基于聚三亚甲基碳酸酯三维网络聚合物的基质型恒速给药体系的设计与构建

The constant-rate delivery systems, like Norplant and Norplant-II, could release hormone drugs into the bloodstream at a slow, steady rate. Although the pesticide effect is excellent, the implants must be removed at the end of their life span because of the non-degradability of the silastic carriers. For the biodegradable constant-rate delivery systems, the reservior devices suffered the drug effusion caused by the degradation of the carriers, while the matrix devides induced the aseprtic inflammation caused by the acidic degradation products. This project aims at designing and developing a biodegradable matrix delivery system with constant rate based on cross-linked poly(trimethylene carbonate) networks with hydrophobic and hydrophilic groups to solve the problems mentioned above . The flexible and strong networks with a controlled degradation rate and good form-stability, which will be used as the drug carrier of the delivery system, are prepared via copolymerization and cross-linking of trimethylene carbonate (TMC) derivates with cross-linking agents, such as bis(TMC), tris(TMC) or tetra(TMC), and the degradation rate of the cross-linked networks could be controlled by tailoring the structure and formulation. The relationship of the degradation rate and the release rate will be established and utilized to optimize the formulation of the cross-linked networks for the constant-release behavior of the system. Novel drug sustained-release carriers and matrix constant-rate delivery system could be obtained through the implementation of this project, and it will provide new thought and method for the future research of the constant-rate delivery system to meet the diverse demands of the clinic application.

本项目针对生物降解型恒速给药体系所面临的药物溢流、载体材料的酸性降解产物易造成局部无菌炎症以及聚三亚甲基碳酸酯的尺寸稳定性与降解速率兼容性差等三个主要问题，设计一种基于聚三亚甲基碳酸酯三维网络聚合物的基质型恒速给药体系。通过类三亚甲基碳酸酯结构的交联剂与三亚甲基碳酸酯及其甲基/羟基化衍生物的开环共聚，制备含有亲/疏水基团的聚三亚甲基碳酸酯三维网络聚合物，通过调控聚三亚甲基碳酸酯三维网络聚合物的交联密度、结构组成以及亲/疏水基团比例等多重因素实现药物载体材料的可控降解及其与药物透过率的等效性。利用聚三亚甲基碳酸酯三维网络聚合物的碳酸酯结构、尺寸稳定性以及降解速率可控性，克服降解型恒速给药体系目前面临的诸多问题，实现对激素类药物的恒速释放。本项目的实施和完成将为基质型恒速给药体系的设计构建提供新的载体材料，促进生物降解型恒速给药体系的开发及其在临床领域的广泛应用。

生物降解型恒速给药体系对于提高药物在生物医药及临床用药水平具有重大意义。然而，药物溢流、酸性降解产物以及载体材料的尺寸稳定性与降解速率兼容性差等问题严重研制了它的广泛应用。为解决上述问题，本项目设计构建了一种基于聚三亚甲基碳酸酯三维网络聚合物的基质型恒速给药体系，其主要研究内容为：（1）载体材料制备与性能研究；（2）基质型恒速给药体系的构建及释放性能研究；（3）药效评价。通过本项目的研究，现已获得一类基于聚三亚甲基碳酸酯三维网络聚合物的药物载体材料，其具有较低的玻璃化转变温度（-16.2~-12.5℃）以及较好的弹性（E=3.16~12.9Mpa）、可在体内保持良好的柔韧性；该载体材料还具有可控的降解速率，可以实现3~24个月或更长时间的可控降解，同时保持良好的尺寸稳定性，在体内维持其初始形状不变，可有效避免药物的爆释行为；该载体材料的降解模式为表面溶蚀降解，可有效避免基质型给药体系的药物溢流现象；更为主要的是，该载体材料的降解产物为二氧化碳与水，无酸性降解产物生成，可有效避免应用部位无菌炎症的发生。以聚三亚甲基碳酸酯三维网络聚合物（TMC：DTC=30:70，BTB: 0.3mol%）为载体材料制备的基质型植入剂可在12个月内维持良好的尺寸稳定性，并能能够维持每日20微克的释放速率释放孕二烯酮，可在大鼠体内持续稳定释放3个月，并且高、中剂量组的避孕效果要优于阳性对照组，避孕率达到了100%。.本项目现已发表论文28篇（SCI论文16篇），编写专著（章节）2部，申请发明专利2项，培养研究生3名，获全国获妇幼健康科学技术奖一等奖1项，中华中医药学会科学技术奖三等奖1项，辽宁省医学科技奖二等1项，辽宁省自然科学学术成果奖三等奖2项。本项目能够为生物降解型长效缓/控释给药系统的研制与开发提供性能良好的药物载体材料，这对建立并完善生物降解型长效缓/控释给药系统研发平台，着力推动产品产业化，降低高端制剂的高技术门槛，提高中国该领域产品在国际市场中的竞争力与影响力具有积极的促进作用。