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无胆固醇的聚乙二醇化脂质体的冷冻干燥及其对通过被动平衡药物装载的影响。

Lyophilization of cholesterol-free PEGylated liposomes and its impact on drug loading by passive equilibration.

机构信息

Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.

出版信息

Int J Pharm. 2012 Jul 1;430(1-2):167-75. doi: 10.1016/j.ijpharm.2012.04.036. Epub 2012 Apr 16.


DOI:10.1016/j.ijpharm.2012.04.036
PMID:22537806
Abstract

The obstacles in translating liposome formulations into marketable products could be attributed to their physical instabilities upon long-term storage as aqueous dispersions. Lyophilization is the most commonly used technique to improve physical stability of liposomes. The development of stable, lyophilized liposomes is focused primarily on the cholesterol-containing liposomes or pure phosphatidylcholine-based liposomes, with minimal studies on cholesterol-free, pegylated (CF-PEG) liposomes which have emerged as an important class of liposome drug carriers. Hence, it is our interest to investigate the effect of lyophilization on CF-PEG liposomes, and specifically, on drug loading via the passive equilibration method. Three different sugar cryoprotectants were used at two different sugar-to-lipid molar ratios (S/L). Our results demonstrated that CF-PEG liposomes lyophilized with sucrose at S/L=5:1 yielded the best cryoprotective effect, as characterized by size, polydispersity indices, and microscopic examination upon liposome reconstitution. The lyophilized liposomes had low water content of 2.59 ± 0.18%. Of note, lyophilized CF-PEG liposomes exhibited two-fold increase in drug content when carboplatin was loaded via the passive equilibration method, and the in vitro drug release profile of these liposomes were not different from that of the non-lyophilized counterparts. Taken together, we envisioned that a stable, lyophilized empty CF-PEG liposome system could be coupled to hydrophilic drug loading via the passive equilibration method to produce a liposomal drug kit product.

摘要

脂质体制剂转化为市售产品的障碍可归因于其在长期储存作为水性分散体时的物理不稳定性。冷冻干燥是提高脂质体物理稳定性最常用的技术。稳定的、冻干的脂质体的开发主要集中在含有胆固醇的脂质体或纯磷脂酰胆碱为基础的脂质体,对无胆固醇、聚乙二醇化(CF-PEG)脂质体的研究很少,后者已成为一类重要的脂质体药物载体。因此,我们有兴趣研究冷冻干燥对 CF-PEG 脂质体的影响,特别是通过被动平衡法进行药物负载。使用了三种不同的糖保护剂,在两种不同的糖与脂质摩尔比(S/L)下使用。我们的结果表明,用蔗糖在 S/L=5:1 冻干的 CF-PEG 脂质体具有最好的保护效果,其特征是粒径、多分散指数和脂质体重构后的显微镜检查。冻干脂质体的水含量低至 2.59±0.18%。值得注意的是,当通过被动平衡法加载卡铂时,冻干的 CF-PEG 脂质体的药物含量增加了两倍,这些脂质体的体外药物释放曲线与非冻干脂质体没有区别。总之,我们设想一个稳定的、冻干的空 CF-PEG 脂质体系统可以通过被动平衡法与亲水性药物加载结合,以生产一种脂质体药物试剂盒产品。

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