Original Articles

Permeation-enhancing effects of chitosan formulations on recombinant hirudin-2 by nasal delivery in vitro and in vivo

Authors: Yu-jie Zhang, Chang-hua Ma, Wan-liang Lu, Xuan Zhang, Xiao-liang Wang, Jian-ning Sun, Qiang Zhang

Abstract

Aim: To investigate the enhancing effects of chitosan with or without enhancers on nasal recombinant hirudin-2 (rHV2) delivery in vitro and in vivo, and to evaluate the ciliotoxicity of these formulations.
Methods: The permeation-enhancing effect of various chitosan formulations was estimated by using the permeation coefficient of fluorescein isothiocyanate recombinant hirudin-2 (FITC-rHV2) across the excited rabbit nasal epithelium in vitro. The effect was further evaluated by measuring the blood concentration level after nasal absorption of FITC-rHV2 in rats. The mucosal ciliotoxicity of different formulations was evaluated with an in situ toad palate model.
Results: Chitosan at a concentration of 0.5% with or without various enhancers significantly increased the permeability coefficient (P) and relative bioavailability (Fr) of FITC-rHV2 compared with the blank control. The addition of 1% sodium dodecylsulfate, 5% Brij35, 5% Tween80, 1.5% menthol, 1% glycyrrhizic acid monoammonium salt (GAM) or 4% Azone into the 0.5% chitosan solution resulted in a further increase in absorption (P/<0.05) compared with 0.5% chitosan alone. But co-administration of chitosan with 5% hydroxyl-propyl-beta-cyclodextrin(HP-beta-CD), 5%lecithin or 0.1% ethylenediamine tetraacetic acid (EDTA) was not more effective than using the 0.5% chitosan solution alone. Chitosan alone and with 5% HP-beta-CD, 0.1% EDTA, 1% GAM or 5% Tween80 was relatively less ciliotoxic.
Conclusion: Chitosan with or without some enhancers was able to effectively promote the nasal absorption of recombinant hirudin, while not resulting in severe mucosal ciliotoxicity. A chitosan formulation system would be a useful approach for the nasal delivery of recombinant hirudin.
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