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" properties with tunable physicochemical and biological properties. The use of ILs in the pharmaceutical industry can address many challenges associated with the use of conventional organic solvents or water. ILs have been established as potential solvents to solubilize many insoluble or sparingly soluble drugs for formulations or delivery. The use of ILs can also address many of the drawbacks of solid-state drugs, including polymorphism and low solubility, stability, and bioavailability. However, many ILs are inherently toxic, which is the main challenge toward developing IL-based drug formulations and drug delivery systems. The use of second- and third-generation ILs comprising more biocompatible cations and anions, compared with the first-generation ILs, has considerably addressed the toxicity issue. A wide range of biocompatible ILs have been designed to improve the pharmacokinetic and pharmacodynamic properties, as well as the biological activity, of drugs. This review describes the advances in the area of green IL-related research and emphasizes the new conceptual development of ILs in pharmaceutics and medicine. Particular attention is given to the mechanistic knowledge in the synthesis of ILs, as well as to the ecotoxicological and biological impact of biocompatible ILs, stimulating the understanding of innovative technologies in IL-based drug delivery systems.
This critical review highlights the recent advancements of using biocompatible ionic liquids as "green" designer solvents and/or materials to overcome the limitations caused by conventional organic solvents/materials in pharmaceutics and medicine.
The generation of oxygen radicals and their derivatives, known as reactive oxygen species, (ROS) is a part of the signaling process in higher plants at lower concentrations, but at higher ...concentrations, those ROS cause oxidative stress. Salinity-induced osmotic stress and ionic stress trigger the overproduction of ROS and, ultimately, result in oxidative damage to cell organelles and membrane components, and at severe levels, they cause cell and plant death. The antioxidant defense system protects the plant from salt-induced oxidative damage by detoxifying the ROS and also by maintaining the balance of ROS generation under salt stress. Different plant hormones and genes are also associated with the signaling and antioxidant defense system to protect plants when they are exposed to salt stress. Salt-induced ROS overgeneration is one of the major reasons for hampering the morpho-physiological and biochemical activities of plants which can be largely restored through enhancing the antioxidant defense system that detoxifies ROS. In this review, we discuss the salt-induced generation of ROS, oxidative stress and antioxidant defense of plants under salinity.
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Transdermal delivery of drugs is more challenging for drugs that are insoluble or sparingly soluble in water and most organic solvents. To overcome this problem, ionic liquid ...(IL)-mediated ternary systems have been suggested as potential drug carriers. Here, we report potent ternary (IL–EtOH–IPM) systems consisting of biocompatible ILs, ethanol (EtOH), and isopropyl myristate (IPM) that can dissolve a significant amount of the sparingly soluble drug acyclovir (ACV). The ternary systems were optically transparent and thermodynamically stable with a wide range of IL pertinence. An in vitro drug permeation study showed that the ILs in the ternary systems dramatically enhanced ACV permeation into and across the skin. Fourier Transform Infrared spectroscopy of the stratum corneum (sc) after treatment with ternary systems showed that the skin barrier function was reduced by disturbance of the regularly ordered arrangement of corneocytes and modification of the surface properties of the sc during permeation. Histological analysis, and skin irritation studies using a reconstructed human epidermis model showed the safety profile of the ternary system, and there were no significant changes in the structures of the sc, epidermis, and dermis. Therefore, ternary systems containing biocompatible ILs are promising for transdermal delivery of insoluble or sparingly soluble drugs.
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 oleate-based ILs. Among the linoleate-based ILs and ibuprofen formulations (drug in 10% IL in IPM), the l-proline ethyl ester linoleate (l-ProEtLin)-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-ProEtLin)-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.
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Human skin contains numerous antigen-presenting cells that are a potential target for several immune-based therapies, including vaccination and cancer immunotherapy. However, the ...outermost layer of the skin—the stratum corneum—acts as a major physical barrier against the permeation of antigens that have a molecular weight > 500 Da. In this study, an ionic liquid-assisted delivery system (ILDS) was developed, which enabled the successful transdermal delivery of an antigenic protein, ovalbumin (OVA), with a toll-like receptor agonist, imiquimod, as an adjuvant, to stimulate a specific immune response. Both the ionic liquids and ILDS were completely biocompatible for topical or transdermal application for therapeutic purposes. The skin permeation of the antigenic protein and adjuvant was found to be significantly enhanced because of the incorporation of a surface-active ionic liquid in the ILDS. An in vivo immunization study showed that there was a high level of OVA-specific IgG antibody production because of the enhanced permeation of the antigen and adjuvant across and into the skin. In a preclusive anticancer study, vaccination through ILDS showed stronger tumor-growth inhibition compared to control group. These results indicated that the ILDS could be a promising strategy for transdermal immunization as future therapeutics.
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 (ChlFAs)comprising three different FAs (C18:0, C18:1, and C18:2)as biocompatible surface-active ILs (SAILs). The MEFs were successfully developed using ChlFAs as surfactants, sorbitan monolaurate (Span-20) as a cosurfactant, choline propionate IL as an internal polar phase, and isopropyl myristate as a continuous oil phase. Ternary phase behavior, dynamic light scattering, and transmission electron microscopy studies revealed that MEFs were thermodynamically stable with nanoparticle size. The 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 ChlC18:2 SAIL-based MEF was transdermally administered, it reduced the BGL by 56% of its initial value. The MEFs were biocompatible and nontoxic (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 nanocarrier for protein and peptide delivery.
We report a one-step emulsification and rapid freeze-drying process to develop a curcumin-ionic liquid (CCM-IL) complex that could be readily dispersed in water with a significantly enhanced ...solubility of ∼8 mg mL
−1
and half-life (
t
1/2
) of ∼260 min compared with free CCM (solubility ∼30 nM and
t
1/2
∼ 20 min). This process using an IL consisting of a long chain carbon backbone as a surfactant, may provide an alternative way of enhancing the solubility of poorly water-soluble drugs.
We report a one-step emulsification and rapid freeze-drying process to develop a curcumin-ionic liquid (CCM-IL) complex that could be readily dispersed in water with a significantly enhanced solubility and half-life compared to free CCM.
We report a new series of lipid-based biocompatible ionic liquids (LBILs) consisting of the long-chain phosphonium compound 1,2-dimyristoyl-
sn-glycero
-3-ethyl-phosphatidylcholine as the cation and ...the long-chain fatty acids stearic acid, oleic acid, or linoleic acid as anions. These materials were found to be completely miscible with many polar and nonpolar organic solvents as well as dispersible in water. These LBILs also exhibited excellent biocompatibility with an artificial three-dimensional human epidermis model.
This study reports a new series of lipid-based biocompatible ionic liquids consisting of long-chain phosphonium compound, 1,2-dimyristoyl-
sn-glycero
-3-ethyl- phosphatidylcholine, as a cation and long chain fatty acids as anions.
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The technological utility of active pharmaceutical ingredients (APIs) is greatly enhanced when they are transformed into ionic liquids (ILs). API-ILs have better solubility, thermal ...stability, and the efficacy in topical delivery than solid or crystalline drugs. However, toxicological issue of API-ILs is the main challenge for their application in drug delivery. To address this issue, 11 amino acid esters (AAEs) were synthesized and investigated as biocompatible counter cations for the poorly water-soluble drug salicylic acid (Sal) to form Sal-ILs. The AAEs were characterized using 1H and 13C NMR, FTIR, elemental, and thermogravimetric analyses. The cytotoxicities of the AAE cations, Sal-ILs, and free Sal were investigated using mammalian cell lines (L929 and HeLa). The toxicities of the AAE cations greatly increased with inclusion of long alkyl chains, sulfur, and aromatic rings in the side groups of the cations. Ethyl esters of alanine, aspartic acid, and proline were selected as a low cytotoxic AAE. The cytotoxicities of the Sal-ILs drastically increased compared with the AAEs on incorporation of Sal into the cations, and were comparable to that of free Sal. Interestingly, the water miscibilities of the Sal-ILs were higher than that of free Sal, and the Sal-ILs were miscible with water at any ratio. A skin permeation study showed that the Sal-ILs penetrated through skin faster than the Sal sodium salt. These results suggest that AAEs could be used in biomedical applications to eliminate the use of traditional toxic solvents for transdermal delivery of poorly water-soluble drugs.
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In order to prevent common hypersensitivity reactions to paclitaxel injections (Taxol), we previously reported an ionic liquid-mediated paclitaxel (IL-PTX) formulation with small ...particle size and narrow size distribution. The preliminary work showed high PTX solubility in the IL, and the formulation demonstrated similar antitumor activity to Taxol, while inducing a smaller hypersensitivity effect in in vitro cell experiments. In this study, the stability of the IL-PTX formulation was monitored by quantitative HPLC analysis, which showed that IL-PTX was more stable at 4 °C than at room temperature. The in vivo study showed that the IL-PTX formulation could be used in a therapeutic application as a biocompatible component of a drug delivery system. To assess the in-vivo biocompatibility, IL or IL-mediated formulations were administered intravenously by maintaining physiological buffered conditions (neutral pH and isotonic salt concentration). From in vivo pharmacokinetics data, the IL-PTX formulation was found to have a similar systemic circulation time and slower elimination rate compared to cremophor EL mediated paclitaxel (CrEL-PTX). Furthermore, in vivo antitumor and hypersensitivity experiments in C57BL/6 mice revealed that IL-PTX had similar antitumor activity to CrEL-PTX, but a significantly smaller hypersensitivity effect compared with CrEL-PTX. Therefore, the IL-mediated formulation has potential to be an effective and safe drug delivery system for PTX.
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