Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Mol Pharm. 2021 Dec 6;18(12):4354-4370. doi: 10.1021/acs.molpharmaceut.1c00547. Epub 2021 Nov 22.
Type III lipid-based formulations (LBFs) combine poorly water-soluble drugs with oils, surfactants, and cosolvents to deliver the drugs into the systemic circulation. However, the solubility of the drug can be influenced by the colloidal phases formed in the gastrointestinal tract as the formulation is dispersed and makes contact with bile and other materials present within the GI tract. Thus, an understanding of the phase behavior of LBFs in the gut is critical for designing efficient LBFs. Molecular dynamics (MD) simulation is a powerful tool for the study of colloidal systems. In this study, we modeled the internal structures of five type III LBFs of loratadine containing poly(ethylene oxide) nonionic surfactants polysorbate 80 and polyoxyl hydrogenated castor oil (Kolliphor RH40) using long-timescale MD simulations (0.4-1.7 μs). We also conducted experimental investigations (dilution of formulations with water) including commercial Claritin liquid softgel capsules. The simulations show that LBFs form continuous phase, water-swollen reverse micelles, and bicontinuous and phase-separated systems at different dilutions, which correlate with the experimental observations. This study supports the use of MD simulation as a predictive tool to determine the fate of LBFs composed of medium-chain lipids, polyethylene oxide surfactants, and polymers.
III 型脂质基制剂 (LBF) 将难溶于水的药物与油、表面活性剂和共溶剂结合，将药物递送到体循环中。然而，药物的溶解度可能会受到胃肠道中形成的胶体相的影响，因为制剂在分散并与胆汁和胃肠道中存在的其他物质接触时会形成胶体相。因此，了解 LBF 在肠道中的相行为对于设计高效的 LBF 至关重要。分子动力学 (MD) 模拟是研究胶体系统的有力工具。在这项研究中，我们使用长时间尺度的 MD 模拟 (0.4-1.7 μs) 对含有聚氧乙烯非离子表面活性剂聚山梨酯 80 和聚氧乙烯氢化蓖麻油 (Kolliphor RH40) 的五种 loratadine III 型 LBF 的内部结构进行了建模。我们还进行了实验研究（用水稀释制剂），包括商业的 Claritin 液体软胶囊。模拟表明，LBFs 在不同稀释度下形成连续相、水增溶的反向胶束、双连续相和相分离体系，这与实验观察结果相关。这项研究支持使用 MD 模拟作为预测工具来确定由中链脂质、聚氧乙烯表面活性剂和聚合物组成的 LBF 的命运。
