title: Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens: in vivo and in vitro evaluations.
abstract: The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were assessed: (1) CIN dissolved in SNEDDS at 80% of equilibrium solubility (Seq) (SNEDDS 80%); (2) supersaturated SNEDDS with CIN dissolved at 200% Seq(super-SNEDDS solution); (3) SNEDDS suspension with CIN added at 200% Seq(CIN partially dissolved and partially suspended) (super-SNEDDS suspension); (4) drug-free SNEDDS co-dosed with aqueous CIN suspension (Chasing principle), and (5) CIN aqueous suspension. The CIN dose was kept constant for all dosing regimens. Therefore, the super-SNEDDS solution and super-SNEDDS suspension contained 2.5-fold less SNEDDS pre-concentrate than SNEDDS 80% and the Chasing principle. In vivo, a higher AUC after dosing CIN in SNEDDS 80% and the Chasing principle was obtained when compared to the super-SNEDDS solution, super-SNEDDS suspension, and aqueous suspension. In vitro, a higher extent of CIN in the aqueous phase was observed for all SNEDDS-containing dosing regimens, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption and solubilization, whereas the drug load, or amount of co-dosed lipid, significantly influenced CIN bioavailability.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
authors.forename: Scheyla D V S
authors.initials: SD
authors.lastname: Siqueira
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark. anette.mullertz@sund.ku.dk.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.affiliation: Roche Pharma Research and Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Gräeser
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
authors.forename: Georgia
authors.initials: G
authors.lastname: Kasten
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
authors.forename: Huiling
authors.initials: H
authors.lastname: Mu
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002936:Cinnarizine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004655:Emulsions; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D053758:Nanoparticles; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013535:Suspensions
chemical_list: D004655:Emulsions; D013535:Suspensions; D002936:Cinnarizine
keywords: SNEDDS; absorption; cinnarizine; drug loading; lipolysis