Brain Uptake of an Anti-Ischemic Agent by Nasal Administration of Microparticles
Brain Uptake of an Anti-Ischemic Agent by Nasal Administration of Microparticles
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DOI：
10.1002/jps.21335
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发表时间：
2008-11-01
影响因子：
3.8
通讯作者：
Giunchedi, Paolo
中科院分区：
文献类型：
--
作者：
Dalpiaz, Alessandro;Gavini, Elisabetta;Giunchedi, Paolo
N-6-环戊基腺苷(CPA)具有神经元抗缺血特性，但它不能从血流中被吸收到大脑中，稳定性差，且会引起副作用。采用喷雾干燥法制备了用于CPA鼻腔给药的甘露醇或壳聚糖微粒给药系统，并对其进行了表征。甘露醇-卵磷脂微球表现出较高的CPA溶出度，而壳聚糖微球控制其释放速率。体外粘附性研究表明，与甘露醇颗粒相比，负载CPA的壳聚糖微颗粒具有更高的粘附性。绵羊鼻黏膜的体外研究表明，与CPA原料相比，甘露醇微粒促进了CPA的渗透，而壳聚糖微粒控制了CPA的渗透速率。体内研究是在老鼠身上进行的。静脉给药后大鼠脑脊液和脑组织切片中未检测到CPA。相反，在鼻腔给药后，在脑脊液中发现CPA的浓度从高NM到MUM值，并且比全身水平的浓度高出两个数量级。在嗅球中也发现了CPA，浓度约为0.1 ng/mg组织。这些结果为应用CPA预防中风后的脑损伤开辟了新的视角。(C)2008 Wiley-Liss，Inc.和美国药剂师协会药学杂志97：4889-4903,2008
N-6-cyclopentyladenosine (CPA) has neuronal anti-ischemic properties, but it is not absorbed into the brain from the bloodstream, where it shows poor stability and induces side effects. Microparticulate drug delivery systems designed for CPA nasal administration and constituted by mannitol or chitosan, were prepared by spray-drying and characterized. Mannitol-lecithin microparticles showed high CPA dissolution rate, whereas chitosan microparticles controlled its release rate. In vitro mucoadhesion studies indicated that CPA-loaded chitosan microparticles had higher mucoadhesive properties compared to mannitol particles. Ex vivo studies on sheep nasal mucosa showed that mannitol microparticles promoted CPA permeation across the mucosa, whereas chitosan microparticles controlled CPA permeation rate in comparison with CPA raw material. In vivo studies were carried out on rats. No CPA was detected in rat cerebrospinal fluid (CSF) and brain sections after intravenous administration. In contrast, after nasal administration of loaded microparticles CPA was found in the CSF at concentrations ranging from high nM to mu M values and up to two order of magnitude higher than those obtained at systemic level. CPA was also found in the olfactory bulb at concentrations around 0.1 ng/mg of tissue. These results can open new perspectives for the employment of CPA against brain damages following stroke. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4889-4903, 2008