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.
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