Permeability-enhancing effects of three laurate-disaccharide monoesters across isolated rat intestinal mucosae

Laurate (C₁₂)-sucrose esters are established intestinal epithelial permeation enhancers (PEs) with potential for use in oral delivery. Most studies have examined blends of ester rather than specific monoesters, with little variation on the sugar moiety. To investigate the influence of varying the sugar moiety on monoester performance, we compared three monoesters: C₁₂-sucrose, C₁₂-lactose, and C₁₂-trehalose. The assays were: critical micellar concentration (CMC) in Krebs-Henseleit buffer, MTS and lactate dehydrogenase assays in Caco-2 cells, transepithelial electrical resistance (TEER) and apparent permeability coefficient (P_app) of [¹⁴C] mannitol across isolated rat intestinal mucosae, and tissue histology. For CMC, the rank order was C₁₂-trehalose (0.21 mM) < C₁₂-sucrose (0.34 mM) < C₁₂-lactose (0.43 mM). Exposure to Caco-2 cells for 120 min produced TC₅₀ values in the MTS assay from 0.1 to 0.4 mM. Each ester produced a concentration-dependent decrease in TEER across rat mucosae with 80% reduction seen with 8 mM in 5 min, but C₁₂-trehalose was less potent. C₁₂-sucrose and C₁₂-lactose increased the P_app of [¹⁴C] mannitol across mucosae with similar potency and efficacy, whereas C₁₂-trehalose was not as potent or efficacious, even though it still increased flux. In the presence of the three esters, gross intestinal histology was unaffected except at 8 mM for C₁₂-sucrose and C₁₂-lactose. In conclusion, the three esters enhanced permeability likely via tight junction modulation in rat intestinal tissue. C₁₂-trehalose was not quite as efficacious, but neither did it damage tissue to the same extent. All three can be considered as potential PEs to be included in oral formulations.