1Kyushu University, Fukuoka, Japan
Therapeutic insulin for type I diabetes is usually provided subcutaneously using a needle or insulin pen, or catheters attached to insulin pumps. These strategies are cumbersome and mostly result in inadequate enforcement, which is a significant factor in poor quality of life for diabetic patients. 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 co-surfactant, choline propionate IL as an internal polar phase, and isopropyl myristate as a continuous oil phase. Insulin was loaded into the core of the MEFs by dissolving it in [Chl][C3] and then the safety, efficacy, and stability of the MEFs were investigated both in vitro and in vivo. Ternary phase behavior, dynamic light scattering, and transmission electron microscopy studies revealed that MEFs were thermodynamically stable with nanoparticle size. This study demonstrated an unprecedented improvement in the transdermal bioavailability of insulin in BALB/c diabetic mice with excellent transdermal efficacy, biocompatibility, and long-term stability. The newly developed 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 non-toxic (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 nano-carrier for protein and peptide delivery. MEFs have the potential to be transdermal delivery carriers for insulin and other proteins/peptides that are presently available in injection form and should be further investigated.