Formulation of Stable Nanosuspensions of a Novel Malaria Therapeutic Though Polymer-Directed Precipitation

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).