UGC Centre of Advanced Studies, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
AAPS PharmSciTech. 2019 Feb 21;20(3):118. doi: 10.1208/s12249-019-1319-x.
The present studies describe quality-by-design-based design and characterization of cationic self-nanoemulsifying formulations of paclitaxel for improving its biopharmaceutical attributes. Solubility and phase titration experiments were designed to select the lipidic and emulsifying excipients. Two different types of lipidic nanoformulations were developed using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). The nanoformulations were optimized by mixture designs and subjected to evaluation for globule size, zeta potential, drug release, and intestinal permeability. Following apt mathematical modeling, the optimum nanoformulation was earmarked using numerical optimization. Further, cationic formulations were developed for both LCT- and MCT-containing formulations and subjected to performance evaluation. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated 2.7-fold improvement in dissolution rate from optimized cationic nanoformulations over powder pure drug. Ex vivo and in situ evaluation performed on Wistar rats exhibited nearly six- to eightfold enhancement in permeation and absorption parameters of the drug for the optimized cationic nanoformulation as compared to the pure paclitaxel. Pharmacokinetic studies indicated nearly 13.4-fold improvement in AUC and C, along with 1.8-fold reduction in T of the drug from cationic nanoformulations as compared to the pure drug suspension. Moreover, nanoformulation containing long-chain lipids exhibited superior performance (1.18-fold improvement in drug absorption) over medium-chain lipids. Cytotoxicity evaluation of cationic nanoformulations on MCF-7 cells revealed significant reduction in growth vis-à-vis the pure drug. Overall, the current paper reports successful systematic development of paclitaxel-loaded cationic self-nanoemulsifying systems with distinctly improved biopharmaceutical performance.
本研究基于质量源于设计理念，设计并表征了紫杉醇的阳离子自微乳给药系统，以改善其生物药剂学性质。通过溶解度和相滴定实验来选择脂质和乳化辅料。使用中链甘油三酯（MCT）和长链甘油三酯（LCT）开发了两种不同类型的脂质纳米制剂。通过混合设计优化纳米制剂，并对其粒径、Zeta 电位、药物释放和肠道渗透性进行评价。经过适当的数学建模，采用数值优化选择最佳纳米制剂。此外，还为含有 LCT 和 MCT 的制剂开发了阳离子制剂，并对其性能进行了评价。对优化后的制剂进行了广泛的评价，体外药物释放研究表明，与纯药粉末相比，优化后的阳离子纳米制剂的溶解速率提高了 2.7 倍。在 Wistar 大鼠进行的离体和在体评价显示，与纯紫杉醇相比，优化后的阳离子纳米制剂的药物渗透和吸收参数分别提高了近 6 到 8 倍。药代动力学研究表明，与纯药物混悬剂相比，阳离子纳米制剂的 AUC 和 C 分别提高了近 13.4 倍，T 降低了 1.8 倍。此外，长链脂质纳米制剂的性能优于中链脂质纳米制剂（药物吸收提高了 1.18 倍）。阳离子纳米制剂对 MCF-7 细胞的细胞毒性评价表明，与纯药相比，其生长显著降低。综上所述，本研究成功系统地开发了载紫杉醇的阳离子自微乳给药系统，具有明显改善的生物药剂学性能。
