Pant Anjali, Sharma Gajanand, Saini Sumant, Kaur Gurjeet, Jain Atul, Thakur Anil, Singh Bhupinder
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, India.
Drug Deliv Transl Res. 2024 Mar;14(3):730-756. doi: 10.1007/s13346-023-01427-3. Epub 2023 Sep 28.
Raloxifene (RLX) is popularly indicated in treatment of osteoporosis and prevention of breast cancer. Owing to its poor aqueous solubility, high pre-systemic metabolism, intestinal glucuronidation, and P-glycoprotein (P-gp) efflux, however, it demonstrates low (< 2%) and inconsistent oral bioavailability. The current work, Quality by Design (QbD)-driven development of phospholipid-embedded nanostructured lipidic carriers (NLCs) of RLX, accordingly, was undertaken to potentiate its lymphatic uptake, augment oral bioavailability, and possibly reduce drug dosage. Factor screening and failure mode effect analysis (FMEA) studies were performed to delineate high-risk factors using solid lipid (glyceryl monostearate), liquid lipid (vitamin E), and surfactant (Tween 80). Response surface optimization studies were performed employing the Box-Behnken design. Mathematical and graphical methods were adopted to embark upon the selection of optimized NLCs with various critical quality attributes (CQAs) of mean particle size as 186 nm, zeta potential of - 23.6 mV, entrapment efficiency of 80.09%, and cumulative drug release at 12 h of 83.87%. The DSC and FTIR studies, conducted on optimized NLCs, indicated successful entrapment of drug into the lipid matrix. In vitro drug release studies demonstrated Fickian diffusion mechanism. In vivo pharmacokinetic studies in rats construed significant improvement in AUC (4.48-folds) and in C (5.11-folds), unequivocally indicating markedly superior (p < 0.001) oral bioavailability of RLX-NLCs vis-à-vis marketed tablet formulation. Subsequently, level "A" in vitro/in vivo correlation (IVIVC) was also successfully attempted between the percentages of in vitro drug dissolved and of in vivo drug absorbed at the matching time points. In vitro cytotoxicity and cellular uptake studies also corroborated higher efficacy and successful localization of coumarin-6-loaded NLCs into MG-63 cells through microfluidic channels.
雷洛昔芬（RLX）常用于治疗骨质疏松症和预防乳腺癌。然而，由于其水溶性差、首过代谢高、肠道葡萄糖醛酸化以及P-糖蛋白（P-gp）外排，其口服生物利用度低（<2%）且不一致。因此，目前开展了以质量源于设计（QbD）为驱动的雷洛昔芬磷脂包埋纳米结构脂质载体（NLCs）的研发工作，以增强其淋巴摄取、提高口服生物利用度，并可能减少药物剂量。使用固体脂质（单硬脂酸甘油酯）、液体脂质（维生素E）和表面活性剂（吐温80）进行了因素筛选和失效模式效应分析（FMEA）研究，以确定高风险因素。采用Box-Behnken设计进行响应面优化研究。采用数学和图形方法选择具有各种关键质量属性（CQA）的优化NLCs，平均粒径为186nm，ζ电位为-23.6mV，包封率为80.09%，12小时累积药物释放率为83.87%。对优化后的NLCs进行的DSC和FTIR研究表明药物成功包封于脂质基质中。体外药物释放研究表明其符合Fickian扩散机制。大鼠体内药代动力学研究表明，AUC（4.48倍）和C（5.11倍）有显著改善，明确表明相对于市售片剂剂型，雷洛昔芬-NLCs的口服生物利用度明显更高（p<0.001）。随后，还成功尝试了在匹配时间点体外药物溶解百分比与体内药物吸收百分比之间建立“A”级体外/体内相关性（IVIVC）。体外细胞毒性和细胞摄取研究也证实了载香豆素-6的NLCs通过微流控通道进入MG-63细胞具有更高的疗效和成功定位。
