Target-Site Penetration of Active Ingredients in Human Skin

Abstract

The skin is a major physical and immunological barrier to the environment, and thus, percutaneous delivery of drugs or active pharmaceutical molecules (APIs) faces a unique set of hurdles. The efficacy of these active ingredients is governed by their release into the underlying tissue, especially when administered topically. However, the factors driving penetration in dermal and transdermal delivery systems remain poorly understood, and robust methods, models, and controls are important to bridge this gap in knowledge. The aim of this study is to understand what influences skin penetration and to identify reliable human skin surrogates for in vitro and ex vivo testing. The lipophilic characteristics of active ingredients determine its penetration, and thus play an important role in enabling access to the target-site. Thus, in addition to vertical penetration, the skin allows a lateral diffusion of active molecules and maintains an intra-donor equilibrium within the stratum corneum, viable epidermis, and dermis. To test this effect, three surrogate systems have been used, the in vitro artificial Strat-M® membrane, ex vivo porcine split-skin, and human split-skin. The reproducibility and validity of these models was tested using hydrophilic caffeine and lipophilic LIP1 as model drugs, which have similar molecular weights, in various formulations. The uptake kinetics were monitored and quantified using a Franz Diffusion Cell and microdialysis, followed by high-performance liquid chromatography to qualify and quantify the active ingredient. Appropriate surrogate models were identified and the conditions required to perform penetration experiments that are most reflective of in vivo conditions were optimized. The findings show that the potential barrier and reservoir function of the different skin layers, donor-specific intra-skin equilibrium with inter-skin difference, and lateral diffusion are significant contributors to the overall penetration ability. The penetration models developed and described herewith help to understand the conditions necessary for the penetration of molecules of interest and standardize the model to be chosen for a specific analytical case. This could in turn lower the attrition rate of active compounds in in vivo trials.