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 in the fasted state when dosed as a crystalline solid.  LMN is therefore dosed with food for achieving adequate adsorption making it sub-optimal for pediatric administrations.  The goal of this work was to produce low-cost, highly orally bioavailable, stable LMN powders applicable for global health applications which can be dosed either in the fed or fasted state.<br/><br/>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 with sizes of 200-250 nm.  The final powders are readily redispersible and are stable over accelerated aging conditions (50°C, 75% RH, open vial) for 4 weeks giving 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 lumefantrine 4X <i>in vivo</i> when compared to the control crystalline formulation.  The three continuous processes (FNP, tangential flow ultrafiltration, and spray drying) were optimized at small and pilot scale to produce the nanoparticles.  We describe the translation of the laboratory-scale process at Princeton University to the clinical manufacturing scale at WuXi AppTech (Shanghai, China).

Formulation and scale-up of fast-dissolving Lumefantrine nanoparticles for oral malaria therapy

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