期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 539, 期 1-2, 页码 11-22出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2018.01.008
关键词
Ussing chamber; Intestinal permeation enhancers; Surfactant toxicity; Intestinal epithelial damage
资金
- Irish Research Council (IRC) Employment based postgraduate programme [EBPPG/2015/133]
- AnaBio Technologies Ltd (Ireland)
- Science Foundation Ireland (SFI)
- European Regional Development Fund [13/RC/2073]
- Irish Research Council (IRC) [EBPPG/2015/133] Funding Source: Irish Research Council (IRC)
Surfactant-based intestinal permeation enhancers (PEs) are constituents of several oral macromolecule formulations in clinical trials. This study examined the interaction of a test panel of surfactant-based PEs with isolated rat colonic mucosae mounted in Ussing chambers in an attempt to determine if increases in transepithelial permeability can be separated from induction of mucosal perturbation. The aim was to assess the effects of PEs on (i) apparent permeability coefficient (P-app) of [C-14]-mannitol (ii) histology score and (iii) short-circuit current (Delta I-sc) responses to a cholinomimetic (carbachol, CCh). Enhancement ratio increases for P-app values followed the order: C-10 > C-9 = C-11:1 > a bile salt blend > sodium choleate > sucrose laurate > Labrasol (R) > C12E8 > C-12 > Cremophor (R) A25 > C-7 > sucrose stearate > Kolliphor (R) HS15 > Kolliphor (R) TPGS. Exposures that increased the P-app by >= 2-fold over 120 min were accompanied by histological damage in 94% of tissues, and by a decreased Delta I-sc response to CCh in 83%. A degree of separation between the increased P-app of [C-14]-mannitol and histological damage and diminution of the Delta I-sc response to CCh was observed at selected concentrations of Labrasol (R). Overall, this surfactant-based PE selection caused transcellular perturbation at similar concentrations to those that enhanced permeability.
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