Division of Nanobiotechnology, Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
Drug Deliv Transl Res. 2019 Feb;9(1):404-413. doi: 10.1007/s13346-018-0587-4.
Liposomes have attracted much attention as the first nanoformulations entering the clinic. The optimization of physicochemical properties of liposomes during nanomedicine development however is time-consuming and challenging despite great advances in formulation development. Here, we present a systematic approach for the rapid size optimization of liposomes. The combination of microfluidics with a design-of-experiment (DoE) approach offers a strategy to rapidly screen and optimize various liposome formulations, i.e., up to 30 liposome formulations in 1 day. Five representative liposome formulations based on clinically approved lipid compositions were formulated using systematic variations in microfluidics flow rate settings, i.e., flow rate ratio (FRR) and total flow rate (TFR). Interestingly, flow rate-dependent DoE models for the prediction of liposome characteristics could be grouped according to lipid-phase transition temperature and surface characteristics. For all formulations, the FRR had a significant impact (p < 0.001) on hydrodynamic diameter and size distribution of liposomes, while the TFR mainly affected the production rate. Liposome characteristics remained constant for TFRs above 8 mL/min. The stability study revealed an influence of lipid:cholesterol ratio (1:1 and 2:1 ratio) and presence of PEG on liposome characteristics during storage. To validate our DoE models, we formulated liposomes incorporating hydrophobic dodecanethiol-coated gold nanoparticles. This proof-of-concept step showed that flow rate settings predicted by DoE models successfully determined the size of resulting empty liposomes (109.3 ± 15.3 nm) or nanocomposites (111 ± 17.3 nm). This study indicates that a microfluidics-based formulation approach combined with DoE is suitable for the routine development of monodisperse and size-specific liposomes in a reproducible and rapid manner.
脂质体作为第一个进入临床的纳米制剂引起了广泛关注。然而，尽管在制剂开发方面取得了很大进展，但在纳米医学发展过程中优化脂质体的理化性质仍然是一项耗时且具有挑战性的工作。在这里，我们提出了一种快速优化脂质体大小的系统方法。微流控技术与实验设计（DoE）方法的结合为快速筛选和优化各种脂质体制剂提供了一种策略，即在 1 天内最多可优化 30 种脂质体制剂。基于临床批准的脂质组成，我们使用微流控流速设置的系统变化（即流速比（FRR）和总流速（TFR））来配制 5 种代表性的脂质体制剂。有趣的是，基于脂质相转变温度和表面特性，可以将依赖流速的 DoE 模型分组，用于预测脂质体的特性。对于所有制剂，FRR 对脂质体的水动力直径和粒径分布有显著影响（p<0.001），而 TFR 主要影响生产速率。当 TFR 高于 8 mL/min 时，脂质体的特性保持不变。稳定性研究表明，在储存过程中，脂质：胆固醇比（1:1 和 2:1 比）和 PEG 的存在对脂质体的特性有影响。为了验证我们的 DoE 模型，我们制备了包含疏水性十二硫醇包覆的金纳米粒子的脂质体。这一概念验证步骤表明，DoE 模型预测的流速设置成功地确定了所得空脂质体（109.3±15.3nm）或纳米复合物（111±17.3nm）的大小。本研究表明，基于微流控的制剂方法与 DoE 相结合，适合于以可重复和快速的方式常规开发单分散且尺寸特定的脂质体。
