Abstract
Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic liquids (ILs) provides one means to enhance drug solubility in LBFs. However, whether different ILs benefit from formulation in different LBFs is largely unknown. In the current studies, lumefantrine was isolated as a number of different lipophilic salt/ionic liquid forms and performance was assessed after formulation in a range of LBFs. The solubility of lumefantrine in LBF was enhanced 2- to 80-fold by isolation as the lumefantrine docusate IL when compared to lumefantrine free base. The increase in drug loading subsequently enhanced concentrations in the aqueous phase of model intestinal fluids during in vitro dispersion and digestion testing of the LBF. To assess in vivo performance, the systemic exposure of lumefantrine docusate after administration in Type II-MCF, IIIB-MCF, IIIB-LCF, and IV formulations was evaluated after oral administration to rats. In vivo exposure was compared to control lipid and aqueous suspension formulations of lumefantrine free base. Lumefantrine docusate in the Type IIIB-LCF showed significantly higher plasma exposure compared to all other formulations (up to 35-fold higher). The data suggest that isolation of a lipid-soluble IL, coupled with an appropriate formulation, is a viable means to increase drug dose in an oral formulation and to enhance exposure of lumefantrine in vivo.
Highlights
Many currently marketed drugs, and drugs in development, are poorly water-soluble and classified as class II or class IV as defined by the Biopharmaceutics Classification System (BCS) [1,2,3,4]
The use of API-ionic liquids (ILs) in conjunction with lipid-based formulations has been examined as a means to enhance the oral exposure of lumefantrine
Isolation as lumefantrine docusate resulted in consistent increases in lipid solubility when compared to lumefantrine free base across a range of lipid-based formulations
Summary
Drugs in development, are poorly water-soluble and classified as class II or class IV as defined by the Biopharmaceutics Classification System (BCS) [1,2,3,4]. Reformulation approaches are commonly employed to improve the bioavailability of class II compounds; for class IV compounds, the challenge is significantly greater and whilst improvements are possible via formulation approaches, it is often more beneficial to develop alternative analogues with more suitable physicochemical properties [5]. The increasing prevalence of poorly water-soluble drugs has necessitated the development of a range of formulation approaches to increase apparent drug solubility in the gastro-intestinal fluids [6,7,8,9]. These include the use of solid dispersions, lipid-based formulations, cyclodextrins, surfactants, and particle size reduction techniques [7]. The low and likely solubility limited bioavailability of lumefantrine may be improved by administration with a fatty meal, but this leads to variable bioavailability [11]
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