(644f) Formulation, Stability, and Scalability of Fast-Releasing Lumefantrine Nanoparticles for the Treatment of Malaria

Authors: 
Armstrong, M., Princeton University
Feng, J., University of Illinois, Urbana-Champaign
Markwalter, C. E., Princeton University
Tian, C., Princeton University
Ristroph, K. D., Princeton University
Wang, L. Z., Princeton University
Yang, J., University of Sheffield
Du, H., Wuxi Apptec
Lin, H., Wuxi Apptec
He, F., Wuxi Apptec
Jiang, S., Wuxi Apptec
Panmai, S., Wuxi Apptec
Ramachandruni, H., Medicines for Malaria Venture (MMV)
Zhang, Y., Princeton University
McManus, S. A., Princeton University
Gong, K., Princeton University
White, C., Princeton University
Rawal, A., The University of New South Wales
Prud’homme, R. K., Princeton University
Lumefantrine, an anti-malaria drug, suffers from low bioavailability due to its hydrophobic character. Via Flash Nanoprecipitation (FNP), we kinetically trap the drug as a nanoparticle in an amorphous state, which increases solubility and therefore bioavailability. 200-400 nm lumefantrine nanoparticles are produced via FNP using safe and inexpensive stabilizers: hydroxypropylmethylcellulose acetate succinate (HPMCAS), zein protein, and lecithin phospholipid. FNP and spray drying are combined to generate solid powders. These powders are stable under hot and humid conditions. Here we demonstrate the use of FNP and spray drying as a continuous and scalable platform to generate and recover nanoparticles without compromising the dissolution kinetics of the drug. Our process for continuous nanoparticle synthesis and recovery is also inexpensive, which makes it viable for low-income countries. Three scales of mixers were utilized, allowing nanoparticle production rates ranging from a few milligrams up to around 1 kg/day, all with similar nanoparticle size and polydispersity.

We compare lyophilized and spray dried lumefantrine NP powders and confirm that using spray drying as our solidification method does not compromise the dissolution kinetics and can therefore be used as a cost effective and scalable drying method. The dissolution kinetics for the spray dried NP powders remain constant under fasted and fed conditions for over a month in accelerated stability testing conditions (50°C, 75% RH, open vial). Via Powder X-ray diffraction, differential scanning calorimetry, and solid-state nuclear magnetic resonance, we confirm that the lumefantrine in the core of the nanoparticle is amorphous. The combination of FNP and spray-drying offers a low-cost, scalable, and continuous nanofabrication platform to produce amorphous nanoparticles in a solid dosage form.