Design and Characterization of Fatty Acid-Based Amino Acid Ester as a New “Green” Hydrophobic Ionic Liquid for Drug Delivery

Abstract

Ionic liquid (IL)-based drug delivery systems have attracted considerable interest owing to their intrinsic tunability and ability to transport small or large molecules through the skin. However, the development of "green" ILs remains challenging. Herein, eight potentially "green" fatty acid-based amino acid ILs (FAAAE-ILs) were synthesized, and their potency in transdermal drug delivery was investigated using ibuprofen and a peptide drug. The synthesized ILs were characterized to evaluate their physicochemical, thermal, and biological (cytotoxicity) properties. The in vitro skin permeability of the synthesized FAAAE-ILs was evaluated through pig skin. All of the FAAAE-ILs are liquid at room temperature and freely miscible with pharmaceuticals-permitted solvents/agents (e.g., isopropyl myristate (IPM), Span-20, and DMSO). In vitro cytotoxicity study showed that the cell viability of all FAAAE-ILs (10% in IPM) was at least 10 times lower than that for a conventional chemical permeation enhancer (CPE), sodium lauryl sulfate. FAAAE-ILs facilitated excellent ibuprofen solubility through multiple hydrogen bonding interactions between the drug and the ILs. An in vitro permeation study showed that the FAAAE-ILs were more effective in enhancing the permeability of drug molecules than the conventional CPE transcutol. The linoleate-based ILs showed a higher degree of permeation than the oleatebased ILs. Among the linoleate-based ILs and ibuprofen formulations (drug in 10% IL in IPM), the L-proline ethyl ester linoleate ([L-ProEt][Lin])-based formulation exhibited best results, followed by β-alanine ethyl ester linoleate, D-proline ethyl ester linoleate, and L-leucine ethyl ester linoleate after 48 h. Interestingly, the same FAAAE-IL ([L-ProEt][Lin])-containing formulation showed significant enhancement of peptide penetration across pig skin compared with CPE-containing formulations (10% in IPM). The results demonstrate that the FAAAE-IL is a promising green alternative to conventional CPEs for the transdermal delivery of small and large therapeutic molecules.

A systematic comparison of the extraction and adsorption of theophylline by new amino acid ester-based ionic liquids

“…It has been found that the hydrophobicity of common hydrophobic anions is in the order: [Tf 2 N] − > [PF 6 ] − > [C(CN) 3 ] − . 28 As for cations, amino acids are regarded as more environmentally friendly than imidazolium ILs, 29 so they were chosen as the cations of potential extractants, and further esterification was used to enhance their hydrophobicity. As a result, l -phenylalanine methyl ester bis(trifluoromethyl)sulfonimide ([PheC 1 ][Tf 2 N]), l -phenylalanine ethyl ester bis(trifluoromethyl)sulfonimide ([PheC 2 ][Tf 2 N]), glycine benzyl ester bis(trifluoromethyl)sulfonimide ([LeuC 2 ][Tf 2 N]), and l -leucine ethyl ester bis(trifluoromethyl)sulfonimide ([GlyOBzl][Tf 2 N]) were designed and screened through pilot experiments.…”

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

“…Consequently, ILs are under the spotlight of the latest research on DTD of therapeutic peptides. For instance, Goto and co-workers developed hydrophobic fatty acid/amino ester-based ILs that were liquid at room temperature (i.e., RTILs) and fully miscible with common CPEs, such as isopropyl myristate (IPM) [ 168 ]. Formulations comprising 10% wt of the RTILs in IPM showed lower cytotoxicity than the standard CPE sodium lauryl sulfate and being also able to better permeate a NSAID (ibuprofen) than the conventional CPE Transcutol ® .…”

“…Formulations comprising 10% wt of the RTILs in IPM showed lower cytotoxicity than the standard CPE sodium lauryl sulfate and being also able to better permeate a NSAID (ibuprofen) than the conventional CPE Transcutol ® . 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 ].…”

Current Status of Amino Acid-Based Permeation Enhancers in Transdermal Drug Delivery

“…ILs were shown to enhance transdermal permeation through mechanisms involving disruption of cell integrity, lipid fluidization and extraction, and several reports on their use in topical emulsions to promote drug solubility and permeation are available [ 115 , 116 , 117 ]. Recently, Moshikur, R and co-workers (2020) developed a new family of IL-based on fatty acids and amino acid esters [ 118 ]. Fatty acids and amino acid esters are well-known potent CPEs with low cytotoxicities.…”