in the next period of time，and have wide prospect of application．This topic researches and developments of daptomycin for injection on the basis of generic imported drug Cubicin (CUBICIN)．Daptomycin for injection for the treatment of infective endocarditis complicated skin、skin and soft tissue infection (cSSSI)，The development of this product has extremely important clinical significance．But Daptomycin is particularly sensitive to temperature and pH, so it is difficult to copy into generic drug product , According to physical and chemical properties of Daptomycin, through the early literature research, we systematically screen the prescription and preparation process for Daptomycin for injection, finally we obtain Daptomycin for injection which meets the criteria.

Using related substances of daptomycin to determine its optimal formulation and preparation process. Daptomycin has poor thermal stability , with reference to the original research data (EMEA 《the scientific discussion 》), it’s prescription has no excipient. The raw materials from the drug itself has a good framework; this product mainly take aseptic manipulation combined with filtration sterilization sterile protection process.Raw material is daptomycin freeze-dried powder， the production process comprises the following steps：liquid distribution，pH and concentration

adjustment，aseptic filtration，filling，freeze-drying ，nitrogen filling pressure plug，light inspection and packaging. In order to avoid the degradation of daptomycin in the production process，we use low temperature while liquid　distribution，andnitrogen filled protection in finished product．In-process product should control　pH from 4.5 to 5.0．When filling in excess of 5% in order to ensure sufficient dosage　after　rehydrationin of clinical medication．Compare the quality inspection index of the middle experiment Daptomycin for injection with the foreign commercial products (CUBICIN) such as water, acidity, related substances and determination of the quality of samples etc., they were basically the same.The research results show that the prescription design is reasonable, the preparation process is stable, and the quality of products can be controlled.

KEYWORDS: Daptomycin for Injection；FormuLation and processing；Prescription screening；Validation of analytical method

目录

摘 要 I

ABSTRACT II

第一章 文献综述 1

1.1 达托霉素的研究概况 1

1.1.1 达托霉素国内外研究情况 1

1.1.2 达托霉素作用机制和药理毒理 2

1.1.3 达托霉素临床研究情况 3

1.2 立题依据及研究思路 6

第二章 注射用达托霉素的处方筛选 7

2.1 实验材料与实验仪器 7

2.1.1实验材料、试剂 7

2.1.2实验仪器 8

2.2 处方组成 9

2.2.1原料药 9

2.2.2 辅料 9

2.3 处方筛选 9

2.3.1 赋形剂及其用量的选择 10

2.3.2 主药与pH调节剂的投料顺序 12

2.4 配液优化 13

2.4.1 配液浓度的选择 13

2.4.2 配液温度的选择 14

2.5 注射用达托霉素处方工艺的确定 16

第三章 总结与讨论 19

第四章 前景与展望 20

参考文献 21

致谢 23

第一章 文献综述

1.1 达托霉素的研究概况

1.1.1 达托霉素国内外研究情况

众所周知，抗生素耐药性的问题在世界范围内都得到了广泛的关注。在过去的二十五年内，诸如耐甲氧西林葡萄球菌、青霉素和红霉素耐药肺炎球菌、万古霉素耐药性肠球菌等革兰氏阳性菌感染引起的耐药性问题的产生已经越来越严重了^[1,2]。随着高致病耐药菌的不断出现，临床上对新抗生素的呼唤声也越来越强了^[3]。达托霉素制剂用药方便，毒副作用小，而且对以上耐药菌均有很好的杀菌效果^[4]。它的问世给一线临床带来了曙光，为医生提供了一种新的治疗方案，成为“病原菌最后一道防线——万古霉素”的最佳替代品^[5]；更具意义的是，达托霉素作为环脂肽类抗生素家族的第一个产品^[6-8]，其化学结构和作用机制不同于已有所有类别的抗生素，是应用到临床的唯一新结构类别抗生素。

请支付后下载全文，论文总字数：20744字