Abstract
PurposeTo evaluate the performance of artificial membranes in in vitro lipolysis-permeation assays useful for absorption studies of drugs loaded in lipid-based formulations (LBFs).MethodsPolycarbonate as well as PVDF filters were treated with hexadecane, or lecithin in n-dodecane solution (LiDo) to form artificial membranes. They were thereafter used as absorption membranes separating two compartments mimicking the luminal and serosal side of the intestine in vitro. Membranes were subjected to dispersions of an LBF that had been digested by porcine pancreatin and spiked with the membrane integrity marker Lucifer Yellow (LY). Three fenofibrate-loaded LBFs were used to explore the in vivo relevance of the assay.ResultsOf the explored artificial membranes, only LiDo applied to PVDF was compatible with lipolysis by porcine pancreatin. Formulation ranking based on mass transfer in the LiDo model exposed was the same as drug release in single-compartment lipolysis. Ranking based on observed apparent permeability coefficients of fenofibrate with different LBFs were the same as those obtained in a cell-based model.ConclusionsThe LiDo membrane was able to withstand lipolysis for a sufficient assay period. However, the assay with porcine pancreatin as digestive agent did not predict the in vivo ranking of the assayed formulations better than existing methods. Comparison with a Caco-2 based assay method nonetheless indicates that the in vitro in vivo relationship of this cell-free model could be improved with alternative digestive agents.
Highlights
Artificial membranes can be a valuable tool for evaluating properties of drug compounds pertaining to barrier 99 Page 2 of 14Pharm Res (2020) 37: 99 interactions [1]
The remaining four were the samples taken at −5 and 30 min of lipolysis (0 and 65% digestion) and applied to GIT-0
Values above the dashed line indicates a major loss of membrane integrity. (a) Hexadecane membranes (HDM), (b) GIT-0 membranes with phosphate buffer (PB, 10 mM) in the receiver compartment, (c) GIT-0 membranes with Acceptor Sink Buffer in receiver compartment, and (d) GIT-0 membranes with PB supplemented with 4% (w/w) bovine serum albumin (BSA) in receiver compartment
Summary
Artificial membranes can be a valuable tool for evaluating properties of drug compounds pertaining to barrier 99 Page 2 of 14. Pharm Res (2020) 37: 99 interactions [1]. When properly used, they can give information about functional characteristics with increased costeffectiveness and fewer ethical concerns than animal- or cellbased experiments. Lipophilic drug compounds often suffer from inter- and intraindividually variable bioavailability. Apart from metabolism, this variability can be caused largely by solubility issues and influenced by factors like gastrointestinal physiology, prandial state during the time of administration, and composition of the latest meal. It is important to consider the formulation of these APIs in such a way that their negative characteristics can be minimized
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