Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization
Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization
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卡巴拉汀鼻至脑微乳给药系统：配方和离体表征
DOI：
10.3109/10717544.2013.878857
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发表时间：
2015
期刊：
影响因子：
6
通讯作者：
H. Padh
中科院分区：
文献类型：
--
作者：
B. Shah;M. Misra;C. Shishoo;H. Padh
摘要阿尔茨海默病（AD）是一种进行性神经退行性疾病，导致神经元、认知功能不可逆的丧失和异常蛋白质聚集体的形成。卡巴拉汀是一种用于治疗AD的可逆性胆碱酯酶抑制剂，经过广泛的首过代谢，因此将其3 mg剂量后的绝对生物利用度限制为仅36%。由于极高的水溶性，利斯的明渗透性差，在脑中的浓度较低，因此需要频繁口服给药。本研究旨在配制rivastigmine的微乳（ME）和粘膜粘附微乳（MME）用于鼻-脑给药，并使用体外和离体研究比较两种系统的药物扩散百分比。通过滴定法制备载卡巴拉汀的ME和MMEs，并对药物含量、小球大小分布、zeta电位、pH、粘度和鼻纤毛毒性研究进行表征。配制了含有8% w/w Capmul MCM EP、44% w/w Labrasol：Transcutol-P（1：1）和48% w/w蒸馏水的卡巴拉汀ME系统，而分别使用0.3% w/w壳聚糖（CH）和十六烷基三甲基溴化铵（作为粘膜粘附剂）配制MME。ME和MMEs制剂是透明的，药物含量、小球尺寸和zeta电位分别在98.59%至99.43%、53.8 nm至55.4 nm和-2.73 mV至6.52 mV范围内。含0.3%w/w CH的MME符合Higuchi模型（r2 = 0.9773），并显示出最高的扩散系数。无鼻纤毛毒性，稳定3个月。然而，仅在体内和生物分布研究后才能确定开发的CH基MME用于rivastigmine鼻-脑递送的潜力。
Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to irreversible loss of neurons, cognition and formation of abnormal protein aggregates. Rivastigmine, a reversible cholinesterase inhibitor used for the treatment of AD, undergoes extensive first-pass metabolism, thus limiting its absolute bioavailability to only 36% after 3-mg dose. Due to extreme aqueous solubility, rivastigmine shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. This investigation was aimed to formulate microemulsion (ME) and mucoadhesive microemulsions (MMEs) of rivastigmine for nose to brain delivery and to compare percentage drug diffused for both systems using in-vitro and ex-vivo study. Rivastigmine-loaded ME and MMEs were prepared by titration method and characterized for drug content, globule size distribution, zeta potential, pH, viscosity and nasal ciliotoxicity study. Rivastigmine-loaded ME system containing 8% w/w Capmul MCM EP, 44% w/w Labrasol:Transcutol-P (1:1) and 48% w/w distilled water was formulated, whereas 0.3% w/w chitosan (CH) and cetyl trimethyl ammonium bromide (as mucoadhesive agents) were used to formulate MMEs, respectively. ME and MMEs formulations were transparent with drug content, globule size and zeta potential in the range of 98.59% to 99.43%, 53.8 nm to 55.4 nm and −2.73 mV to 6.52 mV, respectively. MME containing 0.3% w/w CH followed Higuchi model (r2 = 0.9773) and showed highest diffusion coefficient. It was free from nasal ciliotoxicity and stable for three months. However, the potential of developed CH-based MME for nose to brain delivery of rivastigmine can only be established after in-vivo and biodistribution study.