Lecithin/isopropyl myristate reverse micelles as transdermal insulin carriers: Experimental evaluation and molecular dynamics simulation

Abstract

Reverse micelles are nanoaggregates of surfactants that spontaneously form in a non-aqueous solvent. As a transdermal carrier for delivery of hydrophilic drugs, they can effectively control the release of drugs and improve their bioavailability thus achieving therapeutic levels throughout the body. Here, we prepared insulin-loaded reverse micelles composed of isopropyl myristate (IPM) and lecithin as the solvent and the surfactant, respectively. We tuned the amount of lecithin and volume of insulin leading to significant variations in viscosity. The optimal permeation flux was (6.98 ± 2.85) to (8.95 ± 4.74) μg/cm2/h with a gel viscosity of 1079.56–2956.45 cP. The in vitro insulin permeation through hairless mice skin from reverse micelles gel followed zero-order kinetics (R2 = 0.9234–0.9853) over a period of 24 h with case-II transport mechanism. The in vivo study of optimized reverse micelles gel in alloxan-induced diabetic rabbits demonstrated prolonged hypoglycemic effects of at least 12 h after transdermal administration. The optimal relative bioavailability (RBA) value was 136.74% versus the subcutaneous insulin group. We evaluated coarse grained molecular dynamics simulations (CGMD) to explore the permeation mechanism of reverse micelles to improve transdermal drug delivery and modify the viscosity on insulin release. The results indicated that reverse micelles deform after contacting the stratum corneum and penetrate further through it. There is reduced insulin release with increasing viscosity. The CGMD results confirmed the experimental findings.