逐级释放药物递送系统的构建及在内耳制剂中的应用机制

Drugs entrapped on long-acting sustained-release formulations preparations with biodegradable materials are uncontrollable (burst release, delayed release, incomplete drug release), frequent administration leads to poor compliance due to the effective treatment concentration of drug is hard to maintain stable for a long time. The previous research has verified that silk fibroin molecules have high biocompatibility and unique amino acid sequences and form a stable-folded lamellar structure under external stimulation, which can stabilize drug activity and flexibly regulate drug release rate. In this project, dexamethasone (DEX) will be loaded in various forms of silk fibroin materials by physical embedding method as the model drug, and then to construct multiple barrier carriers (silk nano/microparticles-gel matrix as the carrier) with high drug loading, excellent injectability, stability and adhesion used for gradient release delivery system. In addition, the drug loading of DEX in silk nano/microparticles is 3 times higher than that in silk fibroin gel, which will be benefit for the step-by-step release of DEX in multiple-barrier carriers (the drug prior released from the silk nano/microparticles embedded into the gel, and then released from the gel). On this basis, we will study and reveal the mechanism action between the physical and chemical properties (composition, structure and drug spatial distribution) of multiple-barrier carrier and drug gradual release through in vitro drug release kinetics test, and optimize the best zero-level long-acting sustained release formulation. After that, select optimization formulation (DEX loading amount > 40 mg/ml) and inject in guinea pig by tympanic, evaluate the properties include the hearing recovery, degradation (the retention time of round window membrane), the safety (inflammation) at the animal level, clarify the mechanism of transformation and application, which will provide a theoretical and practical basis for the application of new biodegradable silk fibroin materials in the long-effect sustained release formulation for treatment of inner ear and other chronic diseases.

针对长效缓释制剂存在药物释放速率控制难、药物有效治疗浓度难以长时间维持，需频繁给药造成顺应性差等问题，本项目将发挥高生物相容性的丝素蛋白稳定药物活性、灵活调控药物释放速率的优势,以地塞米松（DEX）为模型药物，采用物理方法将药物装载在多种形式的丝素蛋白材料中，构建具有可注射性、成胶稳定性和粘附性优异的高载药量-多重屏障载体逐级释放药物递送系统，其中DEX在纳微米球中的载药量高于凝胶3倍，有利于DEX在多重屏障载体中形成逐级释放效果。在此基础上，通过体外释放动力学试验，深入研究并揭示多重屏障载体的理化性能与药物逐级释放之间的行为机制，优化最佳的零级长效缓释制剂。随后选择该制剂（DEX载量＞40 mg/ml）用于豚鼠鼓室注射给药，对其体内药效性、降解性以及生物安全性进行评估，明确其转化应用机制，为丝素蛋白多屏障载体逐级释放药物递送系统在内耳制剂的应用及其他慢性疾病的临床治疗提供理论与实践依据。

长效缓释制剂存在药物释放速率控制难，药物有效治疗浓度难以长时间维持，需频繁给药造成顺应性差；高生物相容性丝素蛋白载体能稳定药物活性、灵活调控药物释放速率。制备多重屏障载体逐级释放药物递送系统是本项目的核心内容。围绕项目核心内容，已制备出基于丝素蛋白的纳微米球、构建重屏障载体逐级释放药物递送系统，证实了其具有零级长效缓释的特性，并基于该研究结果，探索了在创伤愈合、芳香长效释放的应用机制，并在此基础上重新优化制备了新型可注射内耳制剂，另外也探索了蓄热调温材料在纺织品中的应用，以下就研究成果、关键数据、科学意义依据所制备材料分类阐述：.1.一步法快速制备了粒径可调控的丝素纳米球，并深入探讨了其形成机理，为后续制备基于丝素蛋白逐级药物递送系统提供方法和材料支撑。.2.利用多种丝素蛋白载体形式灵活调控药物释放速率，采用物理方法将罗丹明B、钙黄素、姜黄素等物装载在丝素蛋白材料中，不带电荷的疏水性药物能基于丝素蛋白构建逐级释放药物递送系统。.3.黄连素-丝素蛋白微球能实现零级释放黄连素并牢固地锚定在细胞上。体内外研究证明了其通过抗菌和抗炎作用加速感染性伤口快速愈合的双重机制。该研究为新型喷雾给药治疗感染性伤口提供了理论依据和实验结果支撑。.4.利用丝素蛋白微球包埋了六种香味剂。相比于纯香味剂，经丝素蛋白微球包埋的香味剂在室温中的留香时间最高达到11倍。经丝素蛋白微球包埋的香味剂可广泛用于功能纺织品芳香整理、护肤品加香、食品加香等方面。.5.开发了基于丝素蛋白纳米颗粒的的多孔支架，研究了其生物安全性和创伤修复的效果和机制，证实了丝素蛋白多孔支架作为创伤敷料的应用价值。.6.分别制备得到了石榴式凝胶球和基于物理和化学交联核壳结构的复合凝胶球两种材料，为慢性创伤修复、突发性耳聋的高效修复提供材料基础和方法支撑。.7.以蚕丝织物为基底材料，以人体最舒适温度为目标，对癸酸和硬脂酸进行二元复配优化，开发了蓄热性能可控，持久性强的功能纺织品。.综上，研究成果达到预期目标要求，累计发表SCI论文3篇，核心期刊论文7篇，授权专利2项。