The effect of PEG derivatives as skin penetration enhancers on the permeability of NSAIDs contained in medicated plasters

This work aimed to investigate the penetration-enhancing effect of poly(ethylene glycol) (PEG) derivatives on the skin permeability of a selection of non steroidal anti-inflammatory drugs (NSAIDs) loaded in patches. Two different series of PEG derivative homologues were selected in order to elucidate the influence of the polar head volume and the carbon chain structure. In the former case, PEG stearates presenting differences only for the oxyethylene chain length were chosen. The latter series included PEG derivatives in the series of PEG 8 or PEG 12 differing in length of C-chain and number of ester functions. Several membranes were also used to assess permeability features of plasters: due to ethical concerns and availability of animal skin, hairless mouse skin (HMS) was selected as the preliminary experimental model, and the most relevant results were further verified in pig ear epidermis (PEE) and human models. By evaluating the skin permeability of aryl-propionic acids in plasters containing PEG-stearates, it emerged that the volume of the polar head group of the non-ionic surfactant had a deep impact in the enhancement effect. Surfactants with ethylene oxide chain of 8 or 12 appeared effective as skin penetration enhancers, while larger volume (ethylene oxide chain of 40) resulted ineffective in promoting the skin penetration. The influence of the hydrophobic portions was also investigated through PEG-derivatives containing saturated C12 (lauric) or unsaturated C18 (oleic) fatty acids due to their optimal chain length for skin permeability, and an ethylene oxide chain of 8 and 12. The influence of the length of C-chain and number of ester functions was not so clear. Since the enhancement effect was measured only in presence of a some of these non-ionic surfactants, it might be assumed that the combination of these two portions was not enough to obtain a significant increase of the flux of lipophilic drugs, such as ketoprofen (KPF). These results can be referred only to skin permeation experiment performed by using HMS, whose real usefulness is widely debated. Indeed the contradictory results obtained by using PEE underlined the inadequacy of HMS as membrane model. Even if PEE is considered the most appropriate experimental skin model, because of the similar histological and physiological characteristics to human skin, the results of in vitro human skin permeation study were almost completely overturned. Indeed, no PEG derivatives significantly enhanced fluxes of KPF with respect to the control. At a first glance, only the plaster containing 10% w/w PEG8-ML resulted suitable to improve the KPF flux. Nevertheless, these data were not confirmed by using skin form different donors in a more accurate evaluation, highlighting the need of using more than one donor in order to take into account the high human skin variability. In conclusion, the use of animal skins as a model, that can shorten and economize the process of drug development and minimize the number of human studies, has to be carefully evaluated.