Sublingual Delivery of Insulin: Effects of Enhancers on the Mucosal Lipid Fluidity and Protein Conformation, Transport, and in Vivo Hypoglycemic Activity

Abstract

The purposes of this study were to evaluate effects of enhancers for sublingual delivering insulin on the mucosal lipid fluidity and protein conformation, transport, and in vivo hypoglycemic activity in normal rats. The effects on sublingual mucosa, and aggregation states of insulin were estimated using fluorescence polarization, and circular dichroism method, respectively. The human immortalized oral epithelial cell monolayer was used for evaluating transport of insulin. Hydroxylpropyl-b b-cyclodextrin (HP-b b-CD), chitosan, polyethylene-polypropylene glycol, polyoxyethylene lauryl ether, polysorbate 80, egg lecithin, or oleic acid, was used as a penetration enhancer, respectively. The fluidity of sublingual mucosal lipid was markedly reduced by these enhancers excluding polysorbate 80, and the secondary structure of the mucosal proteins was also influenced by these enhancers. The hexamers of insulin were dissociated to monomers only by chitosan, polyoxyethylene lauryl ether, and egg lecithin. Nonetheless, plasma glucose levels in normal rats were significantly lowered after sublingual administration of insulin with an enhancer compared with those without an enhancer at the same time-point. The enhancing effects may be due to one or multiple factors: increasing the mucosal lipid fluidity, directly loosing the tight junction of epithelia, and dissociating the hexamers of insulin to monomers. Among these, the opened tight junction may correlate most with the enhancing effect in the mucosal permeability. Because the aggregates of insulin exist, the dissociation of the aggregates by an enhancer would benefit the permeability.

Current Status of Salivary Hormone Analysis

“…Specific transporters for insulin are present in the oral mucosa, as proven after sublingual application in rats (9 ). The selectivity of this active transport is demonstrated by the fact that insulin appears in saliva at similar concentrations to those in plasma after glucose uptake, but the cleavage product C-peptide, which is of a similar size to insulin, does not enter the saliva.…”

“…(D), The SCSா consists of a mouth-rinsing solution (9), yellow collection solution (10), a collection container for draining the saliva mix (11), and a storage unit coated with preservative powder (12). preferred), and then the pad is transferred to a storage container.…”

Oral transmucosal drug delivery for pediatric use

“…For example, fatty acids (e.g. oleic acid) can alter cell membrane structure by inducing lipid fluidization and phase separation within the membrane [80]. Cyclodextrin acts as permeation enhancers by increasing drug availability at the surface of the biological barrier [81].…”

Studies on inclusion complex as potential systems for enhancement of oral bioavailability of olmesartan medoxomil

“…Another important phenomenon is the permeation enhancement due to the presence of HP β-CD. [15,16] To access the stability of the OLM, complexes were stored at 40°C/75%RH for 2 months [ Table 3]. At the end of the study, the formulation was observed for changes in drug content.…”