Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
AAPS J. 2021 Oct 14;23(6):111. doi: 10.1208/s12248-021-00651-4.
Lipid nanoparticles have transformed the drug delivery field enhancing the therapeutic drug performance of small molecules and biologics with several approved drug products. However, in industry, these more complex drug delivery systems such as liposomes require more material and time to develop. Here, we report a liposome and lipodisk decision tree with model compounds of diverse physicochemical properties to understand how to resourcefully optimize encapsulation efficiency (EE) for these lipid-based drug delivery systems. We have identified trends with physicochemical properties such as Log P, where higher Log P compounds such as curcumin were able to efficiently load into the lipid bilayer resulting in high EE with altering the drug/lipid (D/L) ratio. Moderate Log P compounds such as cyclosporine A and dexamethasone had significantly higher encapsulation in lipodisks, which contain higher amounts of PEG lipid compared to liposomes. The EE of negative Log P compounds, like acyclovir, remained low regardless of altering the D/L ratio and PEG concentrations. In this study, microfluidic techniques were employed to fabricate liposomes and lipodisks formulations allowing for a reproducible strategy for formulation development. Both liposome and lipodisk of curcumin demonstrated enhanced in vivo performance compared with a conventional formulation in the rat pharmacokinetic study. This combination of approaches with multiple model compounds and lipid-based drug delivery systems provides a systematic guidance to effective strategies to generate higher EE with minimal drug waste and expedite the process for preclinical development when applied to industry compounds.
脂质纳米粒改变了药物传递领域，提高了小分子和生物制剂的治疗药物性能，已有多种批准的药物产品。然而，在工业界，这些更复杂的药物传递系统，如脂质体，需要更多的材料和时间来开发。在这里，我们报告了一个脂质体和脂质盘决策树，使用具有不同物理化学性质的模型化合物，以了解如何灵活地优化这些基于脂质的药物传递系统的包封效率（EE）。我们已经确定了与物理化学性质相关的趋势，如 Log P，其中 Log P 值较高的化合物，如姜黄素，能够有效地加载到脂质双层中，从而通过改变药物/脂质（D/L）比例实现高 EE。中等 Log P 值的化合物，如环孢素 A 和地塞米松，在脂质盘中的包封率显著更高，因为脂质盘中含有比脂质体更多的 PEG 脂质。负 Log P 值化合物，如阿昔洛韦的 EE 仍然很低，无论改变 D/L 比例和 PEG 浓度如何。在这项研究中，使用微流控技术来制备脂质体和脂质盘制剂，为制剂开发提供了一种可重复的策略。在大鼠药代动力学研究中，姜黄素的脂质体和脂质盘都表现出比传统制剂更好的体内性能。这种使用多种模型化合物和基于脂质的药物传递系统的方法组合，为生成更高 EE 的有效策略提供了系统指导，同时最大限度地减少药物浪费，并在应用于工业化合物时加速临床前开发过程。
