Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden; The Swedish Drug Delivery Center, Department of Pharmacy, Uppsala University, Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden.
J Control Release. 2024 Jul;371:555-569. doi: 10.1016/j.jconrel.2024.06.008. Epub 2024 Jun 13.
The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
使用能够反映模拟环境的计算模型可以最小化动物实验的使用。其中一种环境是肠液和其中形成的胶体。在这项研究中，我们使用分子动力学模拟研究了三种模型药物（卡维地洛、非洛地平、普罗布考）在犬肠液、基于脂质的制剂以及两者混合物中的溶解模式。我们观察到由于肠道环境中的消化过程，脂质发生的形态转变。此外，我们评估了胆汁盐浓度的影响，并观察到个体间变异性的重要性。我们应用了两种基于模拟数据估计增溶效果的方法，其中一种方法与实验观察到的增溶效果具有良好的定性一致性。除了计算模拟，我们还在 i）抽吸的犬肠液样本和 ii）禁食状态下模拟的犬肠液中测量了溶解度，发现两者之间没有统计学差异。因此，适合体外研究的简化溶解介质为所研究的系统提供了具有生理相关性的数据。本研究中使用的计算方案，结合使用模拟肠液的体外研究，可以作为药物输送策略开发过程中的有用预筛选工具。
