Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations

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.

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria

“…The SAXS pattern for the digestion of OZ439 only (no FQ) in milk is also included in panel b for comparison. 6 As was expected from the behavior of the individual drugs, disappearance of the characteristic FQ peak and polymorphic transformation of OZ439-FB from form 1 to form 2 occurred concurrently. However, it was evident that the kinetics of formation of OZ439-FB form 2 were different than in the case of OZ439 alone, where addition of FQ induced an earlier formation of the FB form 2.…”

“…No crystalline OZ439-FB form 2 peak was seen during the dispersion of OZ439 in milk in the absence of FQ. 6…”

“…(d) Corresponding areas of the crystalline X-ray scattering peaks from OZ439-FB form 1 and form 2 in single (OZ439 alone) and combined (OZ439 + FQ) dosage forms in milk during digestion. (Data for OZ439 alone in panels b and d are replotted from our previous study 6 for direct comparison. )…”

Revisiting dispersible milk-drug tablets as a solid lipid formulation in the context of digestion

“…Our group has previously shown the role of milk digestion on the solubilisation of a drug and its polymorphism (Salim et al, 2018). In this study, we aim to understand the effect of digestion of milk and infant formula lipids on the solubilisation of a drug when presented as a solid dosage form.…”

“…In the case of poorly soluble lipophilic drugs, digestion is a crucial component as the nature of the lipids and their digestion products promotes drug solubilisation and transport to the systemic circulation (Pouton, 2006, Feeney et al, 2016, Kaukonen et al, 2004, Mu et al, 2013). It has been recently shown that the digestion of milk can be a particularly effective way to drive solubilisation of co-administered drug (Salim et al, 2018).…”