Department of Pharmaceutics &Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), Cairo, Egypt.
Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Int J Pharm. 2020 Mar 30;578:119073. doi: 10.1016/j.ijpharm.2020.119073. Epub 2020 Jan 23.
A nanoemulsion system was designed for Atorvastatin calcium (ATOR) transdermal delivery to overcome its poor bioavailability of (30%) resulting from the extensive first-pass effect and dissolution rate-limited in vivo absorption. Pseudo ternary phase diagrams were developed, and various NE formulae were prepared using oleic acid (OA), Tween 80 as surfactant and PEG 400 as cosurfactant, ethanol and limonene as permeation enhancers (PEs). NEs were characterized for morphology, droplet size, zeta potential and in vitro release. The optimized formulae were assessed for ex vivo transdermal permeation and in vivo pharmacodynamic/pharmacokinetic studies. Hypocholesterolemic effect after 7 days skin treatment was detected and compared to oral ATOR dispersion. Finally, blood plasma levels were measured for 24 h for rats received the selected transdermal NE and transdermal drug in OA. The obtained results suggested the low potentiality of NE systems in transdermal delivery of lipophilic drugs, only the addition of PEs is driving factor for increasing drug flux through full thickness rat skin. In the optimized formula, the presence of ethanol and PEG 400 disrupts SC lipids exhibiting rapid ex vivo release profile compared to other NEs and to ATOR in OA. In contrast, the optimized NE achieved a prolonged plasma profile. Transdermal NE was significantly more efficient than oral administration in lowering cholesterol plasma level and in increasing ATOR bioavailability. In conclusion, data revealed no correlation between ex vivo and in vivo studies explained by the collapse of the follicles in ex vivo skin permeation study, leaving only the lipoidal pathway for NE to pass through, thus only NE components, neither nanosizing nor other reported mechanisms, are the main influencing factors. In vivo experiments suggested that o/w NE changed ATOR pathway to follicular delivery leading to accumulation of NE in follicles and consequently a prolonged plasma profile.
设计了纳米乳系统以实现阿托伐他汀钙（ATOR）的经皮递送，以克服其由于广泛的首过效应和体内吸收受溶解速率限制导致的生物利用度差（30%）。开发了伪三元相图，并使用油酸（OA）、吐温 80 作为表面活性剂和聚乙二醇 400 作为助表面活性剂、乙醇和柠檬烯作为渗透增强剂（PEs）制备了各种 NE 配方。对 NE 的形态、粒径、Zeta 电位和体外释放进行了表征。对优化的配方进行了离体透皮渗透和体内药效学/药代动力学研究。检测并比较了 7 天皮肤处理后降胆固醇作用，与口服 ATOR 分散体相比。最后，对接受选定的经皮 NE 和 OA 中经皮药物的大鼠进行了 24 小时的血浆水平测量。结果表明，NE 系统在亲脂性药物的经皮传递中潜力较低，只有添加 PEs 才是增加药物通量通过全厚大鼠皮肤的驱动因素。在优化的配方中，与其他 NE 相比，乙醇和 PEG 400 的存在破坏了 SC 脂质，表现出比 ATOR 在 OA 中更快的体外释放曲线。相比之下，优化的 NE 实现了延长的血浆曲线。与口服给药相比，经皮 NE 能更有效地降低胆固醇血浆水平并提高 ATOR 的生物利用度。总之，数据表明，体外和体内研究之间没有相关性，这可以用体外皮肤渗透研究中毛囊的塌陷来解释，这使得 NE 只能通过脂质途径通过，因此，只有 NE 成分，而不是纳米化或其他报道的机制，是主要的影响因素。体内实验表明，o/w NE 改变了 ATOR 的毛囊传递途径，导致 NE 在毛囊中积累，从而延长了血浆曲线。
