Ergin Ahmet Doğan, Üner Burcu, Balcı Şencan, Demirbağ Çağlar, Benetti Camillo, Oltulu Çağatay
Department of Pharmaceutical Technology, Faculty of Pharmacy, Trakya University, Edirne, Turkey; Department of Pharmaceutical Nanotechnology, Institute of Health Sciences, Trakya University, Edirne, Turkey; Department of Neuroscience, University of Turin, Turin, Italy.
Department of Pharmaceutical Technology, Faculty of Pharmacy, St. Louis College of Pharmacy, USA.
J Pharm Sci. 2023 Nov;112(11):2921-2932. doi: 10.1016/j.xphs.2023.07.020. Epub 2023 Jul 26.
Coenzyme Q10 (CoQ10) is a fat-soluble vitamin-with a benzoquinone-like structure. CoQ10 plays a role in membrane stability, energy conversion, and ATP production. It is also one of the important antioxidants in the body. The bioavailability of exogenous CoQ10 is extremely low due to its poor aqueous solubility and large molecular mass. In this study, mixed proniosomal drug delivery systems have been used to increase solubility and bioavailability of CoQ10. Arginine (semi-essential amino acid) was incorporated in the formulation composition to achieve higher efficacy by boosting nitric oxide presence, endothelial dysfunction, and cellular uptake. Proniosomes were investigated in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, and process yield, and optimization studies were carried on by utilizing STATISTICA 8.0 software considering dependent factors (carrier amount, drug amount, and surfactant ratio). Optimum proniosome formulation (particle size 187.5 ± 16.35 nm, zeta potential: -44.7 ± 12.8 mV, encapsulation efficiency 99.05±0.30%, and product yield: 90.55%) was evaluated for thermal analysis, in-vitro drug release using microcentrifuge method. In-vitro cytotoxicity studies of proniosomes were performed on intestinal Epithelial Cells (Cellartis®, ChiPSC18) and no cytotoxic effects was seen during the 72 h. Besides, anti Alzheimer effect was investigated on APPSL-GFP lentivirus-infected human neural cells (APPSL-GFP-l-HNC) and Alzheimer biomarkers (p-tau181 and p-tau217). While CoQ10's relative bioavailability was statistically increased by proniosome compared to CoQ10 suspension (p<0.01, Grubb test). PK parameters of proniosome formulation, obtained with non-compartmental modeling, were fitting to the data (R=0.956±0.026). The study results proved that proniosomal formulation has a high potential drug delivery system for both increasing bioavailability and anti-Alzheimer effect of CoQ10.
辅酶Q10（CoQ10）是一种具有苯醌样结构的脂溶性维生素。CoQ10在膜稳定性、能量转换和ATP生成中发挥作用。它也是体内重要的抗氧化剂之一。由于其水溶性差和分子量较大，外源性CoQ10的生物利用度极低。在本研究中，混合前体脂质体药物递送系统已被用于提高CoQ10的溶解度和生物利用度。精氨酸（半必需氨基酸）被纳入制剂组合物中，以通过增加一氧化氮的存在、改善内皮功能障碍和促进细胞摄取来实现更高的疗效。对前体脂质体进行了粒径、多分散指数、zeta电位、包封率和工艺产率等方面的研究，并利用STATISTICA 8.0软件考虑相关因素（载体量、药物量和表面活性剂比例）进行了优化研究。对优化后的前体脂质体配方（粒径187.5±16.35nm，zeta电位：-44.7±12.8mV，包封率99.05±0.30%，产品产率：90.55%）进行了热分析、使用微量离心法进行体外药物释放研究。对前体脂质体进行了体外细胞毒性研究，实验对象为肠上皮细胞（Cellartis®，ChiPSC18），在72小时内未观察到细胞毒性作用。此外，还对APPSL-GFP慢病毒感染的人神经细胞（APPSL-GFP-l-HNC）和阿尔茨海默病生物标志物（p-tau181和p-tau217）进行了抗阿尔茨海默病作用研究。与CoQ10混悬液相比，前体脂质体使CoQ10的相对生物利用度有统计学意义的提高（p<0.0一，格鲁布检验）。通过非房室模型获得的前体脂质体配方的药代动力学参数与数据拟合良好（R=0.956±0.026）。研究结果证明，前体脂质体制剂是一种具有高潜力的药物递送系统，可提高CoQ10的生物利用度和抗阿尔茨海默病作用。
