Formulation and Particle Size Reduction Improve Bioavailability of Poorly Water-Soluble Compounds with Antimalarial Activity

Decoquinate (DQ) is highly effective at killing malaria parasites in vitro; however, it is extremely insoluble in water. In this study, solid dispersion method was used for DQ formulation which created a suitable physical form of DQ in aqueous phase for particle manipulation. Among many polymers and surfactants tested, polyvinylpyrrolidone 10, a polymer, and L-α-phosphatidylcholine or polysorbate, two surfactants, were chosen as DQ formulation components. The formulation particles were reduced to a mean size between 200 to 400？nm, which was stable in aqueous medium for at least three weeks. Pharmacokinetic (PK) studies showed that compared to DQ microparticle suspension, a nanoparticle formulation orally dosed to mice showed a 14.47-fold increase in area under the curve (AUC) of DQ plasma concentration and a 4.53-fold increase in AUC of DQ liver distribution. WR 299666, a poorly water-soluble compound with antimalarial activity, was also tested and successfully made into nanoparticle formulation without undergoing solid dispersion procedure. We concluded that nanoparticles generated by using appropriate formulation components and sufficient particle size reduction significantly increased the bioavailability of DQ and could potentially turn this antimalarial agent to a therapeutic drug. 1. Introduction DQ has been marketed as a veterinary medicine for inhibiting the growth of coccidiosis in the digestive system of poultry for many years without any obvious adverse effects [1]. This compound has been shown experimentally to have efficacy against diarrheal disease caused by Cryptosporidium parvum [2, 3]. It has also been shown to be highly effective against malaria parasites in both the blood and liver stages as shown in some rodent and primate malaria models [4–8]. Unlike the classic antimalarial drugs such as chloroquine, which enters the red blood cells, is selectively accumulated in the Plasmodium lysosome, inhibits hematin body packaging, and forms highly toxic complex to the parasites by chloroquine and hematin binding, DQ has recently emerged as a potent in vitro and in vivo inhibitor of the Plasmodium liver stage and acts by selectively and specifically inhibiting the parasite’s mitochondrial electron transport chain [6]. DQ exhibited minimal cross-resistance with its analog compound atovaquone, an existing antimalarial drug. Although both DQ and atovaquone inhibit cytochrome bc1 complex, there is evidence that they have distinctly different modes of binding within the ubiquinol-binding site of cytochrome b [6]. DQ has also shown to have potent