Molecular Structuring and Phase Transition of Lipid-Based Formulations upon Water Dispersion: A Coarse-Grained Molecular Dynamics Simulation Approach,Molecular Pharmaceutics

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Molecular Structuring and Phase Transition of Lipid-Based Formulations upon Water Dispersion: A Coarse-Grained Molecular Dynamics Simulation Approach
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-08-29 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00397
Per Larsson ₁ , Linda C. Alskär ₁ , Christel A. S. Bergström ₁

Affiliation

The internal molecular structure of lipid-based formulations (LBFs) is poorly understood. In this work we aimed at establishing coarse-grained molecular dynamics simulations as a tool for rapid screening and investigation of the internal environment of these formulations. In order to study complex LBFs composed of different kinds of lipids we simulated a number of systems containing either medium-chain or long-chain lipids with varying proportions of tri-, di-, and monoglycerides. Structural and dynamic measurements and analyses identified that the internal environment in a mixture of lipids was locally ordered even in the absence of water, which might explain some of the previously reported effects on drug solubility in these systems. Further, phase changes occurring upon water dispersion are well captured with coarse-grained simulations. Based on these simulations we conclude that the coarse-grained methodology is a promising in silico approach for rapid screening of structures formed in complex formulations. More importantly it facilitates molecular understanding of interactions between excipients and water at a feasible time scale and, hence, opens up for future virtual drug formulation studies.

中文翻译：

基于脂质的制剂在水分散时的分子结构和相变：粗粒化分子动力学模拟方法

对基于脂质的制剂（LBF）的内部分子结构了解甚少。在这项工作中，我们旨在建立粗粒度的分子动力学模拟，作为快速筛选和研究这些制剂内部环境的工具。为了研究由不同种类的脂质组成的复杂LBF，我们模拟了许多包含中链或长链脂质以及不同比例的甘油三酯，甘油二酯和甘油单酯的系统。结构和动态测量与分析表明，即使在没有水的情况下，脂质混合物的内部环境也是局部排列的，这可能可以解释先前报道的对这些系统中药物溶解度的影响。此外，通过粗粒度模拟可以很好地捕获在水分散时发生的相变。基于这些模拟，我们得出的结论是，粗粒化方法是一种用于快速筛选复杂配方中形成的结构的有希望的计算机方法。更重要的是，它促进了在可行的时间尺度上分子对赋形剂与水之间相互作用的分子理解，因此为将来的虚拟药物制剂研究开辟了道路。

更新日期：2017-08-29

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