Azelaic acid-integrated therapeutic deep eutectic systems: overcoming solubility and permeability barriers for enhanced transdermal drug delivery.

Azelaic acid (AzA) is a saturated dicarboxylic acid used to treat skin disorders like acne, rosacea, and melasma. However, its transdermal application is limited by its poor water solubility and permeability. In this study, therapeutic deep eutectic systems (THEDES) are synthesized by combining azelaic acid (AzA) and D-panthenol (DP) in various molar ratios (3 : 1, 2 : 1, 1 : 1, 1 : 2, 1 : 3). The optimal molar ratio of the THEDES (AzA : DP = 1 : 2) is analyzed with molecular simulation calculations, polarized optical microscopy (POM), Fourier Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (1H NMR), Thermogravimetric Analysis (TGA), and water solubility and stability tests. In addition, the THEDES system is evaluated for toxicity, antibacterial and anti-inflammatory efficacy, and transdermal properties. The results show that it outperforms AzA raw material by demonstrating good water solubility and permeability, lower transdermal toxicity and skin irritation, and improved bioactivity compared to AzA raw material. Furthermore, its antimicrobial, anti-inflammatory, and transdermal properties are also superior to those of the AzA raw material. Using molecular docking analysis and molecular dynamics simulation, its mechanisms of action in the treatment of acne and skin permeation are investigated. In conclusion, AzA-DP THEDES effectively resolves AzA's solubility and permeability issues while enhancing its efficacy in Transdermal Drug Delivery Systems (TDDS).