european journal of pharmaceutical sciences 37 ( 2 0 0 9 ) 36–42 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/ejps In vitro permeation of desmopressin across rabbit nasal mucosa from liquid nasal sprays: The enhancing effect of potassium sorbate Bortolotti Fabrizio a , Balducci Anna Giulia a,b , Sonvico Fabio b , Russo Paola c , Colombo Gaia a,∗ a Department of Pharmaceutical Sciences, University of Ferrara, I-Ferrara, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy b Department of Pharmacy, University of Parma, I-Parma, Italy c Department of Pharmaceutical Sciences, University of Salerno, I-Fisciano, Italy article info Article history: Received 23 October 2008 Received in revised form 20 December 2008 Accepted 22 December 2008 Published on line 31 December 2008 Keywords: Desmopressin Preservative Nasal spray Potassium sorbate abstract Nasal spray products containing desmopressin acetate (DDAVP) were tested in vitro to evalu- ate the effect of the contained preservatives on drug permeation across rabbit nasal mucosa. Experiments were performed using Franz-type diffusion cells with rabbit nasal mucosa as model barrier. Transport profiles obtained in comparison with a preservative-free solution evidenced that in the presence of preservatives DDAVP permeation in vitro always increased (p < 0.05), although at different extents (chlorobutanol < benzalkonium < sorbate). While for benzalkonium structural damage of the mucosa could occur decreasing its bar- rier properties, the effect of sorbate on drug transport was further investigated, being less studied. After having found that sorbate permeated together with DDAVP, the hypothesis that the two compounds formed an ion pair in solution with improved permeability was made. Additional experiments with aqueous test solutions reconstructed ad hoc contain- ing desmopressin and varying sorbate concentrations confirmed the enhancing effect of sorbate, which however resulted to be independent of sorbate concentration. In conclusion, preservatives significantly enhanced desmopressin permeation in vitro across rabbit nasal mucosa with different mechanisms. 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. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Desmopressin (DDAVP), a synthetic nine-aminoacid cyclic peptide analogue of vasopressin, is used as antidiuretic drug both in adults and children for treating nocturnal enure- sis and central diabetes insipidus (Cvetkovic and Plosker, 2005). Desmopressin is successfully administered via the nasal route, which guarantees higher bioavailability compared to ∗ Corresponding author. Tel.: +39 0532 455909; fax: +39 0532 455953. E-mail address: clmgai@unife.it (C. Gaia). the oral route, due to reduced enzymatic degradation. World- wide, generic liquid formulations (nasal drops or sprays) are available for DDAVP administration to the nose, usually con- taining 0.05–0.1 mg/ml of desmopressin acetate together with preservatives, required to maintain product stability during storage and use. It has been shown that preservatives used in liquid nasal formulations cause adverse effects, such as nasal conges- 0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2008.12.015