Scale-Up of the Manufacturing Process To-Produce Docetaxel-Loaded mPEG-b-p(HPMA-Bz) Block Copolymer Micelles for Pharmaceutical Applications
Scale-Up of the Manufacturing Process To-Produce Docetaxel-Loaded mPEG-b-p(HPMA-Bz) Block Copolymer Micelles for Pharmaceutical Applications
复制标题
DOI：
10.1021/acs.oprd.9b00387
复制
发表时间：
2019-12-01
影响因子：
3.4
通讯作者：
van Hest, Jan C. M.
中科院分区：
文献类型：
--
作者：
Bresseleers, Jaleesa;Bagheri, Mahsa;van Hest, Jan C. M.
为制备多西紫杉醇聚乙二醇-b-聚(N-2-苯甲酰氧丙基甲基丙烯酰胺)(mpeg-b-p(HPMA-BZ))胶束，开发了一种高效、可扩展和良好的制造规范(GMP)兼容的工艺。首先，通过对间歇合成工艺的逐级考察，优化了mpeg-b-p(HPMA-BZ)嵌段共聚物的合成工艺。这导致了1公斤的mpeg-b-p(HPMA-BZ)嵌段共聚物的生产，其中含有5 kDa的聚乙二醇单嵌段，总分子量为22.5 kDa。其次，通过评估关键工艺参数，考察了间歇和连续流动装置中胶束形成的重现性和可扩展性。这导致了一种新的、高效的连续流动工艺的开发，从而产生了100毫升的空载胶束，尺寸为55纳米。最后，成功地微调了抗癌药物多西紫杉醇对胶束的负载，以获得对负载胶束特性的精确控制。结果表明，采用新开发的连续流动工艺可制得粒径为55 nm、包封率为65%、载药量为14%、室温水中稳定性至少为2个月的多西紫杉醇胶束(聚合物浓度为20 mg/m L，进料浓度为5 mg/m L)，包封率为65%，载药量为14%。总之，这项研究为高效、稳健地大规模生产具有高包封率和稳定性的多西紫杉醇胶束铺平了道路，这对其作为临床相关药物输送平台的适用性至关重要。
An efficient, scalable, and good manufacturing practice (GMP) compatible process was developed for the production of docetaxel-loaded poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) micelles. First, the synthesis of the mPEG-b-p(HPMA-Bz) block copolymer was optimized through step-by-step investigation of the batch synthesis procedures. This resulted in the production of 1 kg of mPEG-b-p(HPMA-Bz) block copolymer with a 5 kDa PEG block and an overall molecular weight of 22.5 kDa. Second, the reproducibility and scalability of micelle formation was investigated for both batch and continuous flow setups by assessing critical process parameters. This resulted in the development of a new and highly efficient continuous flow process, which led to the production of 100 mL of unloaded micelles with a size of 55 nm. Finally, the loading of the micelles with the anticancer drug docetaxel was successfully fine-tuned to obtain precise control on the loaded micelle characteristics. As a result, 100 mL of docetaxel-loaded micelles (20 mg/mL polymer and 5 mg/mL docetaxel in the feed) with a size of 55 nm, an encapsulation efficiency of 65%, a loading capacity of 14%, and stable for at least 2 months in water at room temperature were produced with the newly developed continuous flow process. In conclusion, this study paves the way for efficient and robust large-scale production of docetaxel-loaded micelles with high encapsulation efficiencies and stability, which is crucial for their applicability as a clinically relevant drug delivery platform.