Transformation of Hydrophilic Drug into Oil-Miscible Ionic Liquids for Transdermal Drug Delivery

Abstract

The transdermal delivery of hydrophilic drugs remains challenging owing to their poor ability to permeate the skin; formulation with oil media is difficult without adding chemical permeation enhancers or co-solvents. Herein, we synthesized 12 oil-miscible ionic liquid (IL) drugs comprising lidocaine-, imipramine-, and levamisole (Lev)-hydrochloride with fatty acid permeation enhancers, i.e., laurate, oleate, linoleate, and stearate as counterions. A set of in vitro and in vivo studies was performed to investigate the potency and deliverability of the transdermal drug formulations. All of the synthesized compounds were freely miscible with pharmaceutically acceptable solvents/agents (i.e., ethanol, N-methyl pyrrolidone, Tween 20, and isopropyl myristate (IPM)). In vitro permeation studies revealed that the oleate-based Lev formulation had 2.6-fold higher skin permeation capability than the Lev salts and also superior ability compared with the laurate-, linoleate-, and stearate-containing samples. Upon in vivo transdermal administration to mice, the peak plasma concentration, elimination half-life, and area under the plasma concentration curve values of Lev-IL were 4.6-, 2.9-, and 5.4-fold higher, respectively, than those of the Lev salt. Furthermore, in vitro skin irritation and in vivo histological studies have demonstrated that Lev-IL has excellent biocompatibility compared with a conventional ionic liquid-based carrier. The results indicate that oil-miscible IL-based drugs provide a simple and scalable strategy for the design of effective transdermal drug delivery systems.

Pharmaceutical Applications of Ionic Liquids: A Personal Account

“…The API‐ILs of lidocaine, imipramine, and levamisole were freely miscible with pharmaceutically acceptable solvents/agents, i. e., ethanol, N ‐methyl pyrrolidone, tween 20, and IPM, and showed improved in vivo bioavailability, compared with the parent drug [64] . The use of API‐ILs can also address the issues of crystallinity and polymorphism, which result in limited solubility, low drug efficiency, and formulation instability [60] .…”

“…We have successfully managed the polymorphism and bioavailability problems with crystalline drugs, including favipiravir, methotrexate, salicylic acid, ibuprofen, lidocaine, imipramine, and levamisole (Figure 5A). We have investigated the potential pharmaceutical benefits of ILs, which can remove or at least mitigate common issues with solid drugs [60,64] . In similar research, Abbott et al.…”

“…Fatty acids are potential IL‐forming biocompatible counterions that have been used to convert a series of hydrophilic drugs into ILs to promote skin permeability using a new delivery mode for the drugs. Recently, we have successfully transformed hydrophilic drugs into oil‐miscible IL drugs with fatty acid permeation enhancers, i. e., laurate, oleate, linoleate, and stearate ions, as counterions [64] . The results suggested that this method may be a practical and translatable transdermal drug delivery platform for hydrophilic drugs.…”

“…The oils and their constituents in topical formulations can penetrate the skin and enhance the penetration of different drugs into the lower skin layers. After application to the skin, oils and their components are rapidly metabolized and quickly excreted, rather than accumulating in the organism, which strongly suggests that they can be successfully used as safe penetration enhancers [34,39,64] . The topical delivery of acyclovir in an IL‐based delivery system was 151‐fold higher than in a water‐based system [27] .…”

Modification with Conventional Surfactants to Improve a Lipid-Based Ionic-Liquid-Associated Transcutaneous Anticancer Vaccine

“…These immunomodulators, which can activate APCs in the skin, are employed as adjuvants with antigens or antigenic proteins in vaccine formulations to enhance the immune response [ 19 , 20 , 21 ]. Among them, IMQ is an excellent immunostimulatory adjuvant that has been used in various immunotherapies, but IMQ-based formulations are challenging to use for transdermal drug delivery because of their limited solubility and low permeability [ 4 , 22 , 23 , 24 , 25 ]. LBIL-associated formulations might represent a promising TDDS approach to overcome these challenges through the generation of nanocarriers in isopropyl myristate (IPM) in the oil phase.…”