Insulin Transdermal Delivery System for Diabetes Treatment Using a Biocompatible Ionic Liquid-Based Microemulsion

Abstract

Since injection administration for diabetes is invasive, it is important to develop an effective transdermal method for insulin. However, transdermal delivery remains challenging owing to the strong barrier function of the stratum corneum (SC) of the skin. Here, we developed ionic liquid (IL)-in-oil microemulsion formulations (MEFs) for transdermal insulin delivery using choline–fatty acids ([Chl]­[FAs])comprising three different FAs (C18:0, C18:1, and C18:2)as biocompatible surface-active ILs (SAILs). The MEFs were successfully developed using [Chl]­[FAs] as surfactants, sorbitan monolaurate (Span-20) as a cosurfactant, choline propionate IL as an internal polar phase, and isopropyl myristate as a continuous oil phase. Ternary phase behavior, dynamic light scattering, and transmission electron microscopy studies revealed that MEFs were thermodynamically stable with nanoparticle size. The MEFs significantly enhanced the transdermal permeation of insulin via the intercellular route by compromising the tight lamellar structure of SC lipids through a fluidity-enhancing mechanism. In vivo transdermal administration of low insulin doses (50 IU/kg) to diabetic mice showed that MEFs reduced blood glucose levels (BGLs) significantly compared with a commercial surfactant-based formulation by increasing the bioavailability of insulin in the systemic circulation and sustained the insulin level for a much longer period (half-life > 24 h) than subcutaneous injection (half-life 1.32 h). When [Chl]­[C18:2] SAIL-based MEF was transdermally administered, it reduced the BGL by 56% of its initial value. The MEFs were biocompatible and nontoxic (cell viability > 90%). They remained stable at room temperature for 3 months and their biological activity was retained for 4 months at 4 °C. We believe SAIL-based MEFs will alter current approaches to insulin therapy and may be a potential transdermal nanocarrier for protein and peptide delivery.

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules

“…Given the amphiphilic nature, ILs based on choline–fatty acids were scrutinized as surface active reagents to incorporate hydrophilic biomacromolecules into a classic oil-based penetration enhancer such as isopropyl myristate (IPM) [ 69 , 70 , 71 ]. Tahara et al recently reported that ILs derived from choline and oleic acid ([Ch][Ole]) facilitated the dispersion of antigenic peptides in IPM and ethanol (EtOH).…”

“…The EtOH phase could be substituted with another hydrophilic IL derived from choline and propionic acid to robe the biologics before mixing with [Ch][Ole] and IPM [ 71 ]. A similar strategy was explored to disperse insulin in IPM for transdermal delivery, with [Ch][Ole] as a surfactant and Span-20 as a co-surfactant [ 70 ]. The IL-assisted microemulsion enabled higher bioavailability in systemic circulation and sustained insulin levels for a longer period (half-life > 24 h) compared to subcutaneous injection [ 70 ].…”

“…A similar strategy was explored to disperse insulin in IPM for transdermal delivery, with [Ch][Ole] as a surfactant and Span-20 as a co-surfactant [ 70 ]. The IL-assisted microemulsion enabled higher bioavailability in systemic circulation and sustained insulin levels for a longer period (half-life > 24 h) compared to subcutaneous injection [ 70 ].…”

“…Moreover, the phosphate groups of siRNA could be directly taken as anions to form novel IL entities with proper cationic moieties for the dual purposes of enhanced skin transport and cell transfection [68]. Given the amphiphilic nature, ILs based on choline-fatty acids were scrutinized as surface active reagents to incorporate hydrophilic biomacromolecules into a classic oilbased penetration enhancer such as isopropyl myristate (IPM) [69][70][71]. Tahara et al recently reported that ILs derived from choline and oleic acid ([Ch][Ole]) facilitated the dispersion of antigenic peptides in IPM and ethanol (EtOH).…”

“…Furthermore, an IL mixture of CAGE and choline-phenylpropanoic acid (CAPA) was designed to topically deliver siRNA for psoriasis treatment [10]. CAGE played the role of permeation enhancer, while CAPA retained the secondary structure of Given the amphiphilic nature, ILs based on choline-fatty acids were scrutinized as surface active reagents to incorporate hydrophilic biomacromolecules into a classic oilbased penetration enhancer such as isopropyl myristate (IPM) [69][70][71]. Tahara et al recently reported that ILs derived from choline and oleic acid ([Ch][Ole]) facilitated the dispersion of antigenic peptides in IPM and ethanol (EtOH).…”