National UGC Centre of Excellence in Application of Nanomaterials, Nanoparticles, and Nanocomposites (Biomedical Sciences), Panjab University, Chandigarh 160014, India.
University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160014, India.
Int J Pharm. 2021 May 1;600:120482. doi: 10.1016/j.ijpharm.2021.120482. Epub 2021 Mar 15.
Numerous oral treatment options have been reported for neurological disorders, especially Alzheimer's disease (AD). Galantamine (GAL) is one of such drugs duly approved for management of AD. However, it exhibits poor brain penetration, low intestinal permeation and requires frequent dosing in AD treatment. The present studies, accordingly, were undertaken to develop DSPE-PEG 2000-based micelles loaded with GAL for efficient brain uptake, improved and extended pharmacokinetics, along with reduced dosing regimen.
Mixed nanomicelles (MNMs) were systematically formulated using QbD approach, and characterized for morphology, entrapment efficiency andin vitrodrug release.
Studies on CaCo-2 and neuronal U-87 cell lines exhibited substantial enhancement in the cellular permeability and uptake of the developed MNMs. Pharmacokinetic studies performed on rats showed significantly improved values of plasma AUC (i.e., 2.28-fold, p < 0.001), ostensibly due to bypassing of hepatic first-pass metabolism and improved intestinal permeability, together with significant rise in MRT (2.08-fold, p < 0.001) and t (4.80-fold; p < 0.001) values, indicating immense potential for prolonged drug residence in body.Besides, substantial elevation in brain drug levels, distinctly improved levels of biochemical parameters in brain homogenates and cognitive improvement in β-amyloid-treated rats, testify the superiority in MNMs in therapeutic management of AD.
The preclinical findings of the developed nanocarrier systems successfully demonstrate the notable potential of enhanced drug efficacy, extended duration of action and improved patient compliance.
有许多针对神经紊乱的口服治疗方案，尤其是针对阿尔茨海默病（AD）的治疗方案。加兰他敏（GAL）是一种经批准用于 AD 治疗的药物。然而，它在大脑中的穿透性差，肠道通透性低，在 AD 治疗中需要频繁给药。因此，本研究旨在开发载有 GAL 的基于 DSPE-PEG2000 的胶束，以实现高效的脑摄取、改善和延长药代动力学，同时减少给药方案。
使用 QbD 方法系统地制备混合胶束（MNMs），并对其形态、包封效率和体外药物释放进行表征。
在 CaCo-2 和神经元 U-87 细胞系上的研究表明，开发的 MNMs 显著提高了细胞通透性和摄取。在大鼠中进行的药代动力学研究显示，血浆 AUC 值显著提高（即 2.28 倍，p<0.001），显然是由于绕过了肝脏首过代谢和改善了肠道通透性，同时 MRT（2.08 倍，p<0.001）和 t（4.80 倍；p<0.001）值显著升高，表明药物在体内的滞留时间延长。此外，大脑药物水平的显著升高、大脑匀浆中生化参数的明显改善以及β-淀粉样蛋白处理大鼠的认知改善，证明了 MNMs 在 AD 治疗管理中的优越性。
所开发的纳米载体系统的临床前研究结果成功地证明了增强药物疗效、延长作用持续时间和提高患者依从性的显著潜力。
