Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd U3092, Storrs, CT 06269, USA.
Int J Pharm. 2012 Sep 15;434(1-2):349-59. doi: 10.1016/j.ijpharm.2012.06.002. Epub 2012 Jun 7.
Quality by design (QbD) principles were explored in the current study to gain a comprehensive understanding of the preparation of superoxide dismutase (SOD) containing liposome formulations prepared using freeze-and-thaw unilamellar vesicles (FAT-ULV). Risk analysis and D-optimal statistical design were performed. Of all the variables investigated, lipid concentration, cholesterol mol%, main lipid type and protein concentration were identified as critical parameters affecting SOD encapsulation efficiency, while the main lipid type was the only factor influencing liposome particle size. Using a model generated by the D-optimal design, a series of three-dimensional response spaces for SOD liposome encapsulation efficiency were established. The maximum values observed in the response surfaces indirectly confirmed the existence of a specific SOD-lipid interaction, which took place in the lipid bilayer under the following optimal conditions: (1) appropriate membrane thickness and curvature (DPPC liposomes); and (2) optimal "pocket size" generated by cholesterol content. With respect to storage stability, the prepared SOD liposomes remained stable for at least 6 months in aqueous dispersion state at 4°C. This research highlights the level of understanding that can be accomplished through a well-designed study based on the philosophy of QbD.
本研究探索了质量源于设计（QbD）原理，以全面了解使用冻融单层囊泡（FAT-ULV）制备的含超氧化物歧化酶（SOD）的脂质体制剂的制备情况。进行了风险分析和 D-最优统计设计。在所研究的所有变量中，脂质浓度、胆固醇摩尔%、主要脂质类型和蛋白质浓度被确定为影响 SOD 包封效率的关键参数，而主要脂质类型是唯一影响脂质体粒径的因素。使用 D-最优设计生成的模型，建立了一系列 SOD 脂质体包封效率的三维响应面。响应面中观察到的最大值间接证实了 SOD-脂质相互作用的存在，这种相互作用发生在以下最佳条件下的脂质双层中：（1）适当的膜厚度和曲率（DPPC 脂质体）；（2）胆固醇含量产生的最佳“口袋大小”。关于储存稳定性，在 4°C 的水性分散状态下，制备的 SOD 脂质体至少在 6 个月内保持稳定。本研究强调了通过基于 QbD 理念的精心设计研究可以达到的理解水平。
