Silica-Lipid Hybrid (SLH) Versus Non-lipid Formulations for Optimising the Dose-Dependent Oral Absorption of Celecoxib

Abstract

To investigate the dose linearity of celecoxib (CEL) pharmacokinetics from various non-lipid and lipid-based formulations; to probe the mechanisms of CEL absorption from a nano-structured silica-lipid hybrid (SLH) microparticle dosage form. Single-dose pharmacokinetic parameters of CEL were determined in fasted rats at dose levels of 5, 20 and 50 mg/kg in aqueous suspensions of pure CEL, Celebrex® and CEL-SLH microparticles formulated using medium-chain lipids (Miglyol 812 or Capmul MCM) and Aerosil® silica nanoparticles. An in vitro lipolysis model was used to characterise the dynamic solubilisation state of CEL under digesting conditions. CEL-SLH formulations and Celebrex® consistently produced a 2-fold higher maximum plasma concentration (C(max)) and bioavailability (AUC(0→∞)) than pure CEL in a dose-linear manner within the dose range of 5-50 mg/kg CEL (R² > 0.8). Lipolysis drug phase partition data indicate a 2.5-7.5-fold higher CEL solubilising capacity resulting from the digestion of SLH microparticles as compared to the simulated fasted state endogenous micelles. Strong correlations were obtained between maximum CEL solubilisation levels during lipolysis and in vivo pharmacokinetic parameters (R² > 0.9). Collectively, the results highlight the potential of the SLH microparticles in enhancing the bioavailability of CEL in a dose-linear manner as facilitated by supersaturated solubilisation of CEL in the intestinal milieu.