Mechanism and kinetics of the loss of poorly soluble drugs from liposomal carriers studied by a novel flow field-flow fractionation-based drug release-/transfer-assay
Mechanism and kinetics of the loss of poorly soluble drugs from liposomal carriers studied by a novel flow field-flow fractionation-based drug release-/transfer-assay
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DOI：
10.1016/j.jconrel.2016.04.031
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发表时间：
2016-06-28
影响因子：
10.8
通讯作者：
Brandl, Martin
中科院分区：
文献类型：
--
作者：
Hinna, Askell Hvid;Hupfeld, Stefan;Brandl, Martin
脂质体代表了一种多功能的药物制剂方法，例如用于提高难溶性药物的水溶性，还可实现药物靶向和控释。对于后者的应用，药物在血管床中转运期间保持与脂质体载体结合是至关重要的。多年来，人们提出了一系列体外测试方法来预测药物从脂质体载体中的释放。其中大多数未能对水溶性差的药物给出现实的预测，因为此类化合物即使在广泛稀释后仍保持与脂质体双层结合的内在倾向。静脉注射后相反，注射时，由于药物从脂质体载体转移到内源性亲脂性库，例如脂蛋白、血浆蛋白或红细胞和内皮细胞膜，因此经常发生快速药物损失。在这里，我们报告了最近推出的体外预测药物转移测定的应用，该测定基于脂质体药物载体与大型多层脂质体的孵育，后者充当仿生模型水槽，使用流场流分级分离作为分离两种类型脂质体的工具。通过量化与脂质体药物载体相关的剩余药物量以及在不同孵育时间转移到受体脂质体的药物量，可以为模型药物p-THPP（5,10,15,20-四（4-羟苯基）21H，23H-卟啉）建立药物转移和释放到水相的动力学。 p-THPP 在结构上与替莫泊芬相似，替莫泊芬是一种光敏剂，目前正在脂质体制剂中进行临床评估。通过改变脂质体的供体与受体脂质质量比、大小和层状结构，获得了机理见解。与从最外层到内部同心双层的重新分布相比，发现从一种脂质体到另一种脂质体的药物转移动力学具有决定速率的作用，因此可以通过单个一级动力学模型充分描述整个过程。通过在 1:1 至 1:10 范围内改变供体与受体脂质质量比，在供体与受体脂质质量比和转移动力学之间建立了相关性，这被认为对于缩放到生理脂质质量比至关重要。通过将该测定应用于一系列不同双层亲和力的结构相关模型化合物，在脂质体双层相关药物的水溶性和亲脂性方面的整个预期范围内建立了转移和释放动力学。对于水溶性较高的化合物苏丹 II (clogP 5.45) 和苏丹 III (clogP 6.83)，观察到非常快速的转移并从脂质体大量释放到水相。对于亲脂性较高的化合物，从供体脂质体的转移速率遵循苏丹 IV（最快）> 油红 O> 苏丹黑 > p-THPP（最慢）的顺序。对于等摩尔供体与受体脂质质量比，确定了 12 分钟（苏丹 IV）至 1.5 小时（p-THPP）范围内的转移半衰期。从本质上讲，这里提出的结果既可以对暴露于生物池时脂质体载体的药物损失进行机械见解和预测，这比常用的体外释放测试更现实。 (C) 2016 Elsevier B.V. 保留所有权利。
Liposomes represent a versatile drug formulation approach e.g. for improving the water-solubility of poorly soluble drugs but also to achieve drug targeting and controlled release. For the latter applications it is essential that the drug remains associated with the liposomal carrier during transit in the vascular bed. A range of in vitro test methods has been suggested over the years for prediction of the release of drug from liposomal carriers. The majority of these fail to give a realistic prediction for poorly water-soluble drugs due to the intrinsic tendency of such compounds to remain associated with liposome bilayers even upon extensive dilution. Upon i.v. injection, in contrast, rapid drug loss often occurs due to drug transfer from the liposomal carriers to endogenous lipophilic sinks such as lipoproteins, plasma proteins or membranes of red blood cells and endothelial cells. Here we report on the application of a recently introduced in vitro predictive drug transfer assay based on incubation of the liposomal drug carrier with large multilamellar liposomes, the latter serving as a biomimetic model sink, using flow field-flow fractionation as a tool to separate the two types of liposomes. By quantifying the amount of drug remaining associated with the liposomal drug carrier as well as that transferred to the acceptor liposomes at distinct times of incubation, both the kinetics of drug transfer and release to the water phase could be established for the model drug p-THPP (5,10,15,20-tetrakis(4-hydroxyphenyl) 21H, 23H-porphine). p-THPP is structurally similar to temoporfin, a photosensitizer which is under clinical evaluation in a liposomal formulation. Mechanistic insights were gained by varying the donor-to-acceptor lipid mass ratio, size and lamellarity of the liposomes. Drug transfer kinetics from one liposome to another was found rate determining as compared to redistribution from the outermost to the inner concentric bilayers, such that the overall process could be adequately described by a single 1st order kinetic model. By varying the donor-to-acceptor lipid mass ratio in the range 1: 1 to 1: 10, a correlation was established between donor-to-acceptor-lipid mass ratio and transfer kinetics, which is regarded essential for scaling to physiological lipid mass ratios. By applying the assay to a series of structurally related model compounds of different bilayer affinity, transfer and release kinetics were established over the whole expected range of liposome bilayer associated drugs in terms of water solubility and lipophilicity. A very rapid transfer and considerable release from liposomes to the water phase was observed for the more water-soluble compounds Sudan II (clogP 5.45) and Sudan III (clogP 6.83). For the more lipophilic compounds, the rate of transfer from the donor liposomes followed the rank order Sudan IV (fastest) > Oil Red O > Sudan Black > p-THPP (slowest). For an equimolar donor-to-acceptor lipid mass ratio, half-lifes of transfer in the range of 12 min (Sudan IV) up to 1.5 h (p-THPP) were determined. In essence, the results presented here allow for both, mechanistic insights and predictions of drug loss from liposomal carriers upon exposure to biological sinks, which appear more realistic than the commonly employed in vitro release tests. (C) 2016 Elsevier B.V. All rights reserved.