Self-assembling organogelators for artificial stratum corneum models: key-role parameters in skin permeation prediction

The development of in vitro methods to predict in vivo percutaneous absorption of bioactive molecules is a challenge to which the researchers are called in order to eliminate or reduce the pharmacological and toxicological tests on animal models. Artificial stratum corneum (SC) models obtained by self-assembled oganogelators were designed for skin permeation assessment of butyl methoxydibenzoylmethane (BMDBM, log Po/w = 4.68) and methylene blue (MB, log Po/w = 0.91). A multi-analytical approach was adopted to provide detailed understanding about the gelator organization within the models and find possible parameters playing a key-role in in vivo and ex vivo SC permeation prediction. The evaluation of in vitro skin permeation data compared with those obtained ex vivo and previously in vivo on humans for BMDBM showed good correlations vitro/ex vivo and vitro/vivo for both butyl BMDBM, as the lipophilic permeant, and MB, as the hydrophilic permeant, by using TS20 as well as both STS and ME models. With the aim of providing detailed understanding about the organogelator behaviour and organization within the models and find possible parameters playing a key-role in SC permeation prediction a multi-analytical approach was adopted. All the models did not flow upon tube tilting and could be described as gels, with the exception of STS10 model that appeared as thick liquid being gelator concentration lower than mgc value. Unlike SA and TS models that exhibited networks capable of immobilizing completely the solvent, STS and ME10 models revealed the syneresis phenomenon according to gelator concentration. The actual presence of water within STS aggregates (reverse micelles) of ME models was demonstrated by means of TG/DTA analysis showing two thermal events in the range of about 50-130°C related to removal of water molecules. Unlike the pure gelators, XRPD profiles from all the SC models exhibited a broad peak at about 20° 2θ indicating the presence of a networked structure of the gelators where the width of the peak at half maximum is dependent on the crystallinity of the sample, which in turn is dependent on non-covalent interactions amongst the gelator molecules responsible for the formation of an ordered structure. Intermolecular interactions also arisen from FT-IR spectra showing subsided ester group stretching in TS, STS, and ME models. Architectural arrangements of the organogelators within TS, STS, and ME models, as outlined by microscopy analyses, involved round or worm-like architectures of spherulitic clusters. Under polarized light, the occurrence of birefringence revealed the so-called “maltese crosses” in STS models that are characteristic of liquid crystals with lamellar structures. The results demonstrated the relevant role of both the arrangement of gelator packing and crystallinity extent in mimicking SC in vivo/ex vivo skin permeation of both lipophilic and hydrophilic compounds. These findings could account for the behaviour and development of other artificial skin models involving different materials for the skin permeation prediction.