胍基壳聚糖温敏型水凝胶介导的京尼平经鼻嗅区脑靶向递药抗抑郁研究

In recent years, research on the Central nervous system (CNS) diseases has progressed rapidly. However, most macromolecular drugs with potentially therapeutic effects on brain diseases cannot play a therapeutic effect because they cannot penetrate the blood-brain barrier (BBB). According to the physiological and pathological relationship between the nose and the brain, we put forward a novel drug delivery system that uses the Guanidinylated Chitosan thermo-sensitive hydrogel as drug carriers and works as the brain targeting antidepressant by nasal route. In this work, novel brain targeting of thermo-sensitive hydrogels of drug delivery systems (DDss) have been designed and constructed for prolonging the nasal residence time of drug. Brain targeting efficiency of DDss can be quantitatively determined by intranasal administration with Coumarins-6 as fluorescence probes. Genipin is used as a model drug. To improve the bioavailability of genipin, supramolecular chemistry method is used. After intranasal administration with the DDss, differences of genipin concentration in the brain tissue compared with the oral administration control was determined. Depression model can be used to investigate the antidepressant effect of DDss containing genipin-loaded by nasal route to the brain. With the guiding of traditional Chinese medicine treatment experience and the help of modern technology of pharmaceutics, it is useful to discover the new strategy and technology to treat the CNS disease and provide new thought for preventing from severe disease with TCM.

近年来，关于中枢神经系统疾病的研究发展十分迅速。然而大多数的神经活性化合物，由于无法通过血脑屏障而失去疗效。根据鼻腔与大脑的生理、病理关系，结合以往的研究工作基础，我们提出：“使用胍基修饰的壳聚糖温敏型水凝胶作为药物载体，通过鼻腔嗅区给药，达到靶向性治疗抑郁症”的新型给药系统。本项目为增强药物在鼻腔的滞留时间，使用胍基修饰的壳聚糖设计具有温度响应性能的水凝胶递药系统；以香豆素-6为荧光探针，定量确定该递药系统经鼻嗅区给药的脑靶向效率。以京尼平作为模型药物，采用超分子化学方法改善京尼平的生物利用度；以京尼平口服给药作为对照，定量确定胍基壳聚糖温敏型载药凝胶经鼻腔给药后，脑组织的药物成分差异；使用抑郁症模型验证该递药系统经鼻嗅区入脑的抗抑郁药效。将中医药的传统治疗经验和新型制剂技术有效结合起来，探索中枢神经系统疾病治疗的新策略和新技术，为中医药防治重大疾病开辟新的思路。

京尼平属于环烯醚萜类化合物，具有保肝利胆、抗炎、抗氧化、抗血栓形成、抗抑郁等药理活性。但是由于京尼平存在水溶性差，遇光不稳定，肠吸收差，生物利用度低等缺点，其在临床上的应用被大大限制了。本项目以京尼平作为模型药物，依据分子药剂学的理论和方法，采用羟丙基-β-环糊精对京尼平进行分子修饰，经UV、FTIR、DSC分析、XRD和NMR分析验证Genipin被包裹在HP-β-CD的疏水性空腔中形成了包合物，增加了京尼平的水溶性。以GCS为基本成分，通过单因素和正交实验设计了GCS基温敏凝胶DDss。并通过GCS温敏型载药凝胶DDss的流变学实验、体外药物释放实验、黏膜黏附性实验考察、脑组织分布实验、体内药物代谢动力学实验证实了该凝胶剂通过鼻腔给药达到脑靶向的可行性。在此基础上，使用行为绝望抑郁症模型和利血平拮抗的单胺神经功能失常抑郁症模型证实了GCS温敏载药凝胶DDss经鼻给药的抗抑郁作用药效。Genipin/HP-β-CD包合物的设计为生物利用度低的药物提供了研究思路和方法，温度敏感水凝胶作为经鼻腔给药治疗中枢神经系统疾病的剂型具有深入研究和开发的价值。