Heterocycles-Based Ionic Liquids (ILs) in Transdermal Drug Delivery

Abstract

Transdermal drug delivery systems (TDDSs) have become immensely popular over the past few years owing to their safe and noninvasive administration of the drugs across the skin. The TDDSs have provided a better surrogate pathway over conventional routes such as skin patches and injections, thereby resulting in superior and easier acceptance by the patients, minimized side effects, and controlled delivery rates. While TDDSs present these advantages, they also come with their limitations, specifically in delivering both small and macro drug molecules that exhibit moderate solubility in water and/or commonly used volatile organic solvents. To subdue this obstacle, ionic liquids (ILs) are being considered as the potential media not only for the syntheses of drugs but also as suitable carriers for the efficient delivery of both small as well as macromolecules. In this particular book chapter, we have discussed the transdermal drug delivery (TDD) of various partially soluble drugs such as acyclovir, anti-inflammatory drugs like diclofenac and ibuprofen, various anticancer drugs, etc., through heterocyclic-based ILs. Moreover, some green routes for ILs syntheses, including fatty acid-based “amino acid ionic liquids” (FAAAE-ILs) and “magnetic surface-active ionic liquid surfactants” (MSAIL), have also been discussed highlighting their function as the potential transdermal drug delivery agent.

1. Introduction

Notably, heterocycles represent a vital and quite wide-ranging class of organic compounds playing a critical role in our daily lives. They have found prevalent applications in agrochemicals, medicinal chemistry, materials sciences, organic synthesis, supramolecular chemistry, etc. [1]. Among the heterocyclic systems, structurally diverse ionic liquids (ILs) have found significant roles not only in organic syntheses but also in drug delivery besides many more promising applications [2, 3].

Over the years, ILs have engrossed a remarkable interest of the research community because of their unique biochemical properties they possess [4]. Noticeably, ILs were initially discovered by Paul Walden in 1914 [5], while he was researching the “molten salts” (MSs), and realized [EtNH₃][NO₃], afterward a plethora of room temperature ILs have successfully been revealed by researchers worldwide [6]. It is to be pointed out that at present, ILs have immensely grown both in academia as well as at the industry level due to their fascinating signatures [7]. Remarkably, ILs are considered as new greener solvents in lieu of common volatile organic solvents (they often are toxic, flammable, and highly volatile) in the domain of chemistry and biochemistry in general and organic syntheses in particular. Due to extensive uses of the ILs in a wide range of fields, in 2003, they were labeled as “solvents of the future” [8]. Generally, ILs exist in the liquid state at ambient temperature consisting of “cations and anion,” but they are quite different from MSs—as detailed and described by Seddon [9]. They are commonly defined as liquids below an arbitrary temperature (373.15 K), though this particular temperature constraint is not necessary for a substance to be considered an IL [10].

Importantly, the distinctive assets between the MSs and ILs are; the MSs are highly viscous with comparatively high melting temperature besides being corrosive liquid medium, whereas ILs devise high thermal stability, low melting temperature, are noninflammable, and have negligible vapor pressure [11]. The most distinctive features of ILs are—they comprised “bulky organic cations” (imidazolium, pyrrolidinium, thiazolium, triazolium, tetraalkylammonium, etc.), Figure 1 and bulky inorganic and/or organic anionic counterparts (trifluoroacetate, alkyl sulfate, phosphates, aluminates, etc.), Figure 2 [12, 13, 14]. Interestingly, ILs can be improved/modified depending upon their applications, just by changing the structure of ILs, for instance by selecting the appropriate cation or anion or through the proper substituent in the molecules of the cations and/or the anions.

Figure 1.

Structures of some commonly found bulky organic cations in ILs.

Figure 2.

Structures of some frequently used bulky counteranions in ILs.

Noticeably, unique physicochemical characteristics of the ILs lead to a wide range of potential applications spanning from the electrochemistry, analytical chemistry, supramolecular chemistry, physical chemistry, medical chemistry, engineering chemistry, and pharmaceutical chemistry to the solvent systems and/or catalysts [15]. As far as synthetic organic chemistry perspective is concerned, ILs have successfully been employed in a plethora of vital organic transformations (Figure 3), such as Beckmann rearrangement, Diels-Alder reaction, Henry reaction, Friedel-Crafts sulfonylation and sulfamoylation, Fischer indole synthesis, Knoevenagel condensation, Markovnikov addition, Mannich-type reaction, etc. [16, 17, 18]. Moreover, in recent years, ILs have drawn a great interest in the arena of biomedicine—owing to their potential uses in the drug delivery. Importantly, ILs are being considered as potential media for drug synthesis as well as suitable carriers for the effective and selective delivery of both small as well as macromolecules. In addition to drug delivery systems, ILs drugs have also been risen in the biomedical analytics, sensors, excipients, and stabilizers of the important biomolecules.

Figure 3.

Role of ILs in catalyzing various crucial organic named reactions.

Based upon various properties of ILs, they can be classified into numerous categories. Some of them are task-specific, chiral, metallic, neutral, or basic ILs, and some may be protic, acidic, or supported ILs [19].

• Task-specific ILs: Task-specific ILs are being used in the organic synthesis, for example, in esterification reaction, dehydration reaction, etc. One such example of the task-specific ILs is 3-sulfopropyl tri-phenyl phosphonium p-toluene sulfonate.

• Chiral ILs: Chiral ILs are mostly used in stereoselective polymerization, liquid chiral chromatography, nuclear magnetic resonance (NMR) chiral discrimination, etc.

• Neutral ILs: Anions and cations in the neutral ILs are bonded with weak electrostatic forces, which result in lowering the melting points and viscosity. Therefore, they are employed in the applications demanding robust electrochemical and thermal stability.

• Protic ILs: The presence of Brønsted acidic proton(s) in these ILs has opened up the room for a series of reactions, such as hydrolysis, dehydration, and many more [20].

• Basic ILs: Basic ILs replaced inorganic bases in reactions, such as aldol condensation, Michael addition, aza-Michael, Markovnikov addition, etc., because of its noncorrosive and nonvolatile properties.

On the other front, green chemistry focuses upon the principles to reduce or eliminate hazardous chemical and/or processes for the sake of environment as well as humanity [21, 22, 23, 24]. ILs have negligible vapor pressure at ambient temperature, leading to believe them as the “green solvents” due to their low atmospheric pollution; however, the manufacture, uses, and disposal of any solvent must also be taken into account before considering them as eco-friendly. Due to their diverse rising applications, various studies have reported that ILs toxicity is becoming an alarming problem for the environment, especially for aquatic organisms. In many cases, it has been noticed that the replacement of common organic solvents with ILs was even more unsafe than the former one. One such example is carcinogenic chromium (IV) salts, used in chromium electroplating processes [25]. Therefore, it is strictly advised to check thoroughly the toxicity test of the given IL before branding them as greener solvents.

2. Preparations of some important heterocyclic-based ionic liquids

Undoubtedly, heterocyclic compounds are omnipresent, for example, most of the natural products, drug molecules, and even our body also contains heterocyclic scaffold(s) [19, 26, 27]. Moreover, a plethora of vital synthetic molecules of particular interest also consist of the heterocyclic ring system(s) in their structure [28, 29, 30, 31, 32, 33, 34]. Noticeably, most of the ILs also comprise the heterocyclic ring in their cationic portion, as detailed in Figure 1. In this particular section, we have shed light onto the preparation of some vital and commonly used ILs. The general synthetic pathway for the preparation of ILs can be represented as shown in Figure 4.

Figure 4.

Common method for the preparation of nitrogen containing ILs.

The task-specific ILs 59 were prepared by Huang et al. in the year 2012 (Figure 5) [35]. Toward this mission, the authors have commenced from the commercially available starting material, namely 4-formylphenol derivatives (55), by reacting it with the 1,4-dibromobutane (56) in the presence of NaOH/tetrabutylammonium bromide (TBAB) under microwave condition to give the intermediate compound 57. Next, reaction of 57 with 1-methylimidazole (58) under microwave (MW) afforded the anticipated IL derivatives 59.

Figure 5.

Synthesis of benzaldehyde-based task-specific ILs 59.

On the other hand, imidazolium-based chiral ILs 63 and SiO₂-supported anchored ILs 67 have successfully been revealed by the research groups of Cárdenas and Mehnert (Figure 6) [36, 37, 38]. As can be inspected from Figure 6, these crucial ILs were assembled in three steps both involving alkylation and salt metathesis reactions as key steps.

Figure 6.

Synthesis of imidazole-based chiral ILs 63 and SiO₂-supported IL 67.

3. Transdermal drug delivery of sparingly soluble drugs in ILs

In the field of pharmacy and pharmaceutical technology, intelligent delivery of drugs has become a quite challenging task. Target-specific drug delivery has gathered attention in pharmacotherapy and has become a promising research area. Skin being the largest organ of the body, with an average total area of 20 square feet, comprises of two important layers: (1) epidermis and (2) dermis, so the skin becomes the apt and logical target for drug delivery. Although, the outermost layer of skin, stratum corneum (SC), that varies in thickness depending on the region of body causes obstacle. The structurally well-organized corneocytes with lipid layer in the SC provide the most formidable barrier for the systemic distribution of drug molecules. To surmount this barrier function, diverse strategies, encompassing both physical methods (electroporation, iontophoresis, and ultrasound) and chemical approaches (nanoparticles, prodrugs, and penetration enhancers), have been utilized, individually and in combination, to enhance drug permeation [39, 40]. Hence, formulating biocompatible drug delivery systems for both the small and macro drug molecules, especially those with limited solubility in water and most organic solvents, is a complex undertaking. The challenge lies in achieving this without compromising the efficacy and safety of the drugs.

Transdermal drug delivery systems (TDDSs) have gained recognition, owing to their innocuous and nondisruptive administration of the drugs across the system. They provide an alternative route over oral and injection, have improved patient compliance, and minimized undesirable side effects [41, 42]. Although, the oral route offers some advantages like portability, predetermined doses, and patient self-administration; most therapeutic drugs (peptides and proteins) cannot be delivered orally, since they can go through rapid degradation in the stomach and upper section of the intestines (Figure 7) [43]. In a recent study, researchers have demonstrated the efficacy of ILs and their role in transdermal drug deliveries (TDDs), thus highlighting their advantages over the conventional permeation enhancing methods [44]. Even the administration of drugs via injections has its own limitations, such as needle phobia, resulting in lower patient adherence and the requirement of a trained professional for administration. Rationally, these limitations due to conventional routes can be potentially overcome by transdermal drug delivery systems.

Figure 7.

Representation of mechanisms of action of (A) release of drug molecules are through niosomes; (B) niosome constituents acting as penetration enhancer; (C) niosome interaction with the stratum corneum; (D) niosome penetration across intact skin; (E) niosome permeation through hair follicles. Source: Reprinted with the permission from Ref. [43], copyright 2014 Elsevier.

In recent years, transdermal patches have become a popular choice for drug delivery, as they provide reduced gastrointestinal side effects, reduced peak plasma concentrations, minimal drug therapy, as well as avoiding first hepatic elimination. In addition to their simplified application, cost-effectiveness, and tolerance, TDDSs come with their own limitations. Many small and macro drug moieties are nearly insoluble in water and most organic solvents, so they require the aid of chemical permeation enhancers (CPEs) for their transportation. The most common CPEs are ethanol, terpenoids, sulfoxide, and menthol ester derivatives to augment penetration through the stratum corneum (SC) [45]. The presence of corneocytes with lipid layers in the SC causes hindrance for most of the drugs. In spite of a large number of penetration enhancers, very few of them are launched in the market due to their skin toxicity or irritation in most of the cases.

To overcome these obstacles, ILs-mediated drug delivery is introduced, since they offer numerous advantages over CPEs as they have shown an enhancing capacity of drug permeation. ILs are considered novel and green solvents in lieu of organic solvents, which are often toxic and flammable. Although the applications of ILs in the field of pharmaceutical have risen over the years, however, many of these options are not deemed environmentally and geologically friendly. The imidazolium, quinolinium, pyridinium, and fluorinated derivatives of ILs are not as biodegradable and toxic as they are considered [46, 47]. But, ILs comprising of organic anions (such as carboxylate, phosphate, acetate, and amino acids) and cations (amino acid ester, choline, piperidinium, and pyrrolidinium) are superior as they are nontoxic and biodegradable, as well [48, 49].

4. Transdermal drug delivery of sparingly soluble drugs

Delivering a scarcely soluble drug has always been a challenging task, but this has been overcome by the usage of the ILs. These ILs have shown remarkable delivering property without affecting the other cells of the system.

4.1 Anti-inflammatory drug delivery systems

Moshikur et al. have synthesized and characterized eight green hydrophobic fatty acid-based amino acid ionic liquids (FAAAE-ILs) that exist in a liquid state at 25°C and showed desirable thermal as well as physicochemical properties in the transdermal drug delivery (Figure 8). The formed ILs 71, permitted high ibuprofen solubility owing to the hydrogen bonding interactions, and were found to be more effective in enhancing the diffusion of drug molecules than the conventional CPE transcutol by inducing fluidization within the intracellular lipid matrix of the stratum corneum. The l-proline ethyl ester linoleate ([L-ProEt][Lin])-based formulation outperformed the d-proline ethyl ester linoleate, l-leucine ethyl ester linoleate, and alanine ethyl ester linoleate formulations. Notably, compared to CPE-containing formulations, the identical FAAAE-IL ([L-ProEt][Lin]) significantly improved the peptide permeation through pig skin. Moreover, the findings shed fresh light onto the conventional ILs and suggested that the newly developed FAAAE-ILs (Figures 9 and 10)—emerge as a promising transdermal alternative to traditional chemical enhancers by exhibiting the potency to surmount the barrier of transdermal macromolecule distribution [50].

Figure 8.

Synthetic scheme for the hydrophobic ionic liquids.

Figure 9.

Amino acid ester cations of developed FAAAE-ILs.

Figure 10.

Amino acid ester anions of the synthesized FAAAE-ILs.

Mahkam and his teammates have reported two ILs monomers, 1-(4-vinylbenzyl)-4-(dimethylamino)-pyridinium hexafluorophosphate 81 (VDPH) and 1-(4-vinylbenzyl)-3-methyl imidazolium hexafluorophosphate 85 (VMIH), in addition to their polymers 88 and 91, respectively (Figures 11, 12, and 13). The free radical polymerization reactions at 70°C produced homopolymers of VDPH, VMIH, and their copolymers using methyl styrene. Furthermore, naproxen (anionic drug) was efficiently packed into the positive charge polymers (PCPs) and stayed within them under acidic conditions (pH 2–6.5) (Figure 14). This loading of drug molecules can be enhanced by increasing the positive charge density by raising the amount of IL groups. The dispersion of hydrolyzing agents is increased on the polymer, and the hydrolysis rate is raised by raising the ionic strength at the pH > 6. These PCPs are well suited for anionic drug delivery targeting colon by capitalizing on the variation in hydrolysis rates between weakly acidic and neutral pH values [51].

Figure 11.

Synthetic scheme for the preparation of VDPH monomer 81.

Figure 12.

Synthesis of VMIH monomer 85.

Figure 13.

Synthesis of the positive charge polymer (PCP) 91.

Figure 14.

Representation for the release of naproxen adsorbed in the PCP sample.

Shishu and his coworkers have detailed the IL-in-water (IL/w) microemulsion (ME), proficient in solubilizing Etodolac (ETO), a drug with limited water solubility for topical delivery. This formulation employed BMIMPF6 (1-butyl-3-methylimidazolium hexafluorophosphate) as IL, Tween 80 (surfactant), and a co-surfactant ethanol [52]. Particle size, transmission electron microscopy (TEM), pH, zeta potential, and conductometric investigations were performed for the prepared formulation. Ex vivo drug infusion tests via rat skin were carried out using a Franz diffusion cell. The microemulsion formulated with the IL-in-water (IL/w) system exhibited the highest average cumulative percent permeation at 99.030 ± 0.921%, surpassing the oily solution (48.830 ± 2.488%) and the oil-in-water (o/w) ME (61.548 ± 1.875%) of ETO. It was further manifested that ETO-loaded IL/w microemulsion showed efficacy in reducing inflammation without causing any undesirable variation in the skin.

Later, Suksaeree and co-workers have prepared and investigated the transdermal patches used for lidocaine-diclofenac drug delivery comprising of polymer matrix (pectin and Eudragit® NE 30 D) and plasticizer (glycerin) [53]. This lidocaine-diclofenac IL drug was prepared through an ion-pair reaction between the hydrochloride and sodium salts of lidocaine-diclofenac, respectively. The attributes defining the transdermal patch characteristics were dependent on the quantity of Eudragit® NE 30 D, and the loading of lidocaine-diclofenac IL drug. Although raising the amount of Eudragit® NE 30 D in the transdermal fragments reveals drug’s crystal characteristics but it also tends to decrease the drug release from the patches. The drug concentration in these patches was found to be 1.88–2.11 mg/cm² for lidocaine and 2.33–2.64 mg/cm² for diclofenac. Nevertheless, the use of these polymeric matrices incorporating IL drugs for transdermal delivery of lidocaine and diclofenac led to regulate drug release, presenting advantages for forthcoming research.

4.2 Drug delivery of antibiotics

On the other hand, Gao et al. have proposed a microwave (MW)-induced hydrogel antibacterial approach by synthesizing VACPHs (hydrogels) that combine the benefits of microwave thermal conversion with that of drug delivery [54]. These hydrogels were synthesized via the copolymerization of a MW-active IL, vinylbenzyl trimethylammonium chloride 92 (VBTMACl), and [2-(methacryloyloxy)ethyl]trimethylammonium chloride (ChMACl) 94 with acrylic acid 93 (Figure 12). Polyvinylpyrrolidone 95 (PVP) was added to improve the mechanical stability of VACPHs. The moiety 92 enhances the thermal conversion capability of hydrogen, whereas 94 is responsible for the transdermal drug delivery. Moreover, the VACPHs with MW and LEVO (levofloxacin drug) reduce Staphylococcus aureus colonization, and hence, disclosed VACPHs MW therapeutic platform represents a viable technique for tissue infection (Figure 15) [54].

Figure 15.

Synthesis of VACPHs hydrogels.

Isa and his group have analyzed the properties of mesoporous silica nanoparticles (MSNs) using three different parameters: template amount, triethanolamine (TEA) amount, and reaction temperature through the Box-Behnken Design (BBD). The properties, such as surface area and the particle size, are best represented by linear and quadratic models, respectively, which are highly influenced by the temperature variable. In accordance with the drug loading and drug release method, 37% of the drug (quercetin) were efficiently contained in MSNs, with 32% being released within 48 hours. This demonstrates the potency of MSN as a drug delivery agent [55].

4.3 Anticancerous drug delivery

In a separate report, Shu et al. have documented 11 imidazolium-based ILs, serving not only as the precursors for carbon dots (IL-CDs) preparation but also tend to regulate their properties [56]. In a hydrothermal environment, sulfuric acid carbonization of the IL precursors results in hydrophilic (IL-HCDs) 97 and hydrophobic (IL-OCDs) 98 carbon dots (Figure 16). The IL-OCD quantum yields depend on both anionic and cationic moieties. Notably, longer side chains of cations in imidazolium ILs and lesser nucleophilicity of the anions created intensely fluorescent IL-OCDs. Moreover, the ILs 97 and 98 showed low cytotoxicity, albeit the former has the lowest. Nevertheless, IL-OCDs have been found to increase the intracellular transport of the anticancer medication that disrupts the affected cells.

Figure 16.

Synthesis of IL-HCDs and IL-OCDs.

Remarkably, Goto and his teammates have described the transformation of Methotrexate (MTX) into an array of five ILs consisting of a cationic moiety, such as tetramethylammonium (TMA), cholinium (Cho), tetrabutylphosphonium (TBP) or an amino acid ester, and an anionic component (MTX). Each MTX-based IL’s tissue distribution, pharmacokinetics, biocompatibility, and anticancer effectiveness was studied to assess its utility as a medication. As per the pharmacokinetics study, IL[ProEt][MTX] allowed persistent MTX discharge and showed 4.6-fold better oral bioavailability than MTX sodium. Moreover, the IL-based MTX solution was found to have higher antitumor efficacy than MTX sodium, implying that the MTX-ILs had a synergistic antitumor impact in C57BL/6 mice (Figure 17), which in turn ensures a promising platform for boosting the hydrophobic drug’s oral absorption and targeted delivery to the tumor regions. These findings imply that MTX-based ILs offer an extensible method for improving the oral bioavailability of inadequately soluble MTX [53, 57].

Figure 17.

At 2.0 hours postoral administration of 50 mg/kg MTX to mice, MTX distribution in major organs was analyzed (ns = nonsignificant; n = 4; mean ± SD).

Kulshreshta et. al. created a valine-based surfactant [ValCl₆][Cl] along with its magnetic surface-active IL surfactant (MSAIL) [ValCl₆][FeCl₄] and evaluated their drug delivery potential [58]. Specific conductivity, surface tension, and pyrene fluorescence were used to study the self-assembly behavior of [ValCl₆][Cl] and [ValC1₆][FeCl₄], and relevant parameters were obtained. The biocompatibility of [ValC1₆][FeCl₄] was demonstrated through its physicochemical interaction with animal DNA using zeta potential, circular dichroism (CD), ethidium bromide exclusion assay, and agarose gel electrophoresis. Rheology and vibrating sample magnetometry were used to assess magnetic behavior and the gel strength of the generated magnetoresponsive biocomposite hydrogels. The produced magnetic biocomposite gel was used as a drug carrier for ornidazole (69.06%) and for an anticancer drug, 5-fluorouracil (78.03%), with extremely high loading efficiency. Both the drugs’ release kinetics follow the Korsmeyer-Peppas paradigm. These magnetic biocomposite gels, devoid of nanoparticles, can be employed for in vivo investigations and applications including drug transport and tissue engineering.

Jahanshahi et al. have developed a process for synthesizing fluorinated graphene (FG) utilizing synthesized acidic IL 100 and a solid fluorine source (NH₄F) at 80°C (Figure 18). This procedure was initiated by the oxidation of graphite resulting in graphene oxide 99 (GO) followed by a mild-temperature fluorination with an acidic IL, as it allows increased protonation of epoxide and hydroxyl groups that in turn boosts the fluorinating proficiency of the reaction. X–ray photoelectron spectroscopy (XPS) further revealed that the FG 105 showed the maximum degree of fluorination (66.4 wt.% of F) with F/C ratio of 2.2. As a result, the generated FG nanosheets demonstrated a greater Curcumin (a natural anticancer drug) loading efficacy (78.43%), and also these FG nanocarriers loaded with Curcumin precisely transported the drug to the nuclei of cancer cells, causing death of PC-3 cells. Concludingly, the posited approach for preparing FG is proved to be promising in the broad range of organic compounds for further implications in varied disciplines of research [59].

Figure 18.

Synthesis of fluorinated graphene products.

4.4 Antiviral drug delivery

In another report, the research group of Goto has described the IL-based ternary (IL-EtOH-IPM) systems that are thermodynamically stable and optically transparent with an array of IL pertinence. It comprises biocompatible ILs, a co-solvent isopropyl myristate (IPM), and ethanol that can significantly dissolve the moderately soluble drug acyclovir (ACV). In vitro drug testing revealed that these ILs have shown a remarkable increase in ACV permeation through the skin. The ILs’ biocompatibility was proven against fibroblast cells (L-929) when compared to commercially available ILs [C1mim][DMP] and [Bmim][Cl]. Furthermore, the skin irritation studies performed on the human epidermis model (LabCyte EPI-MODEL) revealed that the suggested IL-EtOH-IPM ternary system’s safety and toxicity is equivalent to that of TDDSs [60].

5. Conclusions and outlook

In summary, we have highlighted the role of ILs in the transportation of an array of drugs that demonstrated inefficient delivery through conventional methods. The studies revealed that the ionic liquids displayed the characteristics of a potent drug carrier and are highly recommended for poorly soluble drugs. The scope of these carriers is impeccable in the medical and biochemistry research areas. We hope that this particular chapter will be useful to the readers to further expand the horizon of the ionic liquids in drug delivery systems.

Acknowledgments

We are highly thankful to the Department of Science and Technology-Science and Engineering Research Board (DST-SERB, New Delhi), India for the financial support (Project File no. ECR/2017/000821). Lubna Khan thanks the Prime Minister’s Research Fellowship (PMRF), India (PMRF-ID, 3303671). The authors are also grateful to Jamia Millia Islamia, New Delhi, for providing the necessary research facilities.

Conflicts of interest

The authors declare no conflicts of interest.