School of Chemical and Biomedical Engineering, Nanyang Technological University Singapore, 62 Nanyang Drive, 637 459, Singapore.
Mater Sci Eng C Mater Biol Appl. 2020 Mar;108:110410. doi: 10.1016/j.msec.2019.110410. Epub 2019 Nov 9.
Lipid cochleates are gaining increasing interest as drug-carriers. However, their preparation relies on conventional batch processes that are complex, time consuming and lack batch-to-batch reproducibility; presenting a bottleneck for clinical translation. We report an efficient continuous preparation process for artemisinin-loaded cochleates (ART-cochleates) using inexpensive off-the-shelf flow focusing device. By carefully controlling the flow focusing parameters, we showed along with the mechanism that, ART-cochleates of uniform and tuneable size (180 nm in width and ~1030 nm in length) were obtained with low dispersity (0.18 in width and 0.27 in length), narrow size distribution and high reproducibility compared to the batch process. The device achieved high throughput of 11.5 g/day with ART encapsulation of 64.24 ± 2.5% and loading of 83.37 ± 3.68 mg ART/g of cochleates. Art-cochleates were non-toxic and showed sustained in-vitro release of ART with effective transepithelial permeability across intestinal Caco-2 monolayer (60% and ~25% transport for pure ART and ART-cochleates, respectively) resulting in better in-vitro bioavailability. The off-the-shelf device is envisioned to be highly promising platform for continuous and high-throughput manufacturing of drug-loaded cochleates in a controlled and reproducible manner. It has potential to enable clinical translation of drug-loaded cochleates with predicable drug release, absorption and bioavailability.
脂质耳蜗因其作为药物载体而受到越来越多的关注。然而，它们的制备依赖于传统的批处理工艺，这些工艺复杂、耗时且缺乏批间重现性，成为临床转化的瓶颈。我们报告了一种使用廉价现成的流聚焦装置高效连续制备青蒿素载耳蜗（ART-cochleates）的方法。通过仔细控制流聚焦参数，我们展示了一种机制，即通过这种机制，可以获得均匀且可调尺寸（宽度约为 180nm，长度约为 1030nm）、低分散度（宽度为 0.18，长度为 0.27）、窄粒径分布和高重现性的 ART-cochleates，与批处理工艺相比。该设备的通量高达 11.5g/天，ART 包封率为 64.24±2.5%，耳蜗载药量为 83.37±3.68mg ART/g。ART-cochleates 无毒性，并表现出 ART 的持续体外释放，跨肠 Caco-2 单层的有效经上皮渗透性（分别为纯 ART 和 ART-cochleates 的约 60%和 25%），从而提高了体外生物利用度。这种现成的设备有望成为一种有前途的平台，用于以可控和可重复的方式连续、高通量地制造载药耳蜗。它有可能实现具有可预测药物释放、吸收和生物利用度的载药耳蜗的临床转化。
