Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Bihar, 844102, India.
Naunyn Schmiedebergs Arch Pharmacol. 2021 Aug;394(8):1737-1755. doi: 10.1007/s00210-021-02096-0. Epub 2021 Jun 4.
With the increasing aging population and progressive nature of the disease, Alzheimer's disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.
随着人口老龄化和疾病的进展，阿尔茨海默病（AD）即将成为一种流行疾病，而目前治疗方法有限。AD 的特征是记忆丧失、行为不稳定、认知功能受损，主要表现为由于β-淀粉样蛋白的积累而导致的认知能力下降，同时胆碱能系统功能障碍。利伐斯的明是一种可逆的双重胆碱酯酶抑制剂，是治疗 AD 的一种更耐受和广泛使用的药物选择。然而，利伐斯的明亲水性强，首过代谢，中枢神经系统生物利用度低。包括脂质体和 PLGA 纳米粒在内的纳米制剂可以包裹亲水性药物，并有效地将其递送到大脑。此外，由于其可直接进入大脑，因此鼻内途径最近受到了相当大的关注。因此，本研究试图评估利伐斯的明鼻用脂质体和 PLGA 纳米粒制剂在急性东莨菪碱诱导的遗忘和慢性秋水仙碱诱导的认知功能障碍动物模型中的药代动力学和药效学特性，并通过药代动力学和药效学（PK-PD）建模验证最佳制剂。鼻用脂质体利伐斯的明制剂具有起效快（Tmax=5 分钟）、Cmax 更高（1489.5±620.71）、系统生物利用度增强（F=118.65±23.54；AUC=35921.75±9559.46）、半衰期延长（30.92±8.38 分钟）和清除率降低（Kel（1/min）=0.0224±0.006）等最佳药代动力学特征，与口服利伐斯的明（Tmax=15 分钟；Cmax=56.29±27.05；F=4.39±1.82；AUC=1663.79±813.54；t1/2=13.48±5.79；Kel（1/min）=0.0514±0.023）相比。此外，脂质体制剂在 Morris 水迷宫和被动回避任务中显著改善了东莨菪碱和秋水仙碱引起的记忆障碍，优于其他制剂。PK-PD 模型表明，脂质体制剂的药代动力学参数与乙酰胆碱酯酶抑制之间存在很强的相关性。
