基于蜂胶“解毒生肌”多组分原位液晶给药系统的构建及调控牙周炎症与组织修复研究

Periodontitis is a chronic progressive disease of the periodontal supporting tissue caused by the invasion of microorganisms, which is difficult to achieve the desired effect with simple antibacterial and anti-inflammatory therapy. The total flavonoids of propolis act as main active extracts from traditional Chinese medicine propolis having activities of "Detoxification, detumescence, convergence and myogenicity ". Aiming at the characteristics of polarity difference and synergism of activity in total flavonoids of propolis, we intend to construct multi-component in situ liquid crystal periodontal sustained-release drug delivery system of total flavonoids of propolis. This project is aimed at adjusting periodontal microenvironment and regenerating periodontal tissue by exerting the function of multi-component and multi-target of traditional Chinese medicine. On the basis of previous studies on the properties of drug loading and releasing from liquid crystals, our research team use liquid crystals prepared with phytantriol to encapsulate and synchronously sustained-release of multi-component flavonoids with different polarities. And the properties of drug loading and release can be adjusted by prescription optimization. The multi-link action and related mechanism of the periodontal microenvironment and periodontal tissue repair will be investigated in vivo and in vitro. The novel model of periodontal local drug delivery system is based on the multi-link action of inflammation and periodontal tissue regeneration, and there is no report both in the domestic and overseas. It provides a new idea for the treatment of periodontitis and a useful reference for the study of multi-component liquid crystalline drug delivery system of Chinese traditional medicine.

牙周炎是由微生物侵入引起的牙周支持组织慢性进行性疾病，单纯抗菌药物治疗难以达到理想效果。本课题针对牙周炎发生发展的核心病机，基于蜂胶外用“解毒消肿，收敛生肌”之功效，针对蜂胶活性部位蜂胶总黄酮各成分极性差异大、活性协同的特点，巧妙利用溶致液晶独特的水道和脂质膜结构对其亲水与亲脂性成分同时包载，构建蜂胶总黄酮原位液晶牙周缓释递药系统，旨在发挥其多成分、多环节调控牙周微环境和促进牙周组织修复。在前期液晶载、释药性能研究基础上，以植烷三醇为载体，通过处方优化调节液晶对蜂胶总黄酮多成分的有效包载及不同极性成分的同步缓慢释放；体内外考察该制剂对抑制致病菌、调控牙周微环境及抑制牙槽骨吸收、促进牙周组织修复的多环节作用，阐释相关机制。本项目基于牙周炎发生发展进程中病理变化特点构建多组分、多环节作用的牙周缓释给药系统，国内外尚无报道，可为临床牙周炎治疗提供新思路，也为中药多组分液晶研究提供有益借鉴。

牙周炎是发生在牙周组织的慢性感染性疾病，临床主要表现为牙龈炎症和出血、牙周袋形成以及进行性的牙周附着丧失与牙槽骨吸收，是成人牙齿丧失的最主要原因。牙周炎病因复杂，发病机制多样，针对牙周炎发生发展的进程特点及长期而持续防治的需要，开发兼具抗炎与牙周保护作用的牙周缓释制剂对于牙周炎治疗具有重要意义。本研究利用植烷三醇等基质材料构建蜂胶总黄酮（Total flavonoids in propolis，TFP）溶致液晶载药体系，以最小吸水量、相转化时间等为考察指标优选出TFP原位立方液晶与六角液晶最优处方，其吸水量小、相转化速度快且呈中性。偏光显微镜观察与小角X射线衍射证实所制备的溶致液晶分别为六角相液晶与螺旋型立方液晶；体外释放结果表明两种TFP溶致液晶递药系统具有良好的缓释作用；体内研究结果显示TFP溶致液晶可显著改善牙周炎大鼠的牙龈指数、探诊深度、牙槽骨丢失量并降低牙周组织炎症因子的分泌，降低炎症水平，具有良好的牙周保护作用。体外脂多糖诱导下的炎症模型与TFP共孵育后，TLR4、MyD88等蛋白水平表达降低；成骨蛋白水平表达升高且炎症相关蛋白表达降低，进一步证实TFP可通过抑制TLR4/MyD88信号通路，减轻炎症蛋白的表达并发挥促成骨作用。