Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Int J Mol Sci. 2023 Aug 30;24(17):13417. doi: 10.3390/ijms241713417.
Liposomal formulations offer significant advantages as anticancer drug carriers for targeted drug delivery; however, due to their complexity, clinical translation has been challenging. In addition, liposomal product manufacturing has been interrupted in the past, as was the case for Doxil (doxorubicin hydrochloride liposome injection). Here, interfacial tension (IFT) measurements were investigated as a potential physicochemical characterization tool to aid in liposomal product characterization during development and manufacturing. A pendant drop method using an optical tensiometer was used to measure the interfacial tension of various analogues of Doxil liposomal suspensions in air and in dodecane. The effect of liposome concentration, formulation (PEG and cholesterol content), presence of encapsulated drug, as well as average particle size was analyzed. It was observed that Doxil analog liposomes demonstrate surfactant-like behavior with a sigmoidal-shape interfacial tension vs. concentration curve. This behavior was heavily dependent on PEG content, with a complete loss of surfactant-like behavior when PEG was removed from the formulation. In addition to interfacial tension, three data analyses were identified as able to distinguish between formulations with variations in PEG, cholesterol, and particle size: (i) polar and non-polar contribution to interfacial tension, (ii) liposomal concentration at which the polar and non-polar components were equal, and (iii) rate of interfacial tension decay after droplet formation, which is indicative of how quickly liposomes migrate from the bulk of the solution to the surface. We demonstrate for the first time that interfacial tension can be used to detect certain liposomal formulation changes, such as PEG content, encapsulated drug presence, and size variability, and may make a useful addition to physicochemical characterization during development and manufacturing of liposomal products.
脂质体制剂作为靶向药物递送的抗癌药物载体具有显著优势；然而，由于其复杂性，临床转化一直具有挑战性。此外，过去也曾中断过脂质体产品的制造，就像多柔比星脂质体注射液（Doxil）那样。在这里，我们研究了界面张力（IFT）测量作为一种潜在的物理化学特性表征工具，以帮助在脂质体产品的开发和制造过程中进行特性表征。使用光学张力计的悬滴法用于测量空气中和正十二烷中各种 Doxil 脂质体混悬剂类似物的界面张力。分析了脂质体浓度、配方（PEG 和胆固醇含量）、包封药物的存在以及平均粒径的影响。结果表明，Doxil 类似脂质体表现出表面活性剂样行为，具有界面张力与浓度的 S 形曲线。这种行为严重依赖于 PEG 含量，当从配方中去除 PEG 时，完全失去了表面活性剂样行为。除了界面张力外，还确定了三种数据分析方法能够区分 PEG、胆固醇和粒径变化的配方：（i）界面张力的极性和非极性贡献，（ii）极性和非极性成分相等时的脂质体浓度，以及（iii）液滴形成后界面张力衰减的速率，这表明脂质体从溶液主体迁移到表面的速度有多快。我们首次证明，界面张力可用于检测某些脂质体配方变化，例如 PEG 含量、包封药物的存在和尺寸变化，并且可能成为脂质体产品开发和制造过程中物理化学特性表征的有用补充。
