Bioavailability of cyclosporine in rats after intragastric administration: a comparative study of the L 2-phase and two other lipid-based vehicles

Abstract

The purpose of this study was to evaluate formulations based on surface active dietary lipids only as oral vehicles for cyclosporine. The absolute bioavailability of cyclosporine from two new lipid vehicles was determined in rats after intragastric administration and compared to that of Sandimmun® oral solution, which contain non-ionic surface active substances in addition to dietary lipids. In the new vehicles, cyclosporine was dissolved in two different mixtures of glycerides from long-chained fatty acids. One mixture forms as L 2-phase, an oil with very low interfacial tension towards water, and was administratered both as the oily L 2-phase and as a predispersed emulsion formulation. The other mixture forms a liquid crystalline phase and was administered only as an aqueous dispersion. The mean bioavailability of cyclosporine from Sandimmum® was 8% while it was 34% from the L 2-phase, 38% from the predispersed L 2-phase and 27% from the dispersed liquid crystalline phase. The coefficients of variation in area under the blood concentration curve after administration of the two formulations based on the L 2-phase were quite low (31% for the L 2-phase and 24% for the predispersed L 2-phase) and comparable to that after intravenous administration (24%), while the dispersed liquid crystalline phase gave a higher variability (91%), comparable to that of Sandimmum® oral solution (101%). The low variabilities found with the two L 2-phase vehicles suggest that this formulation is ‘self-emulsifying’ in the gastrointestinal tract. Since the L 2-phase is based on dietary lipids only, it is expected to be well tolerated and could prove to be a good vehicle for long-term clinical use of oral cyclosporine.