石杉碱甲鼻用原位凝胶的制备及其经鼻脑靶向性评价

Preparation of huperzine A nasal in situ gel and evaluation of its brain targeting following intranasal administration

目的探索利用鼻腔嗅觉区的鼻-脑通道开发经鼻脑靶向给药系统的可行性。方法用阳离子敏感性成胶辅料结冷胶，采用pH梯度沉淀法制备了石杉碱甲鼻用原位凝胶。以市售片剂和注射液为对照，用小脑延髓池插管法采集脑脊液，股动脉插管取血，测定其在大鼠脑脊液和血中药物动力学参数；用组织匀浆法，测定其在大鼠脑组织中的分布；用Morris水迷宫法、跳台法和避暗法试验其对大鼠和小鼠模型的药效。结果大鼠鼻腔给药血浆AUC0→6h为静注的0．94倍，但脑脊液AUC0→6h为静注和灌胃的1．3和2．3倍；大鼠鼻腔给药后大脑、海马、小脑、左右嗅球的AUC0→6h分别为静注的1．5，1．3，1．0，1．2和1．0倍，为灌胃的2．7，2．2，1．9，3．1和2．6倍。药效学研究表明以1／4～1／2口服剂量鼻腔给药与口服等效，与药动学结果相符。结论石杉碱甲原位凝胶鼻腔给药较静注和灌胃显著增加了药物在脑内，特别在其改善记忆障碍作用的靶部位——大脑和海马的分布，提高了药物的脑靶向性。

Aim The feasibility of intranasal brain targeting drug delivery system via the olfactory pathway from nose to brain was explored. Methods Using gellan gum, a cation-sensitive gel forming excipient, huperzine A （ Hup A） nasal in situ gel was prepared by pH gradient precipitation method. The pharmacokinetics of Hup A in blood and eerebrospinal fluid （CSF） after intranasal, intravenous and intragastric adminstration to rats was studied using cisternal cannulation for serial CSF sampling and femoral artery cannulation for serial blood sampling. The distributions of Hup A into rat brain tissues following intranasal dosing were compared with those after intravenous and intragastric dosing by tissue homogeneization. The therapeutics effects of Hup A nasal in situ gel on cognitive function were tested in mice and rats with Morris water maze, step down test and step through test. Results The AUC0→6h value in plasma obtained after nasal administration was 0.94 of that after intravenous administration, but the AUC0→6h of CSF after nasal administration was 1.3 and 2.3 times of that after intravenous and intragastric administration. The AUC0→6h of cerebrum, hippocampus, cerebellum, left olfactory bulb and right olfactory bulb after nasal administration were 1.5, 1.3, 1.0, 1.2 and 1.0 of that after intravenous administration, 2.7, 2.2, 1.9, 3. 1 and 2.6 times of that after intragastric administration, respectively. Intranasal adminintration of 17.5 -35 μg·kg^-1 showed equal effects after oral adminintration of 70 μg·kg^-1 commercial tablets, which was in good agreement with the results of pharmacokineties. Conclusion Intranasal administration of huperzine A nasal in situ gel significantly increased the distributions of Hup A into rat brain tissues, especially into cerebrum and hippocampus which should be the target areas of Hup A, and enhanced the brain targeting of Hup A.