Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Switzerland; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland.
Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Switzerland.
J Control Release. 2020 Apr 10;320:214-225. doi: 10.1016/j.jconrel.2020.01.031. Epub 2020 Jan 21.
Drug delivery of poorly soluble drugs in form amorphous solid dispersions (ASDs) is an appealing method to increase in vivo bioavailability. For rational formulation design, a mechanistic understanding of the impact of surfactants on the performance of ASD-based formulations is therefore of importance. In this study, we used hot-melt extrusion to prepare ASDs composed of the model drug substance efavirenz with hydroxypropyl methylcellulose phthalate (HPMCP) as the base polymer, and surfactants. Molecular dynamics simulations and in vitro dissolution studies were used to investigate formation and drug release from polymer vesicles, and their ability to maintain a supersaturation state as a function of surfactant composition. It was possible to identify main factors regulating particle formation and to modify dissolution profiles with different excipient compositions. Animal studies in the rat, in combination with physiologically based pharmacokinetic modeling, demonstrated enhanced drug absorption from formed vesicles. The surfactant composition in the ASD had a direct influence on the morphology of these vesicles, as well as kinetics of drug release, and, therefore, the oral bioavailability. ASDs, prepared by hot-melt extrusion method, were optimized for dissolution and adsorption rates increase. Our findings contribute to a better understanding of dissolution behavior of ASDs with respect to the function of surfactants, aiming to facilitate a rational formulation development and an accelerated transition from in vitro systems to in vivo applications.
将难溶性药物制成无定形固体分散体（ASD）进行药物递送是提高体内生物利用度的一种有吸引力的方法。为了进行合理的配方设计，因此，了解表面活性剂对基于 ASD 的配方性能的影响的机制非常重要。在这项研究中，我们使用热熔挤出法制备了由模型药物依非韦伦和羟丙甲纤维素邻苯二甲酸酯（HPMCP）作为基础聚合物以及表面活性剂组成的 ASD。我们使用分子动力学模拟和体外溶解研究来研究聚合物囊泡的形成和药物释放，以及它们作为功能的维持超饱和状态的能力表面活性剂组成。可以确定调节颗粒形成的主要因素，并通过不同赋形剂成分来改变溶解曲线。在大鼠中的动物研究，结合基于生理学的药代动力学建模，证明了从形成的囊泡中增强了药物吸收。ASD 中的表面活性剂组成直接影响这些囊泡的形态以及药物释放的动力学，因此也影响了口服生物利用度。通过热熔挤出法制备的 ASD 进行了优化，以提高溶解和吸附速率。我们的研究结果有助于更好地了解 ASD 的溶解行为与表面活性剂功能之间的关系，旨在促进合理的配方开发，并加速从体外系统向体内应用的过渡。
