Ionic liquids: Emerging chemical permeation enhancers

Abstract

The human skin and mucosal systems build a continuous exterior barrier that encloses the entire body. This natural barrier protects the body by preventing the free entry of a majority of foreign substances, whereas nutrients and selected substances can be transported via either passive or active mechanisms. Unfortunately, the presence of biobarriers also stymies the absorption of therapeutic agents. Breaking through these absorption barriers is one of the leading challenges in modern drug delivery.

The most direct and efficient approach is to breach the barrier by invasive techniques such as injection, microneedle injection, high-pressure powder injection, ionophoresis, and electroporation. However, owing to the well-known safety concerns of barrier damage, noninvasive alternatives with less optimal efficiency are always preferred. The current key issue with noninvasive permeation enhancement is improving the permeation efficiency while preserving the physiological functions of the protective barriers.

Currently, there are a variety of permeation enhancers that act via different mechanisms, including but not limited to small chemicals, polymers, peptide chaperones, and nanovehicles. Among them, chemical permeation enhancers (CPEs) are simple in structure and stable in terms of their physicochemical properties and are therefore easily applicable for different transdermal or trans-mucosal drug delivery purposes. Traditional CPEs such as ethanol, dimethyl sulfoxide, laurocapram, cholates, salcaprozate sodium (SNAC), essential oils, chitosans, etc., function through intricately orchestrated mechanisms of extracting and fluidizing biomembranes or opening intercellular tight junctions. Recent developments in enhancing the oral bioavailability of proteins and peptides by SNAC have highlighted the benefits that CPEs can offer. Nonetheless, debilitating biobarriers by CPEs may cause simultaneous invasion of toxins and pathogens and pose a safety risk. In recent decades, there has been continuous exploration for more potent and safer CPEs. However, dismally, little progress has been made in discovering new types of CPEs. Despite limited success in clinical applications, the development lags far behind the demand for innovative CPEs. Fortunately, the most recent research on transdermal and transmucosal drug delivery has shed light on ionic liquids (ILs) as a unique kind of novel CPE.

ILs are defined as “liquid salts” formed by organic cations and anions through ionic interactions. Unlike solid salts formed by neutralization reactions between a pair of strong acids and bases, one of the cation/anion pairs should be a weak acid or base. Therefore, the interactions in ILs are weaker than the ionic bonds formed in strong acid/base salts, presenting ILs as “liquid salts” with a melting point less than 100°C or ideally at physiological temperatures to address the unmet needs in biomedicines, especially in drug delivery. Notably, there are not necessarily typical ionic interactions within ILs; the interactions are much weaker, which however has yet to be validated with experimental evidence in addition to in silico simulation. Deep eutectic solvents (DESs) are nonionic counterparts of ILs whose constituents are held together via weak nonionic forces such as hydrogen bonds and van de Waals forces. In addition to applications in the wide field of biomedicines, ILs are emerging as novel carrier systems for the delivery of both small chemicals and biomacromolecules via different administration routes. Pioneering studies have explored the potential of ILs to convert active pharmaceutical ingredients (APIs) into liquid API-ILs, solubilize poorly soluble entities, and, most importantly, enhance the permeation of versatile active ingredients.

ILs proactively enhance drug permeation across dermal, nasal, corneal, buccal, and intestinal barriers. Choline-based ILs, biocompatible ILs that have recently become popular, have been found to enhance the transmembrane delivery of 5-aminolevulinic acid, insulin, glucan, hyaluronic acid, and biomacromolecules, such as small interfering RNAs (siRNAs), with efficacy either higher than or equal to that of traditional CPEs.^{1, 2} Pioneering studies indicate that ILs are potential enhancers for transnasal drug delivery of insulin.³ In this study, ILs (also called deep eutectic solvents) formed by choline chloride and malic acid significantly improved the transnasal absorption of insulin in a dose-dependent manner. ILs achieve similar hypoglycemic effects, calculated as the area above the curve of blood glucose versus time, at a dose of 25 IU/kg in rats in comparison with subcutaneous insulin (1 IU/kg) in a limited observation time of 5 h, but the effect is mild and sustained.³ Recently, ILs of pilocarpine, oligo-polyethylene glycol chloride, and 2-[2-(2-chloroethoxy)ethoxy] ethanol were applied topically to cornea surfaces to enhance the transcorneal absorption of pilocarpine.⁴ The API-IL achieved a corneal permeability coefficient eightfold greater than that of pilocarpine hydrochloride. More evidence for the use of ILs as enhancers for oral drug absorption has been reported.⁴

ILs function through various ways to breach biobarriers. For API-ILs, the formation of ILs first converts the solid API into a fluid with a perfect solubilized state. Second, IL formation neutralizes the acidity or alkalinity of APIs by counterions and endows them with balanced hydrophilicity/hydrophobicity, which is a critical characteristic for the transmembrane transport of substances. The well-known ion pair approach has similarities to API-ILs in the enhancement of transdermal drug delivery. API-free blank ILs work differently toward enhancing permeation. First, ILs can serve as a vehicle to solubilize and carry APIs, rendering APIs in a well-dispersed and readily absorbable state. More importantly, ILs can condition the skin by affecting the lipid layers, thus permeabilizing the skin.^{1, 5} A recent study with ²H nuclear magnetic resonance (NMR) and X-ray diffraction revealed that imidazolium-based ILs favor cholesterol-rich regions, perturb the lamellar arrangement, and induce the formation of an isotropic lipid phase.⁵

The ability of ILs to act as permeation enhancers has only recently been well recognized. For the following reasons, ILs are rapidly emerging as a new generation of CPEs: 1) with a permeabilizing ability higher than or comparable to that of conventional CPEs; 2) with a tailorable permeation ability achieved by modulating either the acid or base; 3) with post-permeation dissociation to terminate permeation; and 4) with low toxicity and good biocompatibility. As both publications and patent applications grow rapidly, a booming amount of research on IL-based drug delivery is expected in the coming years.

Nonetheless, the application of ILs as CPEs is not without limitations or challenges. As ILs are held together by weak interactions between cations and anions, they are prone to dissociation upon dilution by aqueous media. The evidence shows that the efficacy of ILs is greatly reduced by water dilution. Although concentrated ILs can also be directly used, unfriendly sensations associated with high osmolarity, such as irritation, may occur. On the other hand, the high viscosity may hinder the diffusion of payloads in the IL matrices, further undermining the efficiency of permeation enhancement. As ILs are complexes subjected to interactions with additives and the environment, their stability and compatibility with other formulation matrices upon addition or mixing may present a challenge. Importantly, as investigations on ILs as permeation enhancers and drug delivery carriers are still in an early stage, the underlying mechanisms have yet to be elucidated with more experimental evidence.

Wei Wu: Conceptualization, writing-draft and revisio; Yi Lu: Writing-draft and revision; Yanyun Ma: Conceptualization. All authors have read and approved the final manuscript.

The authors declare no conflicts of interest.

Not applicable.