Influence of water content on the structure and performance of CAGE for cutaneous drug delivery

Cutaneous drug delivery provides a painless route of drug administration while avoiding first-pass metabolism and many side effects as the drug can be delivered locally rather than entering the systemic circulation. However, overcoming the skin’s outermost barrier, the stratum corneum (SC), remains a significant challenge [1]. To enhance skin permeability, ionic liquids (ILs) have emerged as promising carriers for the cutaneous delivery of active pharmaceutical ingredients (APIs) due to their tunable physicochemical properties and their ability to solubilize hydrophobic compounds while effectively interacting with the SC. This study investigates the potential of the biocompatible ionic liquid choline geranate (CAGE) at a 1:2 choline-to-geranic acid molar ratio in transdermal drug delivery systems (TDDS), focusing on the relationship between its biophysical characteristics and interactions with the skin barrier. The application of CAGE, as a solvent, on the skin may alter the molecular organization of skin lipids and proteins, affecting properties such as flexibility, softness and permeability, which are closely linked to the skin’s protective function [2]. This phenomenon depends on both the skin’s hydration level and on the solvent’s properties. Therefore, this work specifically investigates how water influences the physicochemical properties and structural stability of CAGE and how this, in turn, impacts skin permeability. CAGE formulations were prepared at a 1:2 choline-to-geranic acid molar ratio with varying water contents (0, 7, 12, 17, 33, 45, 55, 67 vol% water in CAGE). Rheological measurements were performed to assess how hydration affects CAGE’s flow behaviour and viscoelastic properties, while differential scanning calorimetry (DSC) and optical microscopy were used to analyse its thermal behaviour and microstructure. The same analyses were carried out using two model drugs – Lidocaine and Baricitinib – with different physicochemical characteristics, to observe how their presence influences the formulation’s properties. In vitro permeation studies were conducted using Franz diffusion cells to evaluate the system’s functional performance. Increasing the water content from neat CAGE to 67 vol% water resulted in marked changes in the material’s physicochemical properties. Specifically, at 17 and 33 vol % water in CAGE, both viscosity and G’ modulus increased, indicating a transition toward a more structured and elastic system. Furthermore, the permeability data suggested that water content in CAGE affects both drug permeation and retention in porcine skin. Overall, this study provides insight into the role of water in modulating the properties of CAGE-based ionic liquids, contributing to the rational design and development of next-generation transdermal drug delivery systems.