Development of High-Energy Amorphous Solid Dispersion of Nanosized Nobiletin, a Citrus Polymethoxylated Flavone, with Improved Oral Bioavailability

Nobiletin (NOB), a citrus polymethoxylated flavone, attracts attention because of a wide range of pharmacological activities such as anti-inflammation, anticancer, and most notably ameliorative actions on memory impairment and β-amyloid pathology. However, clinical use of NOB could be partly limited due to its poor solubility and bioavailability, which might necessitate high doses in order to reach therapeutic plasma concentrations in the central nervous system (CNS) after oral administration. In the present study, amorphous solid dispersion (SD) of nanosized NOB (NOB/SD) was prepared by wet-milling technique with the aim of improving dissolution behavior and pharmacokinetic properties of NOB. Physicochemical properties of the NOB/SD were characterized with focus on surface morphology, particle size distribution, dissolution, and crystallinity assessment. Wet-milled NOB particles in NOB/SD appeared to be amorphous with a diameter of approximately 270 nm, and there was marked improvement in the dissolution behavior compared with that of crystalline NOB. After oral administration of NOB/SD, higher exposure of NOB was observed with increases of bioavailability and CNS distribution by 13- and sevenfold, respectively, compared with those of crystalline NOB. These findings suggest that an amorphous, nanosized SD could be a viable option for enhancing the bioavailability and CNS delivery of NOB. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3793–3801, 2011