Department of Chemical and Biological Engineering, Princeton University, Princeton NJ 08544.
STA Pharmaceutical, a WuXi AppTec Company, Shanghai, China, 200131.
J Pharm Sci. 2023 Aug;112(8):2267-2275. doi: 10.1016/j.xphs.2023.04.003. Epub 2023 Apr 7.
Lumefantrine (LMN) is one of the first-line drugs in the treatment of malaria due to its long circulation half-life, which results in enhanced effectiveness against drug-resistant strains of malaria. However, LMN's therapeutic efficacy is diminished due to its low bioavailability when dosed as a crystalline solid. The goal of this work was to produce low-cost, highly bioavailable, stable LMN powders for oral delivery that would be suitable for global health applications. We report the development of a LMN nanoparticle formulation and the translation of that formulation from laboratory to industrial scale. We applied Flash NanoPrecipitation (FNP) to develop nanoparticles with 90% LMN loading and sizes of 200-260 nm. The integrated process involves nanoparticle formation, concentration by tangential flow ultrafiltration, and then spray drying to obtain a dry powder. The final powders are readily redispersible and stable over accelerated aging conditions (50°C, 75% RH, open vial) for at least 4 weeks and give equivalent and fast drug release kinetics in both simulated fed and fasted state intestinal fluids, making them suitable for pediatric administration. The nanoparticle-based formulations increase the bioavailability of LMN 4.8-fold in vivo when compared to the control crystalline LMN. We describe the translation of the laboratory-scale process at Princeton University to the clinical manufacturing scale at WuXi AppTec.
磷酸萘酚喹（LMN）是治疗疟疾的一线药物之一，因其半衰期长，对耐药疟原虫的疗效增强。然而，当以结晶固体给药时，其生物利用度低，导致 LMN 的治疗效果减弱。本工作的目的是制备低成本、高生物利用度、稳定的 LMN 粉末，用于口服给药，适用于全球健康应用。我们报告了 LMN 纳米颗粒制剂的开发以及该制剂从实验室规模向工业规模的转化。我们应用 Flash NanoPrecipitation（FNP）开发了载药量为 90%、粒径为 200-260nm 的纳米颗粒。该集成工艺包括纳米颗粒的形成、切向流超滤浓缩，然后喷雾干燥得到干粉。最终的粉末易于再分散，在加速老化条件（50°C、75%RH、敞口瓶）下至少稳定 4 周，并在模拟进食和禁食状态的肠道液中具有等效和快速的药物释放动力学，使其适合儿科给药。与对照结晶 LMN 相比，基于纳米颗粒的制剂使 LMN 的体内生物利用度提高了 4.8 倍。我们描述了从普林斯顿大学的实验室规模工艺到药明康德的临床生产规模的转化。
