Recent Developments in Ionic Liquid-Assisted Topical and Transdermal Drug Delivery.

Ionic liquids (ILs) have attracted growing interest as designer solvents/materials for exploring unrealized functions in many areas of research including drug formulations and delivery owing to their inherent tunable physicochemical and biological properties. The use of ILs in the pharmaceutical industry can address challenges related to the use of conventional organic solvent-based chemical permeation enhancers. Their tunability in forming ion pairs with a diverse range of ions enables the task-specific optimization of ILs at the molecular level. In particular, ILs comprising second- and third-generation cations and anions have been extensively used to design biocompatible drug delivery systems to address the challenges related to conventional topical and transdermal drug delivery, including limited permeability, high cytotoxicity, and skin irritation. This review highlights the progress in IL-related research with particular emphasis on the very recent conceptual developments in transdermal drug delivery. Technological advancement and approaches for the formation of IL-based topical and transdermal delivery systems, as well as their promising application in drug delivery, are also discussed.

Methotrexate-based ionic liquid as a potent anticancer drug for oral delivery: In vivo pharmacokinetics, biodistribution, and antitumor efficacy.

Oral delivery of the sparingly soluble drug methotrexate (MTX) is challenging owing to its poor bioavailability and low solubility. To address this challenge, the present study reports the conversion of MTX into a series of five ionic liquids (ILs) comprising a cationic component-i.e., cholinium (Cho), tetramethylammonium (TMA), tetrabutylphosphonium (TBP), or an amino acid ester-and an anionic component-i.e., MTX. The biocompatibility, pharmacokinetics, tissue distribution, and antitumor efficacy of each MTX-based IL were investigated to determine its usefulness as a pharmaceutical. Oral administration to mice revealed that proline ethyl ester MTX (IL[ProEt][MTX]) had 4.6-fold higher oral bioavailability than MTX sodium, followed by aspartic diethyl ester MTX, IL[TBP][MTX], IL[Cho][MTX], and IL[TMA][MTX]. The peak plasma concentration, elimination half-life, area under the plasma concentration, mean absorption time, and body clearance of IL[ProEt][MTX] were significantly (p < 0.0001) higher by 1.7-, 6.2-, 4.6-, 2.5-, and 3.6-fold, respectively, than those of MTX sodium. MTX accumulation in the lungs, spleen, kidney, and gastrointestinal tract was also reduced by 5.6-, 1.8-, 1.5-, and 1.4-fold, respectively, indicating the IL formulations had lower systemic toxicity than free MTX. Mechanistic studies revealed that the IL[ProEt][MTX] solution formed spherical structures with an average size of 190 nm. This was probably responsible for its improved oral absorption performance in vivo. In vivo antitumor studies also demonstrated that IL[ProEt][MTX] suppressed tumor growth more than MTX sodium. These results suggest that MTX-based ILs provide a simple scalable approach to improving the oral bioavailability of poorly soluble MTX.

Favipiravir-Based Ionic Liquids as Potent Antiviral Drugs for Oral Delivery: Synthesis, Solubility, and Pharmacokinetic Evaluation.

Coronavirus disease 2019 (COVID-19) has spread across the world, and no specific antiviral drugs have yet been approved to combat this disease. Favipiravir (FAV) is an antiviral drug that is currently in clinical trials for use against COVID-19. However, the delivery of FAV is challenging because of its limited solubility, and its formulation is difficult with common organic solvents and water. To address these issues, four FAV ionic liquids (FAV-ILs) were synthesized as potent antiviral prodrugs and were fully characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectrometry, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC). The aqueous solubility and in vivo pharmacokinetic properties of the FAV-ILs were also evaluated. The FAV-ILs exhibited improved aqueous solubility by 78 to 125 orders of magnitude when compared with that of free FAV. Upon oral dosing in mice, the absolute bioavailability of the ß-alanine ethyl ester FAV formulation was increased 1.9-fold compared with that of the control FAV formulation. The peak blood concentration, elimination half-life, and mean absorption time of FAV were also increased by 1.5-, 2.0-, and 1.5-fold, respectively, compared with the control. Furthermore, the FAV in the FAV-ILs exhibited significantly different biodistribution compared with the control FAV formulation. Interestingly, drug accumulation in the lungs and liver was improved 1.5-fold and 1.3-fold, respectively, compared with the control FAV formulation. These results indicate that the use of ILs exhibits potential as a simple, scalable strategy to improve the solubility and oral absorption of hydrophobic drugs, such as FAV.

Biocompatible Ionic Liquid-Mediated Micelles for Enhanced Transdermal Delivery of Paclitaxel.

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.

Synthesis and characterization of choline-fatty-acid-based ionic liquids: A new biocompatible surfactant.

Ionic liquid (IL) surfactants have attracted great interest as promising substitutes for conventional surfactants owing to their exceptional and favorable physico-chemical properties. However, most IL surfactants are not eco-friendly and form unstable micelles, even when using a high concentration of the surfactant. In this study, we prepared a series of halogen-free and biocompatible choline-fatty-acid-based ILs with different chain lengths and degrees of saturation, and we then investigated their micellar properties in aqueous solutions. Characterization of the synthesized surface-active ILs (SAILs) was performed by 1H and 13C nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and elemental analysis. The surface-active properties of the SAILs were investigated by tensiometry, conductometry, and dynamic light scattering measurements. The critical micelle concentration of the SAILs was found to be 2-4 times lower than those of conventional surfactants. The thermodynamic properties of micellization (ΔG0m, ΔH0m, and ΔS0m) indicate that the micellization process of the SAILs is spontaneous, stable, and entropy-driven at room temperature. The cytotoxicity of the SAILs was evaluated using mammalian cell line NIH 3T3. Importantly, [Cho][Ole] shows lower toxicity than the analogous ILs with conventional surfactants. These results clearly suggest that these environmentally friendly SAILs can be used as a potential alternative to conventional ILs for various purposes, including biological applications.