Investigation of flurbiprofen pharmacokinetics in rats following dermal administration of optimized cyclodextrin-based nanogel.

PURPOSE: The main purpose of this study was to optimize a cyclodextrin-based nanogel of flurbiprofen (FP) for prolonged dermal administration and evaluate its stability, in vitro release, ex vivo skin permeation, and in vivo pharmacokinetic profile.

METHODS

The nanogels were prepared via emulsification/solvent evaporation process and optimized through design of experiments. Optimal formulation was characterized via particle size (PS), polydispersity index (PDI), zeta potential (ZP), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD), solubility, stability, in vitro release/ex vivo permeation studies and mathematical modeling, and pharmacokinetic studies conducted in rats. Results were compared to HPMC-based gel that was not nano-sized (i.e.FP-HPMC gel).

RESULTS

The PS, PDI and ZP values of optimal FP-loaded nanogel were 295.5 nm, 0.361 and -31.9 mV, respectively and it was stable for 12 months. In in vitro release studies, the flux from the optimal FP-loaded nanogel (96.3 µg/hcm2) was three times slower (i.e.more controlled) than that of the FP-HPMC gel (287 µg/hcm2); the permeability coefficient of the nanogel (0.015 cm/h) was slightly less than that of FP-HPMC gel (0.046 cm/h). Rat skin studies showed FP-loaded nanogel provided higher drug retention in the skin, compared to FP-HPMC gel. Mathematical modeling from rat skin permeation showed the Hixson-Crowell model was the best fitting model for FP-loaded nanogel, suggesting surface area of the nanogel is changing during the release process. In rat pharmacokinetic studies, the FB-loaded nanogel exhibited prolonged and flatter plasma profile than the FP-HPMC gel, consistent with the higher drug retention in the skin.

CONCLUSION

The optimized nanogel provided prolonged drug permeation and more sustained pharmacokinetic performance compared to FP-HPMC gel.