PDF(Pubmed)
Abstract：
The study is based on using SeDeM expert system in developing controlled-release tramadol HCl osmotic tablets and its in-silico physiologically based pharmacokinetic (PBPK) modeling for in-vivo pharmacokinetic evaluation. A Quality by Design (QbD) based approach in developing SeDEM-driven full factorial osmotic drug delivery was applied. A 24 Full-factorial design was used to make the trial formulations of tramadol HCl osmotic tablets using NaCl as osmogen, Methocel K4M as rate controlling polymer, and avicel pH 101 as diluent. The preformulation characteristics of formulations (F1-F16) were determined by applying SeDeM Expert Tool. The formulation was optimized followed by in-vivo predictive pharmacokinetic assessment using PBPK \"ACAT\" model of GastroPlus™. The FTIR results showed no interaction among the ingredients. The index of good compressibility (ICG) values of all trial formulation blends were ≥5, suggesting direct compression is the best-suited method. Formulation F3 and F4 were optimized based on drug release at 2, 10, and 16 h with a zero-order kinetic release (r 2 = 0.992 and 0.994). The SEM images confirmed micropores formation on the surface of the osmotic tablet after complete drug release. F3 and F4 were also stable (shelf life 29.41 and 23.46 months). The in vivo simulation of the pharmacokinetics of the PBPK in-silico model revealed excellent relative bioavailability of F3 and F4 with reference to tramadol HCl 50 mg IR formulations. The SeDeM expert tool was best utilized to evaluate the compression characteristics of selected formulation excipients and their blends for direct compression method in designing once-daily osmotically controlled-release tramadol HCl tablets. The in-silico GastroPlus™ PBPK modeling provided a thorough pharmacokinetic assessment of the optimized formulation as an alternative to tramadol HCl in vivo studies.
摘要：
该研究基于使用SeDeM专家系统开发盐酸曲马多控释渗透片及其基于体内药代动力学评估的计算机生理学药代动力学（PBPK）模型。在开发SeDEM驱动的全因子渗透药物递送中应用了基于设计质量(QbD)的方法。使用24全因子设计，以NaCl为渗透剂，制作盐酸曲马多渗透片的试验配方，MethocelK4M作为速率控制聚合物，和avicelpH101作为稀释剂。通过应用SeDeM专家工具测定制剂(F1-F16)的预制剂特征。使用GastroPlus™的PBPK“ACAT”模型对制剂进行优化，然后进行体内预测药代动力学评估。FTIR结果显示各成分之间没有相互作用。所有试验配方共混物的良好可压缩性指数(ICG)值≥5,表明直接压缩是最合适的方法。基于在2、10和16小时的药物释放以及零级动力学释放(r2=0.992和0.994)来优化制剂F3和F4。SEM图像证实在药物完全释放后在渗透片剂的表面上形成微孔。F3和F4也是稳定的(保质期29.41和23.46个月)。PBPK计算机模型的药代动力学的体内模拟显示，相对于盐酸曲马多50mgIR制剂，F3和F4具有出色的相对生物利用度。在设计每日一次渗透控释盐酸曲马多片剂时，最好利用SeDeM专家工具来评估选定的制剂赋形剂及其混合物的压缩特性，以用于直接压缩方法。SimuloGastroPlus™PBPK模型提供了对优化制剂的全面药代动力学评估，作为盐酸曲马多的体内研究的替代品。
