Abstract
The present study aimed to develop an amorphous solid dispersion of nobiletin (ASD/NOB) using hydroxypropyl cellulose-SSL (HPC-SSL) to improve the pharmacokinetic properties and hypouricemic effect of NOB. ASD/NOB was prepared by the freeze-drying method (ASD/NOB). ASD/NOB was characterized with a focus on crystallinity, dissolution, pharmacokinetic behavior, and hypouricemic action in a rat model of hyperuricemia. ASD/NOB showed significant improvement in dissolution behavior, as evidenced by a 4.4-fold higher dissolved NOB concentration than crystalline NOB at 2 h in distilled water. After the oral administration of ASD/NOB (50 mg NOB/kg) in rats, higher systemic exposure to NOB was observed with an 18-fold enhancement in oral bioavailability, and the Tmax value of orally administered ASD/NOB was 60% shorter than that of orally administered crystalline NOB. In a rat model of hyperuricemia, orally dosed ASD/NOB showed an improved hypouricemic effect by a 16% reduction in the plasma uric acid level compared with orally administered crystalline NOB. Based on these findings, ASD/NOB may be an efficacious dosage option to improve the nutraceutical potential of NOB for the treatment of hyperuricemia.
Highlights
In rats, higher systemic exposure to NOB was observed with an 18-fold enhancement in oral bioavailability, and the Tmax value of orally administered amorphous solid dispersion (SD) formulation (ASD)/NOB was 60% shorter than that of orally administered crystalline NOB
amorphous SD formulation (ASD)/NOB was prepared with the same ratio of crystalline NOB and hydroxypropyl cellulose-SSL (HPC-SSL) to achieve both amorphization and high stability under the accelerated conditions
Showed relatively large needle-like particles, while needle-shaped NOB powder was negligible in amorphous solid dispersion of nobiletin (ASD/NOB), suggesting that micronized NOB was dispersed into the polymer in ASD/NOB after lyophilization
Summary
Chemicals in an amorphous state tend to be unstable during long-term storage, and SD techniques are often used to prepare stable amorphous formulations [15]. A previous study demonstrated that an HPC-SSL-based ASD formulation with 50 wt% NOB prepared by freeze-drying resulted in high storage stability without recrystallization and transition in the morphology after storage for 4 weeks under accelerated conditions (40 ◦ C/75% RH) [6]. ASD/NOB was prepared with the same ratio of crystalline NOB and HPC-SSL to achieve both amorphization and high stability under the accelerated conditions. DSC thermograms of crystalline NOB showed a thermal event at 137 ◦ C (Figure 2B). No thermal event was observed in DSC thermograms of ASD/NOB within the examined temperature range. From these findings, NOB in ASD/NOB was found to be in an amorphous state, and amorphization of NOB resulted in better wettability.
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