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Updated: Mar 24, 2026

Development, Characterization, and Evaluation of CAGE-based Ionic Liquid Systems for Transdermal Delivery
Published on: September 26, 2025
The molecular assembly of the ionic liquid/aliphatic carboxylic acid/aliphatic amine as effective and safety
Koji Kubota1, Akira Shibata1, Toshikazu Yamaguchi2
1Laboratory of Physical Chemistry, Department of Pharmacy, Faculty of Pharmacy, Yasuda Women's University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima-shi, Hiroshima 731-0153, Japan.
Abstract:
In spite of numerous advantages, transdermal drug delivery systems are unfeasible for most drugs because of the barrier effect of the stratum corneum. Ionic liquids were recently used to enhance transdermal drug delivery by improving drug solubility. In the present study, safe and effective ionic liquids for transdermal absorption were obtained as salts generated by a neutralization reaction between highly biocompatible aliphatic carboxylic acids (octanoic acid or isostearic acid) and aliphatic amines (diisopropanolamine or triisopropanolamine) (Medrx Co., Ltd., 2009). The mechanism of skin permeability enhancement by ionic liquids was investigated by hydrophilic phenol red and hydrophobic tulobuterol. Further, the skin permeation enhancing effect was remarkably superior in the acid excess state rather than the neutralization state. Infrared absorption spectrum analysis confirmed that ionic liquids/aliphatic carboxylic acid/aliphatic amine are coexisting at all mixing states. In the acid excess state, ionic liquids interact with aliphatic carboxylic acids via hydrogen bonds. Thus, the skin permeation enhancing effect is not caused by the ionic liquid alone. The "liquid salt mixture," referred to as a complex of ingredients coexisting with ionic liquids, forms a molecular assembly incorporating hydrophilic drug. This molecular assembly was considered an effective and safety enhancer of transdermal drug permeation.
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