Abstract
PurposeCriticalSorb™, with the principal component Solutol® HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol® HS15.MethodsMicelle size and CMC of Solutol® HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeability of a panel of biological drugs, and to assess changes in TEER, tight junction and F-actin morphology. The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2–10.ResultsThis work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a ‘classical’ tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton.ConclusionSolutol® HS15 is the principle component of CriticalSorb™ that has shown an enhancement in permeability of medium sized biological drugs across epithelia. This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.
Highlights
The potential benefit of delivering biological drugs across the mucosa as opposed to via the parenteral route has attracted considerable attention, as advances in biotechnology have created a capacity to produce biologically active macromolecules (‘biologics’) on a commercial scale
These generally lie in the order of 6.5–10.2 mM solutions, whereby for Calu-3 cells EC50 values are statistically greater when compared to Caco-2 and A549 cell lines, indicating higher tolerance to Solutol® HS15 toxicity
The work further demonstrated that the critical micelle concentration (CMC) and the size of Solutol® HS15 micelles do not appear to be influenced by the composition of biologically relevant buffers (HBSS:HBSS [supplemented with mM 4-(2Hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) and phosphate buffered saline (PBS)) or the temperature examined, which is in accordance with the behaviour of non-ionic surfactants [22]
Summary
The potential benefit of delivering biological drugs across the mucosa as opposed to via the parenteral route has attracted considerable attention, as advances in biotechnology have created a capacity to produce biologically active macromolecules (‘biologics’) on a commercial scale. Different approaches have been investigated to improve the absorption and the resulting bioavailability of biological drugs following mucosal administration, including manipulation of the formulation and/or co-administration with agents that improve its transport across the mucosa (absorption enhancers) [3]. The term ‘absorption enhancer’ incorporates chemically diverse compounds, ranging from surfactants, polymers, chelating agents, and enzymes, which exert their absorption enhancing effect through different mechanisms. The action of permeability enhancers has been attributed to effects on the cell membrane fluidity (exerted by surfactanttype molecules and fatty acids), thereby enhancing drug delivery via the transcellular route [4, 5], or alterations in junctional proteins caused by, for example chitosan [6, 7], resulting in promotion of drug translocation through the paracellular route
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