Influence of drug loading and lipid dose on the in vivo performance of fenofibrate in medium- and long-chain triglyceride solutions.

The influence of drug loading relative to the saturation solubility of a lipid vehicle and the administered lipid dose on the in vivo performance of lipid-based formulations remains incompletely understood. The present study investigated these formulation variables using fenofibrate dissolved in medium-chain triglyceride (MCT) and long-chain triglyceride (LCT) vehicles. The saturated solubility of fenofibrate in MCT and LCT at 37°C was assessed to determine suitable concentrations for in vivo studies. Fenofibrate showed higher solubility in MCT (185.8 mg/mL) compared to LCT (70.8 mg/mL), consistent with previous findings indicating lipid chain length affects solubilization. In vivo studies using rats involved administering a fixed lipid dose (2 mL/kg), with fenofibrate solubilized in the lipid solution at 25 %, 50 %, and 90 % of its saturation solubility. In a separate dose-escalation study, the relative drug loading was maintained at 90 % of its saturation solubility while the administered lipid volume, and consequently the fenofibrate dose, was increased. Pharmacokinetic analysis revealed that fenofibrate in MCT achieved higher plasma concentrations before dose correction, whereas fenofibrate in LCT led to higher plasma concentrations after dose correction. In the dose-escalation study, systemic exposure increased with increasing fenofibrate dose in both vehicles; however, less-than-dose-proportional increases in AUC0-30h and Cmax were observed over the dose ranges investigated. The deviation from proportionality in AUC0-30h was greater for MCT than for LCT, while decreasing dose-normalized exposure was observed for the higher doses of both vehicles. These findings demonstrate that drug loading relative to saturation solubility, lipid type, and administered lipid dose can all influence the in vivo performance of lipid-based formulations and should be considered when designing and comparing such formulations.