Objective This study aimed to establish an evaluation system for screening transdermal penetration enhancers suitable for traditional Chinese medicine (TCM) compound formulations and to apply it to the optimization of a composite penetration enhancer for Erxian Decoction (EXD, 二仙汤). Methods Menthol, azone, and borneol were selected as penetration enhancers, and an L₉(3³) orthogonal design was employed. The 48 h cumulative permeation per unit area (Q₄₈), steady-state flux (J_ss), and enhancement ratio (ER) of ten marker components (phellodendrine, mangiferin, ferulic acid, berberine, curculigine, epimedin A1, epimedin A, epimedin B, epimedin C, icariin) were measured. Principal component analysis (PCA) was performed separately for Q₄₈ and J_ss datasets to reduce dimensionality, while fingerprint similarity (S) was incorporated as a quality constraint. The PCA scores and S were weighted and integrated via the satisfaction function to calculate the comprehensive satisfaction (D). With D as the response value, range analysis and analysis of variance were performed to screen the optimal formulation of penetration enhancers. Results The optimal compound penetration enhancer formulation was identified as 2% menthol combined with 1% azone. Validation studies showed that this formulation exhibited excellent penetration-enhancing effect, while the fingerprint similarity S remained above 0.9, achieving both “high-efficiency penetration enhancement” and “quality fidelity”. Conclusion The constructed “PCA dimension reduction-fingerprint constraint-satisfaction function integration” system can effectively solve the problems of information redundancy and decision contradiction in multi-index optimization, providing a referable research paradigm for screening composite penetration enhancers of TCM compound prescriptions.

Erxian Decoction  /  penetration enhancer  /  principal component analysis  /  fingerprint similarity  /  desirability function  /  in vitro transdermal permeation  /  phellodendrine  /  mangiferin  /  ferulic acid  /  berberine  /  curculigoside  /  epimedin A1  /  epimedin A  /  epimedin B  /  epimedin C  /  icariin  /  menthol  /  azone  /  borneol