Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Laboratory of Physiochemistry and Preformulation Research, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba 260-0856 Japan.
Mol Pharm. 2023 Nov 6;20(11):5701-5713. doi: 10.1021/acs.molpharmaceut.3c00562. Epub 2023 Oct 12.
The bicelle, a type of solid lipid nanoparticle, comprises phospholipids with varying alkyl chain lengths and possesses the ability to solubilize poorly water-soluble drugs. Bicelle preparation is complicated and time-consuming because conventional drug-loading methods in bicelles require multiple rounds of thermal cycling or co-grinding with drugs and lipids. In this study, we proposed a simple drug-loading method for bicelles that utilizes passive diffusion. Drug-unloaded bicelles were placed inside a dialysis device and incubated in a saturated solution of ketoconazole (KTZ), which is a model drug. KTZ was successfully loaded into bare bicelles over time with morphological changes, and the final encapsulated concentration was dependent on the lipid concentration of the bicelles. When polyethylene glycol (PEG) chains of two different lengths (PEG2K and 5K) were incorporated into bicelles, PEG2k and PEG5k bicelles mitigated the morphological changes and improved the encapsulation rate. This mitigation of morphological changes enhanced the encapsulated drug concentration. Specifically, PEG5k bicelles, which exhibited the greatest prevention of morphological changes, had a lower encapsulated concentration after 24 h than that of PEG2k bicelles, indicating that PEGylation with a longer PEG chain length improved the loading capacity but decreased the encapsulation rate owing to the presence of a hydration layer of PEG. Thus, PEG with a certain length is more suitable for passive loading. Moreover, loading factors, such as temperature and vehicles used in the encapsulation process, affected the encapsulation rate of the drug. Taken together, the passive loading method offers high throughput with minimal resources, making it a potentially valuable approach during early drug development phases.
双立方脂(Bicelle),一种固体脂质纳米颗粒,由具有不同烷基链长度的磷脂组成,具有增溶疏水性药物的能力。双立方脂的制备复杂且耗时,因为常规的双立方脂载药方法需要多次热循环或与药物和脂质共研磨。在这项研究中,我们提出了一种简单的双立方脂载药方法,利用被动扩散。将未载药的双立方脂置于透析装置中,并在酮康唑(KTZ)的饱和溶液中孵育,KTZ 是一种模型药物。随着时间的推移,药物成功地装载到裸双立方脂中,形态发生变化,最终包封浓度取决于双立方脂的脂质浓度。当两种不同长度的聚乙二醇(PEG)链(PEG2K 和 5K)被掺入双立方脂中时,PEG2k 和 PEG5k 双立方脂减轻了形态变化并提高了包封率。这种形态变化的减轻提高了包封药物的浓度。具体来说,PEG5k 双立方脂表现出最大的形态变化缓解,在 24 小时后包封浓度低于 PEG2k 双立方脂,表明更长的 PEG 链长的 PEG 化提高了载药量,但由于 PEG 的水合层的存在,包封率降低。因此,具有一定长度的 PEG 更适合被动加载。此外,载药过程中的加载因素,如温度和载体,影响药物的包封率。综上所述,被动加载方法具有高通量、资源消耗少的特点,在药物开发的早期阶段具有潜在的应用价值。
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