title: In vitro assessment of drug-free and fenofibrate-containing lipid formulations using dispersion and digestion testing gives detailed insights into the likely fate of formulations in the intestine.
abstract: The solubilizing properties of lipid-based formulations (LBFs) can change dramatically following dispersion and digestion of the formulation components. This study investigated the performance of self-emulsifying LBFs consisting of four different long-chain (LC)/medium-chain (MC) lipid blends formulated with the lipophilic drug fenofibrate and either a water-insoluble surfactant polysorbate 85 (Tween 85) or its more hydrophilic relative, polysorbate 80 (Tween 80). These components allowed closely related Type II and IIIA LBFs of fenofibrate to be evaluated during in vitro dispersion and in vitro digestion testing. Initial assessment of the solvent capacity of drug-free LBFs during dispersion and digestion revealed that the solubility of fenofibrate was more dependent on the surfactant type rather than lipid composition. Type II LBFs in the dispersed state were generally better at solubilizing fenofibrate than equivalent Type IIIA LBFs, regardless of lipid composition. However, even when high drug loadings were used, supersaturation/drug precipitation after dispersion of Type II or Type IIIA LBFs was only moderate. In contrast, digestion of both Type II and IIIA LBFs led to much higher levels of drug supersaturation, and this resulted in drug precipitation. After digestion the ability of each LBF to maintain drug in a solubilized state was highly dependent on lipid composition as well as the choice of surfactant. Notably, MC lipids exhibited very good solubilizing properties in the dispersed state, but resulted in a higher degree of supersaturation on digestion, leading to higher susceptibility to drug precipitation. This study showed that replacing LC lipids with MC lipids in Type II and IIIA LBF, in the proportions used here has little effect on fenofibrate solubilization during dispersion, but is likely to promote supersaturation on digestion. Without careful consideration of drug loading and choice of surfactant in Type II/IIIA MC lipid formulations, there is a high risk of precipitation of drug in the intestine.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Melbourne, Victoria, Australia.
authors.forename: Ravi
authors.initials: R
authors.lastname: Devraj
authors.forename: Hywel D
authors.initials: HD
authors.lastname: Williams
authors.forename: Dallas B
authors.initials: DB
authors.lastname: Warren
authors.forename: Kazi
authors.initials: K
authors.lastname: Mohsin
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
authors.forename: Colin W
authors.initials: CW
authors.lastname: Pouton
mesh_terms: D011345:Fenofibrate / Q000737:chemistry*; D007413:Intestinal Mucosa / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry*; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D008055:Lipids; D011136:Polysorbates; D013501:Surface-Active Agents; D011345:Fenofibrate
keywords: Digestion; LFCS; Lipid-based drug delivery systems; Poorly water-soluble drugs; Precipitation; Supersaturation