title: In vitro permeation of desmopressin across rabbit nasal mucosa from liquid nasal sprays: the enhancing effect of potassium sorbate.
abstract: Nasal spray products containing desmopressin acetate (DDAVP) were tested in vitro to evaluate 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 barrier 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 containing 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, I-Ferrara, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bortolotti
authors.forename: Bortolotti
authors.initials: B
authors.lastname: Fabrizio
authors.forename: Anna Giulia
authors.initials: AG
authors.lastname: Balducci
authors.forename: Balducci Anna
authors.initials: BA
authors.lastname: Giulia
authors.forename: Fabio
authors.initials: F
authors.lastname: Sonvico
authors.forename: Sonvico
authors.initials: S
authors.lastname: Fabio
authors.forename: Paola
authors.initials: P
authors.lastname: Russo
authors.forename: Russo
authors.initials: R
authors.lastname: Paola
authors.forename: Gaia
authors.initials: G
authors.lastname: Colombo
authors.forename: Colombo
authors.initials: C
authors.lastname: Gaia
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D001548:Benzalkonium Compounds / Q000737:chemistry; D002724:Chlorobutanol / Q000737:chemistry; D003894:Deamino Arginine Vasopressin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004058:Diffusion / Q000187:drug effects; D066298:In Vitro Techniques; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D011310:Preservatives, Pharmaceutical / Q000494:pharmacology*; D011817:Rabbits; D013011:Sorbic Acid / Q000494:pharmacology*; D013810:Therapeutic Equivalency
chemical_list: D000277:Adjuvants, Pharmaceutic; D001548:Benzalkonium Compounds; D011310:Preservatives, Pharmaceutical; D003894:Deamino Arginine Vasopressin; D002724:Chlorobutanol; D013011:Sorbic Acid