Lipid-Based Ionic-Liquid-Mediated Nanodispersions as Biocompatible Carriers for the Enhanced Transdermal Delivery of a Peptide Drug

Abstract

Lipid-based biocompatible ionic liquids (LBILs) have attracted attention as carriers in transdermal drug delivery systems (TDDSs) because of their lipophilic character. In this study, we report the formulation of a peptide−LBIL complex microencapsulated in an oil phase as a potential carrier for the transdermal delivery of leuprolide acetate as a model hydrophilic peptide. The peptide−LBIL complexes were prepared via a water-in-oil emulsion composed of 1,2-dimyristoyl-sn-glycerol-3-ethyl-phosphatidylcholine (EDMPC), a fatty acid (stearic, oleic, and linoleic acid)-based LBIL, and cyclohexane followed by freeze-drying to remove the water and cyclohexane. Then, the peptide−LBIL complexes were nanodispersed and stabilized in isopropyl myristate (IPM) using sorbitol laurate (Span-20). Ionic-liquid-in-oil nanodispersions (IL/ O-NDs) were prepared with varying weight ratios of LBILs and Span-20 as the surfactant and the cosurfactant, respectively. Keeping the overall surfactant constant at 10 wt % in IPM, a 5:5 wt % ratio of surfactant (IL) and cosurfactant (Span-20) in the IL/O-NDs significantly (p < 0.0001) increased the physiochemical stability, drug-loading capacity, and drug encapsulation efficiency. The in vitro and in vivo peptide delivery across the skin was increased significantly (p < 0.0001) using IL/O-NDs, compared with non-ILtreated groups. Of all of the LBIL-based formulations, [EDMPC][Linoleate]/O-ND was considered the most preferable for a TDDS based on the pharmacokinetic parameters. The transdermal delivery flux with [EDMPC][Linoleate]/O-ND was increased 65-fold compared with the aqueous delivery vehicle. The IL/O-NDs were able to deform the lipid and protein arrangements of the skin layers to enhance the transdermal permeation of the peptide. In vitro and in vivo cytotoxicity studies of the IL/O-NDs revealed the biocompatibility of the LBIL-based formulations. These results indicated that IL/O-NDs are promising biocompatible carriers for lipid−peptide TDDSs.

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

“…F-C18:2 facilitated the permeation of more insulin than other SAIL-based MEFs because of the double π-bond in its anion structure. It has been reported that ILs and IL-based formulations can facilitate the permeation of drugs, proteins, and peptides because of their ionic character and ability to extract SC lipid. , It has also been reported that the presence of one or more π-bonds in the IL structure increases the hydrophobicity of the IL, resulting in greater reduction of the barrier function. , The presence of double bonds in unsaturated FAs enables the lipid structure to bend or kink, allowing successful permeation through the skin. Because it has more double bonds than the other SAILs investigated, [Chl]­[C18:2] is able to increase the permeation more by creating greater fluidity or more kinks in the lipid structure of the skin. , …”

“…29,49 It has also been reported that the presence of one or more π-bonds in the IL structure increases the hydrophobicity of the IL, resulting in greater reduction of the barrier function. 52,56 The presence of double bonds in unsaturated FAs enables the lipid structure to bend or kink, allowing successful permeation through the skin. Because it has more double bonds than the other SAILs investigated, [Chl][C18:2] is able to increase the permeation more by creating greater fluidity or more kinks in the lipid structure of the skin.…”

The Emerging Role of Ionic Liquid-Based Approaches for Enhanced Skin Permeation of Bioactive Molecules: A Snapshot of the Past Couple of Years

“…These formulations (especially the L-proline ethyl ester linoleate-based one), enhanced the percutaneous permeation of an antigenic peptide accross porcine skin [ 168 ]. The same authors have very recently used similar fatty acid-based ILs to formulate IL-in-oil nanodispersions that were optimized for higher physicochemical stability, as well as increased loading capacity and in vivo transdermal delivery of the anticancer nonapeptide leuprolide [ 169 ]. The nanodispersions showed no significant toxicity both in vitro and in vivo, and peptide transdermal delivery could be enhanced by as much as 65-fold compared with the aqueous delivery vehicle [ 169 ].…”

Transdermal Delivery of Antigenic Protein Using Ionic Liquid-Based Nanocarriers for Tumor Immunotherapy

“…33 In a previous study, we developed a formulation for transdermal peptide delivery that comprised an LBIL-biocompatible surfactant and Span 20 as a co-surfactant. 8 The LBIL-mediated formulation significantly enhanced topical and transdermal peptide delivery compared with the aqueous formulation. An LBIL plays the pivotal role of increasing the bioavailability and pharmacokinetics parameters of a peptide compared with an aqueous subcutaneous injection.…”

“…24 [Glu] were used to increase the TDD of caffeine and salicylate. 25 Our group reported the effective transdermal delivery of acyclovir, 26 leuprolide acetate, 8 curcumin, 27 insulin, 28 and paclitaxel 29 using ILs as solubilizing agents/solvents as well as skin permeation enhancers. In such systems, an IL plays the key role of increasing the penetration and permeation of therapeutic agents into/across the skin through the noninvasive disruption of the lipid bilayers of the SC.…”