title: Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: case studies with fenofibrate.
abstract: The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (~70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65-72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in vitro digestion did not adversely impact fenofibrate bioavailability in vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.
authors.affiliation: School of Pharmacy, University College Cork, Ireland. Electronic address: brendan.griffin@ucc.ie.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
authors.affiliation: Faculty of Pharmacy, National & Kapodistrian University of Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Vertzoni
authors.affiliation: Institut für Pharmazeutische Technologie, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: Edmund S
authors.initials: ES
authors.lastname: Kostewicz
authors.affiliation: Institut für Pharmazeutische Technologie, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fei
authors.affiliation: School of Pharmacy, University College Cork, Ireland.
authors.forename: Waleed
authors.initials: W
authors.lastname: Faisal
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland.
authors.forename: Cordula
authors.initials: C
authors.lastname: Stillhart
authors.affiliation: School of Pharmacy, University College Cork, Ireland.
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
authors.affiliation: Faculty of Pharmacy, National & Kapodistrian University of Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Reppas
authors.affiliation: Institut für Pharmazeutische Technologie, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Dressman
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D011345:Fenofibrate / Q000737:chemistry*; D005544:Forecasting; D000960:Hypolipidemic Agents / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D008297:Male; D013552:Swine; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000960:Hypolipidemic Agents; D008055:Lipids; D011345:Fenofibrate
keywords: Fenofibrate; In vitro digestion; In vitro dispersion testing; In vivo bioavailability; Lipid-based formulations; Poorly soluble drugs; Precipitation; Solid state characterisation