基于介孔硅固化自微乳的西罗莫司缓释片的制备与评价

Preparation and evaluation of sirolimus sustained release tablets based on mesoporous silicon loaded self-microemulsion

通过研制西罗莫司自微乳-介孔硅缓释片,以期提高难溶性药物西罗莫司的溶出度,并降低其毒副作用。首先,制备西罗莫司自微乳,用介孔硅进行固化。其次,以外观、硬度、体外释放度为指标筛选适宜的辅料,采用粉末直接压片法制备以羟丙基甲基纤维素(HPMC)为骨架材料的缓释片,以星点设计优化处方,考察其体外释药情况。最后,以市售西罗莫司片作为参比制剂,进行比格犬体内药动学实验(动物实验和福利过程均已获得联勤保障部队第九〇〇医院动物伦理委员会的审核并批准)。结果表明,缓释片的最终处方[西罗莫司自微乳-介孔硅(1∶1,w/w)]的用量为162 mg,HPMC K4M为80 mg,羧甲基淀粉钠为80 mg,微晶纤维素为168 mg。体外释药实验结果显示,自制缓释片在12 h内缓慢释药,符合Ritger-Peppas模型。体内实验结果显示,与市售西罗莫司片相比,缓释片的C_(max)降低了49.47%;T_(max)延长了5.1倍,相对生物利用度为105.81%。西罗莫司自微乳-介孔硅缓释片具有良好的体外、体内缓释效果,为其他难溶性药物的增溶及其缓释制剂的研发提供了参考。

Sirolimus self-microemulsion-mesoporous silicon sustained release tablets were prepared in order to improve the dissolution of the insoluble drug sirolimus and reduce its side effects.Firstly,sirolimus selfmicroemulsion was prepared and cured with mesoporous silicon.Secondly,the suitable excipients were selected according to the appearance,hardness and in vitro release rate.The sustained-release tablets with hydroxypropyl methylcellulose(HPMC)as skeleton material were prepared by powder direct pressing method,and the formulation was optimized by central composite design-response surface method to investigate the drug release in vitro.Finally,the pharmacokinetics was carried out in beagle dogs using the commercial sirolimus tablets as references.The final formulation of sustained-release tablets is as follows:162 mg of sirolimus self-microemulsionmesoporous silica(1∶1,w/w),80 mg of HPMC K4M and 80 mg of carboxymethyl starch sodium,the microcrystalline cellulose is 168 mg.The results of in vitro release test showed that the self-made sustained-release tablets released slowly within 12 h,which conformed to the Ritger-Peppas model.The in vivo test results showed that compared with the commercial sirolimus tablets,the C_(max) of the sustained-release tablets decreased by 49.47%,the T_(max) of the sustained-release tablets was prolonged by 5.1 times,and the relative bioavailability was 105.81%.Sirolimus self-microemulsion-mesoporous silicon sustained-release tablets have good sustained-release effects in vitro and in vivo,which provides a reference for the solubilization of other insoluble drugs and the research and development of sustained-release preparations.Animal experiments and welfare processes were reviewed and approved by the Animal Ethics Committee of the 900TH Hospital of the Joint Logistics support Force.