Background: OZ439 is a new chemical entity which is active against drug-resistant malaria and shows potential as a single-dose cure. However, development of an oral formulation with desired exposure has proved problematic, as OZ439 is poorly soluble (BCS Class II drug). In order to be feasible for low and middle income countries (LMICs), any process to create or formulate such a therapeutic must be inexpensive at scale, and the resulting formulation must survive without refrigeration even in hot, humid climates. We here demonstrate the scalability and stability of a nanoparticle (NP) formulation of OZ439. Previously, we applied a combination of hydrophobic ion pairing and Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Lyophilization was used to process the NPs into a dry form, and the powder’s in vitro solubilization was over tenfold higher than unprocessed OZ439.
Methods: In this study, we optimize our previous formulation using a large-scale multi-inlet vortex mixer (MIVM). Spray drying is a more scalable and less expensive operation than lyophilization and is, therefore, optimized to produce dry powders. The spray dried powders are then subjected to a series of accelerated aging stability trials at high temperature and humidity conditions.
Results: The spray dried OZ439 powder’s dissolution kinetics are superior to those of lyophilized NPs. The powder’s OZ439 solubilization profle remains constant after 1 month in uncapped vials in an oven at 50 °C and 75% RH, and for 6 months in capped vials at 40 °C and 75% RH. In fasted-state intestinal fuid, spray dried NPs achieved 80–85% OZ439 dissolution, to a concentration of 430 µg/mL, within 3 h. In fed-state intestinal fuid, 95–100% OZ439 dissolution is achieved within 1 h, to a concentration of 535 µg/mL. X-ray powder difraction and diferential scanning calorimetry profles similarly remain constant over these periods.
Conclusions: The combined nanofabrication and drying process described herein, which utilizes two continuous unit operations that can be operated at scale, is an important step toward an industrially-relevant method of formulating the antimalarial OZ439 into a single-dose oral form with good stability against humidity and temperature. Keywords: Nanocarrier, Hydrophobic ion pairing, Malaria, Spray drying, Drug delivery, Oral therapeutic, Drug solubilization, OZ439, Artefenomel, Flash NanoPrecipitation
Read the full publication in the Journal of Translational Medicine.