Abstract

The present study was to screen an optimal absorption enhancer for enhancing the nasal absorption of basic fibroblast growth factor (bFGF), a promising therapeutic agent to neurodegenerative diseases. In this study, four absorption enhancers including chitosan, sodium caprate, poly-L-arginine (poly-L-Arg, 92.0 kDa) and dimethyl-β-cyclodextrin were chosen to evaluate their toxicity using in situ toad palate model and in vitro Calu-3 cell model. Transport study of bFGF across Calu-3 cell monolayers in the absence or presence of chitosan was performed to determine the optimal concentration of chitosan. Pharmacokinetics study was conducted to monitor changes in the blood concentration of bFGF following nasal administration of bFGF solution with or without 0.5% (w/v) chitoson, in comparison with intravenous administration of bFGF alone. Of the absorption enhancers tested, chitosan at the concentration of 0.25 and 0.5% showed little toxicity to nasal cilia and Calu-3 cells, and exerted reversible effect on the reduction of transepithelial electrical resistance. Transport study showed that the apparent permeability coefficient (Papp) value was increased by about 16- and 2-fold, respectively with addition of 0.5 and 0.25% chitosan, compared with bFGF solution alone. Following nasal administration to rats, the formulation containing 0.5% chitosan significantly enhanced the absorption of bFGF with an area under curve (AUC_0-120min) nearly 1.4-fold that of bFGF solution (p<0.05). The absolute bioavailability of bFGF after intranasal administration was 5.35 and 7.53% for bFGF alone and 0.5% chitosan group, respectively. These results indicated that 0.5% chitosan is a safe and effective absorption enhancer for intranasal delivery of bFGF.

Key words: Basic fibroblast growth factor, absorption enhancer, chitosan, toxicity, pharmacokinetics, intranasal delivery.