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 studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.

中文翻译：

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给予和不给予脂质制剂的狗肠液中的药物溶解


通过能够反映模拟环境的计算模型可以最大限度地减少动物实验的使用。一种这样的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来研究三种模型药物（卡维地洛、非洛地平和普罗布考）在狗肠液、脂质制剂以及两者的混合物中的溶解模式。我们观察到脂质由于肠道环境中的消化过程而发生形态转变。此外，我们评估了胆盐浓度的影响并观察了个体差异的重要性。我们应用了两种基于模拟数据来估计溶解度增强的方法，其中一种与实验观察到的溶解度增强具有良好的定性一致性。除了计算模拟之外，我们还测量了 i) 吸出的狗肠液样本和 ii) 禁食状态下模拟犬肠液样本的溶解度，发现两者之间没有统计差异。因此，适合研究的简化溶出介质为所探索的系统提供了生理相关数据。本研究中使用的计算方案与使用模拟肠液的研究相结合，可以作为药物输送策略开发过程中有用的预筛选工具。