Simultaneous determination of the skin penetration of drug and vehicle compounds

The aim of the current project is to analyse for the first time simultaneously the skin penetration of active drugs and passive components like fluorinated surfactants or lipids by 19F-NMR. For this purpose three categories of important formulations will be newly developed or optimised: liposomes based on fluorinated lipid, liquid crystals and microemulsions including fluorinated surfactants and semi solid preparations with fluorinated surfactants. After characterising the preparations by particle or droplet sizes, rheology and microstructure, the passive porcine skin diffusion of the active and passive component will be analysed and compared using the tape stripping technique as well as the FRANZ cell technique. ATR-FTIR investigations of the porcine skin samples after application of the systems will identify a possible skin conformation change. After all these in vitro investigations on porcine skin the best formulations will be investigated in vivo on healthy volonteers. Within these investigations also silmultaneously skin penetration profiles of actives and passives will be recorded.

The skin, our largest organ, is designed to prevent the intrusion of xenobiotic substances, which might be harmful to our organism. Thus, the delivery of drug into or even through the skin is a challenging task. For a long time, dermal and transdermal drug delivery was mainly associated with approved classical dosage forms such as cream bases, gels or ointments. During the last decades, these classical formulations have been extended by colloidal drug delivery systems, systems that consist of dispersed particles or droplets in the range of nanometers or micrometers. They include microemulsions, liposomes, nanocarriers and numerous semi-solid preparations. Despite decades of research, the exact mechanisms of skin penetration of different applied compounds are still not entirely clear. The main difficulty is that the way substances penetrate into the skin strongly depends on numerous variables, like their physical properties and the presence of penetration enhancers. The main goal of this project was to study the mechanisms of the simultaneous penetration of surfactant or other additives of applied formulations and their potential effect on the penetration of the co-applied drugs. Formulations involved during this project were microemulsions, liposomes and semi-solid double emulsions as well as water-in-oil emulsions and nanoemulsions. Due to the utilization of fluorinated vehicle compounds, it was possible to analyze them by 19F-NMR (19F nuclear magnetic resonance) spectroscopy simultaneously with the penetration of the active substance. Apart from the skin penetration enhancing effects of vehicles, also their influence on skin health plays an important role. Therefore, one part of this project was an in vivo study carried out to examine the effect of selected vehicles on the skin parameters sebum content, skin hydration and transepidermal water loss. The vehicles included a multiple W/O/W emulsion, liposomes and a microemulsion gel. This project demonstrates the parallel determination of the diffusion of a vehicle component and of a model drug. Due to simultaneous investigation of their penetration, correlations of their diffusion process could be derived. Permeation studies and tape stripping experiments indicated a push-effect on the skin penetration of the incorporated drug exerted by the used microemulsions and liposomes. Furthermore, a relationship of the microemulsion droplet structure and the penetration behavior of the incorporated active component was detected. Contrary, the semi-solid double emulsions showed no penetration enhancement effect induced by the employed perfluoropolyethers. Besides, skin studies showed an influence of the configuration of the oil phase on the in vitro release of a hydrophilic model drug incorporated in water-in-oil emulsions. A positive influence of appropriate vehicles on sebum content, skin hydration and TEWL could be demonstrated during the in vivo estimation. The multiple W/O/W emulsion as well as liposomes were identified to be well-tolerated vehicles for application on skin.