Synthesis and Solid State Pharmaceutical Centre (SSPC), University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland.
School of Pharmacy, University College Cork, Cork, Ireland; Faculty of Pharmacy, Minia University, Minya, Egypt.
J Control Release. 2017 Mar 28;250:86-95. doi: 10.1016/j.jconrel.2016.12.043. Epub 2017 Jan 27.
Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships, was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations.
介孔硅系统的药物释放已在体外使用 USP 类型 II（桨）溶解装置进行了广泛研究。然而，尚不清楚观察到的体外溶出增强是否能预测体内药物生物利用度。在这项研究中，研究了不同的体外溶解模型在猪模型中预测体内口服生物利用度的能力。将载有非诺贝特的介孔硅制剂与商业参比制剂 Lipantil Supra®进行了直接比较。考虑了三种体外溶解方法；USP 类型 II（桨）装置、USP 类型 IV（流动池）装置和 USP IV 转移模型（包含 SGF 到 FaSSIF-V2 介质转移）。还研究了使用基于生理学的药代动力学建模和模拟软件包（Gastroplus™）进行体内/体外关系的计算机模拟。该研究表明，介孔硅制剂的体外溶解性能取决于所用的溶解装置和实验设计。研究结果表明，USP IV 转移模型是预测体内生物利用度的最佳模型。USP 类型 II（桨）装置不能有效预测体内行为。这种观察结果可能是由于两种装置之间的流体动力学差异以及转移模型更好地模拟胃肠道转运的能力所致。转移模型在预测促进药物过饱和的制剂的体内行为方面具有优势，因此容易沉淀到更具能量优势、溶解度较低的形式。USP IV 转移模型可能在未来的介孔硅制剂开发中证明是有用的。计算机模拟具有辅助该过程的潜力。然而，需要进一步研究来克服模型对溶解度增强制剂的限制。
