Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, 20131, Thailand.
Department of Manufacturing Pharmacy, College of Pharmacy, Rangsit University, Pathum Thani, 12000, Thailand.
Int J Nanomedicine. 2024 Aug 27;19:8729-8750. doi: 10.2147/IJN.S474775. eCollection 2024.
Lipid-based nanoparticles (LNPs) is increasingly recognized for their potential in drug delivery, offering protection to hydrophobic drugs from degradation. Industrial synthesis of LNPs, exemplified by Pfizer-BioNTech and Moderna mRNA vaccines, utilizes flow chemistry or microfluidics, showcasing its scalability. This study explores the utilization of a novel design reactor, the vortex tube reactor, within flow chemistry for LNPs synthesis, aiming to optimize its conditions and compare them with batch synthesis.
LNPs were synthesized using the vortex tube reactor, incorporating bovine serum albumin (BSA) as a model drug in the aqueous phase, alongside 1.2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol in the organic phase. Design of experiments (DoE), specifically Box-Behnken design, was employed to optimize parameters, including X: the flow rate ratio (10-100 mL/min), X: the aqueous-to-organic volumetric ratio (1:1-10:1), and X: the number of reactor units (1-5 units). Responses evaluated encompassed physical properties and productivity. Optimized conditions were determined by minimizing particle size (Y), polydispersity index (Y), and zeta potential (Y), while maximizing entrapment efficiency (Y), drug loading (Y), and productivity (Y).
Results indicated that optimal conditions were achieved at X of 100 mL/min, X of 5.278, and X of 1 unit. LNPs synthesized under these conditions exhibited favorable physical properties and productivity, with uniformity maintained across batches. The vortex tube reactor demonstrated superiority over batch synthesis, yielding smaller particles (166.23 ± 0.98 nm), more uniform nanoparticles (PDI 0.17 ± 0.01), and higher entrapment (67.75 ± 1.55%) and loading capacities (36.39 ± 0.83%), indicative of enhanced productivity (313.4 ± 12.88 mg/min).
This study elucidates the potential of flow chemistry, particularly utilizing the vortex tube reactor, for large-scale LNPs formulation, offering insights into parameter relationships and advancing nanoparticle synthesis for drug delivery applications.
脂基纳米粒（LNPs）因其在药物输送方面的潜力而日益受到关注，可为疏水性药物提供降解保护。工业合成 LNPs 的方法，如辉瑞-生物科技和 Moderna 的 mRNA 疫苗，利用流化学或微流控技术，展示了其可扩展性。本研究探索了在流化学中利用新型设计反应器——涡流管反应器来合成 LNPs，旨在优化其条件并将其与批量合成进行比较。
使用涡流管反应器合成 LNPs，将牛血清白蛋白（BSA）作为模型药物纳入水相，同时将 1.2-二棕榈酰-sn-甘油-3-磷酸胆碱（DPPC）和胆固醇纳入有机相。采用设计实验（DoE），具体为 Box-Behnken 设计，优化参数，包括 X：流速比（10-100 mL/min）、X：水相与有机相的体积比（1:1-10:1）和 X：反应器单元数（1-5 个单元）。评价的响应包括物理性质和生产能力。通过最小化粒径（Y）、多分散指数（Y）和 zeta 电位（Y），同时最大化包封效率（Y）、药物载量（Y）和生产能力（Y），确定最佳条件。
结果表明，在 X 为 100 mL/min、X 为 5.278 和 X 为 1 个单元的条件下可达到最佳条件。在这些条件下合成的 LNPs 表现出良好的物理性质和生产能力，批次间均匀性保持不变。涡流管反应器优于批量合成，产生更小的颗粒（166.23 ± 0.98nm）、更均匀的纳米颗粒（PDI 0.17 ± 0.01）和更高的包封率（67.75 ± 1.55%）和载药量（36.39 ± 0.83%），表明生产能力提高（313.4 ± 12.88mg/min）。
本研究阐明了流化学，特别是利用涡流管反应器，在大规模 LNPs 配方中的潜力，为药物输送应用中的参数关系提供了深入了解，并推进了纳米颗粒合成。
