Abstract
Recent studies have shown that the solubilization of two antimalarial drug candidates, artefenomel (OZ439) and ferroquine (FQ), designed to provide a single-dose combination therapy for uncomplicated malaria can be enhanced using milk as a lipid-based formulation. However, milk as an excipient faces significant quality and regulatory hurdles. We therefore have investigated infant formula as a potential alternative formulation approach. The significance of the lipid species present in a formula with different lipid compositions upon the solubilization of OZ439 and FQ during digestion has been investigated. Synchrotron small-angle X-ray scattering was used to measure the diffraction from a dispersed drug during digestion and thereby determine the extent of drug solubilization. High-performance liquid chromatography was used to quantify the amount of drug partitioned into the digested lipid phases. Our results show that both the lipid species and the amount of lipids administered were key determinants for the solubilization of OZ439, while the solubilization of FQ was independent of the lipid composition. Infant formulas could therefore be designed and used as milk substitutes to tailor the desired level of drug solubilization while circumventing the variability of components in naturally derived milk. The enhanced solubilization of OZ439 was achieved during the digestion of medium-chain triacylglycerols (MCT), indicating the potential applicability of MCT-fortified infant formula powder as a lipid-based formulation for the oral delivery of OZ439 and FQ.
Highlights
Lipid-based formulations (LBF) are one of the most widely used strategies to improve oral bioavailability of poorly watersoluble drugs by enhancing the dissolution of drugs in the gastrointestinal (GI) tract, prolonging the gastric retention time and potentially reducing the activity of efflux transporters on the intestinal wall.[1]
We have recently shown that the solubilization of the antimalarial drugs artefenomel (OZ439) and ferroquine (FQ) was enhanced during digestion in full-cream bovine milk,[8,9] which was analogous to the results of bioavailability studies.[10−12] the positive effects of milk on the solubilization of OZ439 and FQ during intestinal lipolysis were clear, the use of milk and its practical application for oral coadministration with drugs in developing countries are limited by challenges
Previous studies have shown that variations in the lipid species in milk and infant formula are key to the formation of different liquid crystalline structures during digestion,[21] which may subsequently impact the delivery of nutrients and coadministered drugs
Summary
Lipid-based formulations (LBF) are one of the most widely used strategies to improve oral bioavailability of poorly watersoluble drugs by enhancing the dissolution of drugs in the gastrointestinal (GI) tract, prolonging the gastric retention time and potentially reducing the activity of efflux transporters on the intestinal wall.[1]. We have recently shown that the solubilization of the antimalarial drugs artefenomel (OZ439) and ferroquine (FQ) was enhanced during digestion in full-cream bovine milk,[8,9] which was analogous to the results of bioavailability studies.[10−12] the positive effects of milk on the solubilization of OZ439 and FQ during intestinal lipolysis were clear, the use of milk and its practical application for oral coadministration with drugs in developing countries are limited by challenges These include the need to refrigerate the milk prior to consumption and the presence of variations in the quality of milk, which will make its implementation as a Food and Drug Administration (FDA)-approved excipient for drug delivery difficult.[13,14] powdered milk substitutes such as infant formulas may provide an alternative solution to the limited shelf life of fresh milk and offer a well-. High-performance liquid chromatography (HPLC) was used to quantify the distributions of OZ439 and FQ in the digested phases of the infant formulas
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