Hydroxypropyl-β-Cyclodextrin-Enhanced Azelaic Acid Hydrogel for Acne Treatment: Evaluation of Antimicrobial, Anti-inflammatory, and Skin Penetration Properties

Abstract

Purpose

Azelaic acid (AZE) is a widely used agent in acne treatment, but its poor water solubility limits its therapeutic potential. In this study, the effectiveness of azelaic acid (AZE)—a compound with limited therapeutic efficacy due to its poor water solubility—was investigated in HPMC-based hydrogel formulations, in which solubility was enhanced through complexation with hydroxypropyl-β-cyclodextrin (HβCD).

Methods

The developed AZE-HβCD hydrogel (F1) was evaluated in comparison with a conventional AZE hydrogel (G1) and a commercial cream formulation. In vitro antiacne activity was tested by the disk diffusion method. COX-1 and COX-2 enzyme inhibition and quantification of TNF-α levels were determined to evaluate the anti-inflammatory effectiveness. On the other hand, cytotoxicity, irritation, ex vivo penetration, and short-term stability studies were carried out.

Results

The F1 formulation exhibited significant antimicrobial activity, particularly against Cutibacterium acnes and Staphylococcus aureus compared to the control groups (at least p < 0.01). The In vitro COX-2 inhibition rate and the 4.7-fold reduction in TNF-α levels in LPS-stimulated RAW 264.7 macrophages demonstrated the notable anti-inflammatory properties of F1. Cytotoxicity assays revealed that F1 was highly biocompatible in both human keratinocyte (HaCaT) and HEK293 cells. In ex vivo studies using Franz diffusion cells, F1 showed significantly higher AZE accumulation and skin penetration compared to the commercial product (p < 0.05).

Conclusion

These findings suggest that HPMC-based hydrogel formulations containing AZE-HβCD may serve as promising alternatives for acne treatment by enhancing anti-inflammatory and antimicrobial efficacy as well as skin penetration.

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Materials

Hydroxypropyl methylcellulose K4M (HPMC, medium molecular weight) was donated by Colorcon (Germany). AZE and HβCD were purchased from Acros Organics (USA) and Shandong Binzhou Zhiyuan Biotechnology (China), respectively. Phosphoric acid was purchased from Isolab (Germany). Potassium phosphate monobasic was purchased from Merck (USA). pH 7.4 buffer tablet, MTT salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and benzalkonium chloride were purchased from Sigma (USA). Cell culture reagents were obtained from Gibco (UK). Antimicrobial activity reagents were obtained from Merck (USA). COX-1/COX-2 enzyme assay kit was obtained from Cayman Chemical (USA). The TNF-α assay kit was purchased from Elabscience (USA).

Arpa, M.D., Biltekin Kaleli, S. & Doğan, N. Hydroxypropyl-β-Cyclodextrin-Enhanced Azelaic Acid Hydrogel for Acne Treatment: Evaluation of Antimicrobial, Anti-inflammatory, and Skin Penetration Properties. J Pharm Innov 20, 106 (2025). https://doi.org/10.1007/s12247-025-10020-9