Abstract
Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.
Highlights
Malaria is a mosquito-borne parasitic disease that poses a global concern; about half a million children under the age of 5 die from malaria each year.[1]
Our group has previously shown that liquid crystalline nanostructures are formed during the digestion of bovine milk due to the selfassembly of amphiphilic digestion products that consist of fatty acids, monoglycerides, and diglycerides.[32,33]
In situ monitoring of diffraction peaks and thereby solubilization of OZ439 in milk as the formulation vehicle during the course of digestion was investigated by using synchrotron X-ray scattering
Summary
Malaria is a mosquito-borne parasitic disease that poses a global concern; about half a million children under the age of 5 die from malaria each year.[1] The emergence of parasite resistance to current artemisinin-based therapies has led to the need for new antimalarial drugs.[2,3] OZ439 is a synthetic trioxolane drug (Figure 1) that is highly potent against arteminisin-resistant strains of Plasmodium falciparum and can potentially be used as a single-dose cure in combination with a partner drug.[4−6]. OZ439 is an amphiphilic poorly water-soluble drug[7] that can self-assemble into colloidal structures in aqueous solution.[8]. The mesylate salt of OZ439 has an apparent high solubility in water, the free base forms of the drug are poorly soluble in fluids representative of those in the gastrointestinal (GI) tract. GI environment is anticipated to be a limitation to absorption through the intestinal membrane.[9,10]
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