Abstract：
Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer\'s disease. Nevertheless, its low oral bioavailability and poor solubility limit clinical application. By utilizing either a direct or indirect approach, intranasal administration is a non-invasive drug delivery method that can deliver drugs to the brain rapidly. But large molecule drug delivered to the brain through intranasal administration may be insufficient to reach required concentration for therapeutic effect. In this study, using GF1 as a model drug, the feasibility of intranasal administration in combination with absorption enhancers to increase brain distribution of GF1 was explored. First of all, the appropriate absorption enhancers were screened by in situ nasal perfusion study. GF1-HP-β-CD inclusion complex was prepared and characterized. Thereafter, in vivo absorption of GF1 after intranasal or intravenous administration of its inclusion complex with/without absorption enhancers was investigated, and safety of the formulations was evaluated. The results showed that 2% Solutol HS 15 was a superior absorption enhancer. HP-β-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%. Upon further addition of 2% Solutol HS 15, the absolute bioavailability was increased to 75%, with DTI 315% and DTP 66%. Both nasal cilia movement and biochemical substances (total protein and lactate dehydrogenase) leaching studies demonstrated 2% Solutol HS 15 was safe to the nasal mucosa. In conclusion, intranasal administration combining with safe absorption enhancers is an effective strategy to enhance drug distribution in the brain, showing promise for treating disorders related to the central nervous system.
摘要：
人参皂苷F1(GF1)是治疗阿尔茨海默病的潜在候选药物。然而，其口服生物利用度低,溶解度差,限制了临床应用。通过使用直接或间接的方法，鼻内给药是一种非侵入性药物递送方法，可以将药物快速递送到大脑。但是通过鼻内给药递送至脑的大分子药物可能不足以达到治疗效果所需的浓度。在这项研究中,使用GF1作为模型药物，探讨了鼻内给药联合吸收促进剂增加GF1脑分布的可行性。首先,通过原位鼻灌注研究筛选合适的吸收促进剂。制备并表征了GF1-HP-β-CD包合物。此后,研究了在鼻内或静脉内给予含有/不含吸收促进剂的包合物后GF1的体内吸收，并评估制剂的安全性。结果表明，2％SolutolHS15是一种优异的吸收促进剂。HP-β-CD包合物使GF1溶解度提高150倍。鼻内给药后,包合物的绝对生物利用度为46%,药物脑靶向指数（DTI）为247%，鼻脑直接转运率（DTP）为58%。在进一步添加2％SolutolHS15后，绝对生物利用度增加到75％，DTI为315%，DTP为66%。鼻纤毛运动和生化物质（总蛋白和乳酸脱氢酶）浸出研究均表明，2％SolutolHS15对鼻粘膜是安全的。总之,鼻内给药结合安全的吸收促进剂是增强药物在大脑中分布的有效策略，显示出治疗与中枢神经系统有关的疾病的希望。
