Tao Chun, Wen Xu, Zhang Qian, Song Hongtao
Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (Fuzhou General Hospital), Fuzhou 350025, PR China.
Department of Inorganic Chemistry, College of Pharmacy, Fujian Medical University, Fuzhou 350108, PR China.
Iran J Pharm Res. 2019 Fall;18(4):1648-1658. doi: 10.22037/ijpr.2019.1100847.
The clinical application of sirolimus (SRL) as an immunosuppressive agent is largely hampered by its narrow therapeutic range. This study focused on developing SRL tablets with a sustained release profile for better safety. SRL was highly water insoluble and its solubility has been efficiently enhanced by preparing self-microemulsifying drug delivery system (SMEDDS). The SRL-SMEDDS was physically adsorbed by microcrystalline cellulose (MCC). The sustained release of SRL was achieved by addition of hydroxypropyl methylcellulose (HPMC) to prepare tablets. The formulation of the tablets was optimized by single factor test and orthogonal design. The optimal formulation was composed of 10% of HPMC 100lv and 5% of HPMC K4M. The release profiles of the optimal tablets were further investigated for the influence of hardness, shape, preparing method, release method, stirring speed, and medium. The release kinetic of SRL from the tablets was demonstrated to be erosion of HPMC. Pharmacokinetic study on beagle dogs showed that the SRL-SMEDDS tablets were bio-equivalent to the commercial tablets but lower C and larger T were achieved. In conclusion, the SMEDDS tablets were presented as promising delivery system for sustained release of SRL.
西罗莫司（SRL）作为一种免疫抑制剂，其临床应用在很大程度上受到其狭窄治疗窗的限制。本研究致力于开发具有缓释特性的SRL片剂，以提高安全性。SRL高度水不溶性，通过制备自微乳化药物递送系统（SMEDDS）有效提高了其溶解度。SRL-SMEDDS被微晶纤维素（MCC）物理吸附。通过添加羟丙基甲基纤维素（HPMC）制备片剂来实现SRL的缓释。通过单因素试验和正交设计对片剂的配方进行优化。最佳配方由10%的HPMC 100lv和5%的HPMC K4M组成。进一步研究了最佳片剂的释放曲线受硬度、形状、制备方法、释放方法、搅拌速度和介质的影响。结果表明，SRL从片剂中的释放动力学是HPMC的溶蚀过程。对比格犬的药代动力学研究表明，SRL-SMEDDS片剂与市售片剂生物等效，但C值较低且T值较大。综上所述，SMEDDS片剂有望成为SRL缓释的给药系统。
