title: Enniatin-containing solutions for oromucosal use: Quality-by-design ex-vivo transmucosal risk assessment of composition variability.
abstract: Fusafungine, a mixture of the cyclic hexadepsipeptides enniatins, is currently on the market for the treatment of upper respiratory tract diseases because of its bacteriostatic and anti-inflammatory effects. In this study, a quality-by-design risk assessment was performed with two objectives: (i) investigate whether enniatins are able to permeate the mucosa and reach blood circulation, as the summary of product characteristics indicates this is not the case, and if so, to quantify their transmucosal kinetics and (ii) study the influence of excipient concentration variability on mucosal permeation. First, the concentration of the two main excipients isopropyl myristate and ethanol, known penetration enhancers, in several marketed samples was determined using GC-FID. Then, the transmucosal kinetics of the enniatins were quantitatively evaluated for different dose solutions, using porcine buccal mucosa in an ex-vivo in-vitro Franz diffusion cell set-up, with UHPLC-MS/MS bioanalytics. This study demonstrated that enniatins are capable of permeating the mucosa. However, no risk of a significant different transmucosal permeability with varying excipient concentrations was detected.
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Taevernier
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Detroyer
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Veryser
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: Bart.DeSpiegeleer@UGent.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Spiegeleer
mesh_terms: D000818:Animals; D047630:Depsipeptides / Q000737:chemistry* / Q000378:metabolism*; D004058:Diffusion; D000431:Ethanol / Q000737:chemistry; D005079:Excipients / Q000737:chemistry; D005670:Fusarium / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D009061:Mouth Mucosa / Q000378:metabolism*; D009226:Myristates / Q000737:chemistry; D010539:Permeability; D018570:Risk Assessment; D012996:Solutions / Q000737:chemistry*; D013552:Swine
chemical_list: D047630:Depsipeptides; D005079:Excipients; D009226:Myristates; D012996:Solutions; C100264:enniatins; C008205:isopropyl myristate; D000431:Ethanol; C014001:fusafungin
keywords: Cyclic depsipeptide mycotoxins; Enniatins; Excipient variability; Fusafungine; Plasma concentration after oromucosal use; Transmucosal Franz diffusion cell