Ionic liquids (ILs) have been used as solvents or materials, or both, in many applications, including pharmaceutics and medicine due to their exceptional properties consisting of the combination of “green”...

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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.

Paclitaxel (PTX) injection (i.e., Taxol) has been used as an effective chemotherapeutic treatment for various cancers. However, the current Taxol formulation contains Cremophor EL, which causes hypersensitivity reactions during intravenous administration and precipitation by aqueous dilution. This communication reports the preliminary results on the ionic liquid (IL)-based PTX formulations developed to address the aforementioned issues. The formulations were composed of PTX/cholinium amino acid ILs/ethanol/Tween-80/water. A significant enhancement in the solubility of PTX was observed with considerable correlation with the density and viscosity of the ILs, and with the side chain of the amino acids used as anions in the ILs. Moreover, the formulations were stable for up to 3 months. The driving force for the stability of the formulation was hypothesized to be the involvement of different types of interactions between the IL and PTX. In vitro cytotoxicity and antitumor activity of the IL-based formulations were evaluated on HeLa cells. The IL vehicles without PTX were found to be less cytotoxic than Taxol, while both the IL-based PTX formulation and Taxol exhibited similar antitumor activity. Finally, in vitro hypersensitivity reactions were evaluated on THP-1 cells and found to be significantly lower with the IL-based formulation than Taxol. This study demonstrated that specially designed ILs could provide a potentially safer alternative to Cremophor EL as an effective PTX formulation for cancer treatment giving fewer hypersensitivity reactions.

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Developing a universal drug delivery vehicle of sparingly soluble drugs remains a challenge, with surface-active ionic liquid (SAIL)-based ionic liquid-in-oil (IL/O) microemulsions (MEs) being the most suitable vehicles. In this study, a series of SAILs were formulated to prepare novel IL/O MEs composed of SAIL, sorbitan laurate (Span-20), and isopropyl myristate. On the basis of the constructed pseudoternary diagrams, the SAILs played vital surfactant roles with Span-20 acting as a cosurfactant. Excellent drug solubility of MEs prepared with a ratio of 2:1 (SAIL­[Cho]­[Ole]:Span-20) was observed. Examination of the droplet shape, size, and size distribution of the MEs revealed well-distributed particle sizes of 6.5–21.2 nm that formed spherical micelles with the IL 1,3-dimethylimidazolium dimethyl phosphate at the core of the MEs. The MEs showed excellent solubility of sparingly soluble drugs (i.e., celecoxib, acyclovir, methotrexate, and dantrolene sodium). In vitro cytotoxicity of the new carrier using a three-dimensional reconstructed human epidermis model revealed that the cell viability of SAIL-based MEs (94%) was similar when compared to conventional Tween-80-based MEs (96%) at the same IL concentration (4%). The results indicate that the SAIL surfactant in the MEs represents a potential alternative to conventional surfactants for solubilizing insoluble drug molecules.

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Chemotherapeutic cytotoxic agents such as paclitaxel (PTX) are considered essential for the treatment of various cancers. However, PTX injection is associated with severe systemic side effects and high rates of patient noncompliance. Micelle formulations (MFs) are nano-drug delivery systems that offer a solution to these problems. Herein, we report an advantageous carrier for the transdermal delivery of PTX comprising a new MF that consists of two biocompatible surfactants: cholinium oleate ([Cho][Ole]), which is a surface-active ionic liquid (SAIL), and sorbitan monolaurate (Span-20). A solubility assessment confirmed that PTX was readily solubilized in the SAIL-based micelles via multipoint hydrogen bonding and cation−π and π−π interactions between PTX and SAIL-[Cho][Ole]. Dynamic light scattering (DLS) and transmission electron microscopy revealed that in the presence of PTX, the MF formed spherical PTX-loaded micelles that were well-distributed in the range 8.7−25.3 nm. According to DLS, the sizes and size distributions of the micelle droplets did not change significantly over the entire storage period, attesting to their physical stability. In vitro transdermal assessments using a Franz diffusion cell revealed that the MF absorbed PTX 4 times more effectively than a Tween 80-based formulation and 6 times more effectively than an ethanol-based formulation. In vitro and in vivo skin irritation tests revealed that the new carrier had a negligible toxicity profile compared with a conventional ionic liquid-based carrier. Based on these findings, we believe that the SAIL[Cho][Ole]-based MF has potential as a biocompatible nanocarrier for the effective transdermal delivery of poorly soluble chemotherapeutics such as PTX.