In vitro permeation of desmopressin across rabbit nasal mucosa from liquid nasal sprays: the enhancing effect of potassium sorbate

Three commercial nasal sprays containing desmopressin acetate (DDAVP) were tested in vitro to evaluate the effect of different preservatives on drug permeation across rabbit nasal mucosa. In particular, the enhancement mechanism of potassium sorbate was investigated. Experiments were performed using Franz-type diffusion cells with rabbit nasal mucosa as model tissue. DDAVP permeated in 4 hours was quantitated by HPLC and transport parameters (steady state flux, permeability) were calculated. Permeation profiles obtained in comparison with a preservative-free solution evidenced that the preservative excipents always enhanced DDAVP permeation in vitro (p<0.05), although at different extents (chlorobutanol < benzalkonium < sorbate). While for benzalkonium structural damage of the mucosa could occur decreasing its barrier properties, the enhancing mechanism of sorbate was further investigated, being less understood. After finding that sorbate permeated together with DDAVP, A hypothesis was made that the two compounds could form an ionic pair in solution with improved permeability characteristics. Additional experiments with aqueous test solutions containing desmopressin and varying sorbate concentrations confirmed the enhancing effect, however this effect resulted to be independent of sorbate concentration. In conclusion, preservatives significantly enhanced desmopressin permeation in vitro across rabbit nasal mucosa. If a correlation existed between these data and in vivo DDAVP bioavailability after nasal administration, this could strengthen the safety concerns related to the use of this medication in adults and children.