Sublingual delivery of insulin: effects of enhancers on the mucosal lipid fluidity and protein conformation, transport, and in vivo hypoglycemic activity.
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-beta-cyclodextrin (HP-beta-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.
Cui
Chun-Ying
CY
School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Lu
Wan-Liang
WL
Xiao
Lan
L
Zhang
Shuang-Qing
SQ
Huang
Yan-Bei
YB
Li
Sheng-Lin
SL
Zhang
Rui-Juan
RJ
Wang
Gui-Ling
GL
Zhang
Xuan
X
Zhang
Qiang
Q
D000286:Administration, Sublingual; D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D004337:Drug Carriers; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin