Kostewicz Edmund S, Abrahamsson Bertil, Brewster Marcus, Brouwers Joachim, Butler James, Carlert Sara, Dickinson Paul A, Dressman Jennifer, Holm René, Klein Sandra, Mann James, McAllister Mark, Minekus Mans, Muenster Uwe, Müllertz Anette, Verwei Miriam, Vertzoni Maria, Weitschies Werner, Augustijns Patrick
Institute of Pharmaceutical Technology, Goethe University, Frankfurt/Main, Germany.
Department of Global Medicines Development, AstraZeneca R&D, S-431 83 Mölndal, Sweden.
Eur J Pharm Sci. 2014 Jun 16;57:342-66. doi: 10.1016/j.ejps.2013.08.024. Epub 2013 Aug 27.
Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract.
准确预测口服药物制剂的体内生物制药性能对于高效药物开发至关重要。传统上，口服药物制剂的体外评估主要集中在用于质量控制（QC）目的的崩解和溶出度测试。与体内生物制药性能的联系常常被忽视。最近，转向以更具生物相关性和机制性的方式评估药品，加深了对药物制剂行为的理解。尽管有这种发展，但预测依赖复杂腔内过程（如溶解、过饱和、沉淀……）的制剂的体内生物制药性能仍然极具挑战性。与此同时，对复杂制剂以克服低药物溶解度或控制药物释放速率的需求不断增加，促使开发新的体外工具。开发和优化创新的、预测性的口服生物制药工具是创新药物计划（IMI）框架内OrBiTo项目的主要目标。物理化学测量、体外试验、体内方法和基于生理学的药代动力学建模的结合有望创建一个独特的知识平台，消除药物开发中的瓶颈，使药物开发的整个过程更高效。作为OrBiTo项目的部分基础，本综述总结了制剂行为预测性体外评估工具的现状。讨论了药典列出的仪器和更先进的工具。特别关注限制传统工具预测能力的主要问题，包括胃肠道条件动态变化的模拟、胃肠蠕动的充分再现、过饱和和沉淀的模拟以及溶解度-渗透性相互作用的实现。预计OrBiTo项目产生的创新体外生物制药工具将改善对胃肠道中药物制剂体内行为的预测。
