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The purpose of this study is to illustrate the non-equilibrium properties of drug permeation through stratum corneum (SC) to provide theory and method for transdermal drug delivery (TDD). The side-by-side permeation cell in vitro was supposed to be isolated system, thus conditions for equilibrium state were decided and a network thermodynamic model was established. We completed non-equilibrium experiment with which Tinidazole was pattern drug. Results show that the non-equilibrium properties include: (1) long term to reach equilibrium state; (2) delay-start of the permeation; and (3) uncertainty of initial drug permeable flux. Results also demonstrate the properties of leakage which include degression of drug permeable flux and changeability of permeation time constant. Hence, the permeation cell is believed to be a non-linear and time variable system.