(496d) Formulation of Stable Nanosuspensions of a Novel Malaria Therapeutic Though Polymer-Directed Precipitation

Ristroph, K. D., Princeton University
Lu, H., Princeton University
McManus, S. A., Princeton University
Zhang, Y., Princeton University
Feng, J., Princeton University
Mulhearn, W. D., Princeton University
Prud'homme, R., Princeton University

A new
antimalarial drug, which has been identified as a potentially revolutionary and
single-dose therapeutic to treat malaria is under investigation by Medicines
for Malaria Venture (MMV). The drug has limited efficacy as an oral therapy
because of its poor water solubility and dissolution kinetics; for a single-use
dose, up to 800 mg of compound must be delivered at once. To improve drug
dissolution kinetics in water, the mesylate salt of the
drug was encapsulated into stable nanoformulations
100-300 nm in size using the polymer-directed self-assembly technique Flash
NanoPrecipitation (FNP). As part of the FNP process, the drug was modified via
hydrophobic ion-pairing (HIP) in order to increase its hydrophobicity and
improve its encapsulation efficiency in the precipitation. Varying the drug’s
salt form and polymeric coatings yielded formulations with supersaturated drug
concentrations for as short as half an hour to as long as six hours. The
nanoparticles formed were water dispersible following lyophilization
and showed improved dissolution kinetics in water, gastric fluid, and
intestinal fluids compared to the drug mesylate
powder. Nanoformulated drugs exhibited up to nearly
one order magnitude higher supersaturation concentrations compared to
non-formulated compounds. Physical characterization of the formulations
indicate that encapsulated compound exists in amorphous form, which yields the
supersaturated drug concentrations. These results suggest that these
nanoparticles, which were prepared by FNP and which contain ion-paired drug,
may offer improved efficacy in oral administration for the treatment of malaria
in developing countries.

Drug release
over time when lyophilized NPs (blue) and drug powder (red) were suspended in
simulated fasted intestinal fluid (FaSSIF).