Solubility-Permeability-Matrix Interplay in Percutaneous Absorption Exemplified by Theophylline

The stratum corneum represents the main barrier to transdermal drug delivery, particularly for hydrophilic and ionized compounds such as aminophylline. In this study, the solubility-permeability-matrix interplay was investigated using aminophylline and theophylline as model drugs in various matrix-type transdermal patches based on either hydroxypropyl methylcellulose (HPMC) or silicone-based Bio-PSA (Biomedical Pressure-Sensitive Adhesive). Franz diffusion cells with porcine ear skin were used to evaluate in vitro skin permeation, and complementary release studies were conducted using dialysis membranes. Aminophylline exhibited significantly higher transdermal flux than theophylline in both matrix systems, despite its increased hydrophilicity and ionization. This effect is attributed to its capacity to maintain high thermodynamic activity when formulated as a suspension, thereby intensifying chemical potential gradients and supporting aqueous pathway permeation. Penetration enhancers showed distinct mechanisms of action. Geraniol, a lipophilic terpene alcohol, significantly increased skin permeation by disrupting stratum corneum lipid lamellae and facilitating transient hydrophilic channels. In contrast, Transcutol P acted primarily by increasing drug solubility within the matrix and forming a reservoir in the stratum corneum. However, its enhancing effect remained modest due to limited interaction with the barrier and slow release from the silicone matrix. These findings highlight the critical role of drug solubility and enhancer molecular properties in the transdermal delivery of hydrophilic drugs. In addition, matrix parameters like thickness, hydration and release properties need to be properly engineered for making optimal use of the involved solubility-permeability interplay.