Abstract
Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H+ and ionized liberated free fatty acids resulted in the formation of amorphous salts, which removes the low-energy crystalline state as a barrier to dissolution of FQ, while inhibiting the solubilization of OZ439. We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation.
Highlights
The free base form 1 underwent a polymorphic transformation to the stable crystalline OZ439-FB form 2 during digestion in milk, which was subsequently partially solubilized into the digested milk
Milk can be used to enhance the solubilization of OZ439 and FQ during in vitro lipolysis under intestinal conditions
The overall solubilization of OZ439 during digestion was, reduced by the presence of FQ when co-formulated in milk
Summary
Article absorption.[1] Many poorly water-soluble drugs exhibit strong food effects,[1,2] and co-administration of full-cream milk with artefenomel (OZ439, logP ≈ 5.4 predicted using Chemicalize developed by ChemAxon), for example, leads to an improved bioavailability in patients with uncomplicated malaria.[3,4] Milk has been demonstrated to be an effective drug delivery system when digestion is considered as an essential factor in understanding its performance as a formulation.[5] In our previous work, we attempted to understand the solubilization behavior of OZ439 in milk during in vitro digestion.[6] The mesylate salt of OZ439 is the preferred salt form that has been prepared commercially; upon exposure of a solution of the mesylate salt in water to low-pH chloride solutions mimicking the gastric environment, the crystalline hydrochloride salt immediately precipitated. The bioavailability of OZ439 when given with milk in the clinic was sufficient to elicit its therapeutic effect.[8]
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