title: In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation.
abstract: Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships, was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations.
authors.affiliation: Synthesis and Solid State Pharmaceutical Centre (SSPC), University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Carol A
authors.initials: CA
authors.lastname: McCarthy
authors.affiliation: School of Pharmacy, University College Cork, Cork, Ireland; Faculty of Pharmacy, Minia University, Minya, Egypt.
authors.forename: Waleed
authors.initials: W
authors.lastname: Faisal
authors.affiliation: School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: O'Shea
authors.affiliation: School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Colm
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Synthesis and Solid State Pharmaceutical Centre (SSPC), University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ahern
authors.affiliation: School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Katie B
authors.initials: KB
authors.lastname: Ryan
authors.affiliation: School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
authors.affiliation: Synthesis and Solid State Pharmaceutical Centre (SSPC), University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland. Electronic address: a.crean@ucc.ie.
authors.forename: Abina M
authors.initials: AM
authors.lastname: Crean
mesh_terms: D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D005260:Female; D011345:Fenofibrate / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D057446:Hydrodynamics; D008954:Models, Biological; D016062:Porosity; D012822:Silicon Dioxide / Q000737:chemistry*; D012995:Solubility; D013552:Swine
chemical_list: D004337:Drug Carriers; D012822:Silicon Dioxide; D011345:Fenofibrate
keywords: Dissolution; Fenofibrate; Hydrodynamics; Mesoporous silica; Supersaturation; Transfer model; in vitro in vivo relationship (IVIVR)