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.

中文翻译：

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消化过程中Artefenomel（OZ439）与牛奶的相互作用：消化驱动的增溶作用和多态转化的见解

在临床试验过程中，牛奶已被用作抗疟药的载体，以测试食物效果，而青蒿琥酯（OZ439）则显示出口服牛奶的生物利用度得到提高。但是，人们对牛奶与胃肠道中OZ439之间相互作用的性质了解甚少。为了了解牛奶消化对OZ439增溶和多态性的作用，我们使用同步加速器X射线散射对包含OZ439的牛奶进行体外肠脂分解过程中，对悬浮液中的结晶药物进行了实时监测。OZ439在肠道pH值下形成不稳定的固态中间体游离碱形式（OZ439-FB形式1），在脂解之前被乳脂球部分溶解。在牛奶中体外脂解过程中，发生了游离碱形式1的溶解和更稳定的多晶型形式（OZ439-FB形式2）的OZ439重结晶。在不存在脂肪酶的情况下，简单地搅拌牛奶/药物悬浮液，或在无脂质缓冲液中向OZ439添加脂肪酶，都不会引起这种多态性转化。因此，OZ439-FB晶型1的溶解通过乳汁消化过程中OZ439-FB晶型1的溶解而加速。我们的发现证实，尽管体外消化后仍可检测到OZ439-FB 2型的结晶沉淀物，但与不含脂质的制剂相比，基于牛奶的脂质制剂可显着减少OZ439的结晶，这归因于胶体结构的形成被消化的乳脂。