Transdermal therapeutic systems (TTS) have numerous pharmacological benefits. Drug release, for example, is independent of whether a patient is in a fed or a fasted state, and lower doses can be given as gastrointestinal and hepatic first-pass metabolism is avoided. In addition, inter- and intrapatient variability is minimized as the release of the drug is mainly controlled by the system. This makes TTS interesting as alternative systems to the most common dosage form of oral tablets. The difficulty with the dermal administration route is transporting the drug through the skin, since the skin is an efficient barrier against foreign bodies. Various strategies have been reported in the literature of how drug penetration can be improved. Most of them, however, focus on overcoming the stratum corneum as the first (mechanical) skin barrier. However, penetration is much more complex, and the skin’s barrier function does not only depend on the stratum corneum; what has been underestimated is the second (biological) skin barrier formed of enzymes. Compared to the stratum corneum, very little is known about these enzymes, e.g., which enzymes are present in the skin and where exactly they are localized. Hence, very few strategies can be found for how to bypass or even use the skin enzyme barrier for TTS development. This review article provides an overview of the skin enzymes considered to be relevant for the biotransformation of dermally applied drugs. Also, we discuss the use of dermal prodrugs and soft drugs and give the stereoselectivity of skin metabolism careful consideration. Finally, we provide suggestions on how to make use of the current knowledge about skin enzymes for rational TTS design.

Rutin is a well-known antioxidant from the group of flavonoids. Its use in cosmetic dermal products is, however, limited due to its poor water solubility. In order to increase rutin saturation solubility and improve the diffusion to the skin, rutin nanocrystals were produced by the smartCrystal process, e.g., bead milling followed by high pressure homogenization. Rutin nanocrystals were further incorporated into hydroxypropyl cellulose (HPC) gel and its long-term stability was assessed. Determination of the antioxidant activity was made by the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay for these formulations: rutin nanocrystals (mean size 300 nm), rutin raw drug powder (mean size 33 µm) and commercial product. Furthermore, the skin penetration profile of rutin was investigated by the tape-stripping method on porcine skin. This study demonstrated that rutin nanocrystal gel had the highest neutralizing activity (90%), followed by a commercial product and rutin raw drug powder. According to the skin study, rutin nanocrystals penetrated to the deeper layers of the stratum corneum, the horny layer of the skin.

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