Improved self-assembled micelles based on supercritical fluid technology as a novel oral delivery system for enhancing germacrone oral bioavailability

Abstract

The main objective of this study was to develop a novel self-assembled micelle system to improve the oral bioavailability of the water-insoluble and thermal instable germacrone (GEM). Micelles were prepared with an improved supercritical reverse phase evaporation (ISCRPE) method, and the thin-film hydration (TFH) method was used for comparison. Physicochemical characterization confirmed the nanospherical morphology of the micelles prepared by the ISCRPE method (GEM@SDL-SCF Micelles) had smaller particle size and greater encapsulation efficiency than that of the micelles prepared by the TFH method (GEM@SDL-THF Micelles). Dilution resistance and stability experiments were performed to assess the structural integrity. In vitro GEM release was analyzed by the dialysis diffusion method, and the micelle system showed sustained and cumulative release. Furthermore, the fluorescence results from the cellular uptake study revealed improved drug absorption of GEM since the green fluorescence intensity of C6@SDL-SCF Micelles were stronger than that of C6@SDL-TFH Micelles. The transcellular transport study showed a distinct increase in the apparent permeability coefficient (AP → BL) in a Caco-2 cell transport model, and free GEM solution, GEM@SDL-TFH Micelles and GEM@SDL-SCF Micelles had permeability coefficients of 7.30 × 10^-6, 8.01 × 10^-6, and 10.57 × 10^-6 cm·s^-1, respectively. The pharmacokinetics study in Sprague-Dawley rats showed that the oral absorption capacity of the GEM@SDL-SCF Micelles was obviously enhanced, with a relative oral bioavailability of 298% and 147% compared with that of free GEM solution and GEM@SDL-TFH Micelles, respectively. The gastrointestinal safety assessment demonstrated that the micelles used in the experiment did not cause gastrointestinal toxicity. These results indicated that self-assembled micelles are promising nanocarriers aimed at enhancing the oral absorption of drugs with thermal sensitivity and low aqueous solubility, and micelles prepared by supercritical fluid (SCF) technology showed better performance than those prepared by the TFH method.

Keywords: DSPE-PEG(2000); Germacrone; Oral bioavailability; Self-assembled micelles; Soluplus®; Supercritical fluid.