University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, 160 014, India.
University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, 160 014, India; UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles & Nanocomposites Biomedical Sciences, Panjab University, Chandigarh, 160 014, India.
Colloids Surf B Biointerfaces. 2017 Nov 1;159:869-879. doi: 10.1016/j.colsurfb.2017.08.050. Epub 2017 Aug 31.
The present work entails systematic development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) of rosuvastatin calcium containing long-chain lipophiles using QbD-driven Formulation by Design (FbD) approach. Elements of quality target product profile (QTPP) were defined and critical material attributes (CQAs) earmarked. Excipient screening was performed for selecting a suitable long-chain lipophile along with a surfactant and a cosolvent. Maximal drug solubility was observed in Peceol (i.e., lipid), Tween 80 (i.e., surfactant) and Transcutol HP (i.e., cosolvent), which during pseudoternary phase titration study indicated maximal nanoemulsion region at 1:1 ratio of surfactant: cosolvent mixture. Risk analysis and factor screening study indicated selection of excipient levels as the critical material attributes (CMAs). D-optimal mixture design was used for systematic optimization of L-SNEDDS, which exhibited emulsification time of 131s, globule size <100nm and faster drug release rate >80% in 15min. Ex vivo permeability showed >70% permeation of drug across the rat intestine, while in situ perfusion study indicated up to 1.8 and 2.1-folds improvement in permeability and absorptivity parameters of the drug from optimized L-SNEDDS over the plain drug suspension. In vivo pharmacokinetic studies revealed 1.8- and 5.7-folds enhancement in AUC and C, and 0.33-folds reduction in T of drug from the optimized L-SNEDDS vis-à-vis the pure plain drug suspension. In vivo pharmacodynamic studies also indicated superior antihyperlipidemic activity of optimized L-SNEDDS in normalizing serum lipid levels. Overall, the research work construed significant role of long-chain lipophiles in enhancing biopharmaceutical attributes of the L-SNEDDS of rosuvastatin.
本工作采用基于 QbD 的制剂设计（FbD）方法，系统地开发了含有长链亲脂性物质的瑞舒伐他汀钙的液体制剂自微乳给药系统（L-SNEDDS）。定义了质量目标产品概况（QTPP）的要素，并指定了关键质量属性（CQAs）。进行了辅料筛选，以选择合适的长链亲脂性物质以及表面活性剂和共溶剂。在 Peceol（即脂质）、Tween 80（即表面活性剂）和 Transcutol HP（即共溶剂）中观察到最大药物溶解度，在伪三元相滴定研究中，表明在表面活性剂：共溶剂混合物 1:1 比例下具有最大的纳米乳区域。风险分析和因素筛选研究表明，选择赋形剂水平为关键材料属性（CMA）。D-最优混合物设计用于 L-SNEDDS 的系统优化，其乳化时间为 131s，粒径<100nm，在 15min 内药物释放率>80%。体外渗透研究表明药物在大鼠肠内的渗透>70%，而在体灌注研究表明，与普通药物混悬剂相比，优化的 L-SNEDDS 使药物的渗透和吸收参数分别提高了 1.8 倍和 2.1 倍。体内药代动力学研究表明，与纯普通药物混悬剂相比，优化的 L-SNEDDS 使药物的 AUC 和 C 分别提高了 1.8 倍和 5.7 倍，T 降低了 0.33 倍。体内药效学研究还表明，与普通药物混悬剂相比，优化的 L-SNEDDS 具有更好的降血脂活性，能更有效地调节血清脂质水平。总的来说，这项研究工作表明长链亲脂性物质在增强瑞舒伐他汀钙 L-SNEDDS 的生物制药特性方面发挥了重要作用。
