In vitro skin model for characterization of sunscreen substantivity upon perspiration.

OBJECTIVE: The resistance of sunscreens to the loss of ultraviolet (UV) protection upon perspiration is important for their practical efficacy. However, this topic is largely overlooked in evaluations of sunscreen substantivity due to the relatively few well-established protocols compared to those for water resistance and mechanical wear. METHODS: In an attempt to achieve a better fundamental understanding of sunscreen behaviour in response to sweat exposure, we have developed a perspiring skin simulator, containing a substrate surface that mimics sweating human skin. Using this perspiring skin simulator, we evaluated sunscreen performance upon perspiration by in vitro sun protection factor (SPF) measurements, optical microscopy, ultraviolet (UV) reflectance imaging and coherent anti-Stokes Raman scattering (CARS) microscopy. RESULTS AND CONCLUSION: Results indicated that perspiration reduced sunscreen efficiency through two mechanisms, namely sunscreen wash-off (impairing the film thickness) and sunscreen redistribution (impairing the film uniformity). Further, we investigated how the sweat rate affected these mechanisms and how sunscreen application dose influenced UV protection upon perspiration. As expected, higher sweat rates led to a large loss of UV protection, while a larger application dose led to larger amounts of sunscreen being washed-off and redistributed but also provided higher UV protection before and after sweating.

OBJECTIF: La résistance des écrans solaires à la perte de protection contre les ultraviolets (UV) à cause de la transpiration est importante quant à leur efficacité pratique. Cependant, ce point est généralement négligé dans les évaluations de la substantivité des écrans solaires en raison du nombre relativement faible de protocoles bien établis, en comparaison avec ceux pour la résistance à l'eau et l'usure mécanique. MÉTHODES: Dans le but de parvenir à une meilleure compréhension fondamentale du comportement des écrans solaires en cas d'exposition à la sueur, nous avons développé un simulateur de peau transpirante, dont la surface de substrat imite la transpiration de la peau humaine. À l'aide de ce simulateur, nous avons évalué les performances des écrans solaires lors de la transpiration par des mesures in vitro du facteur de protection solaire (FPS), par microscopie optique, par imagerie de la réflectance ultraviolette (UV) et par microscopie cohérente de diffusion Raman anti-Stokes (coherent anti-Stokes Raman scattering, CARS). RÉSULTATS ET CONCLUSION: Les résultats ont montré que la transpiration réduisait l'efficacité de l'écran solaire en raison de deux mécanismes, à savoir le lavage de l'écran solaire (altération de l'épaisseur du film) et la redistribution de l'écran solaire (altération de l'uniformité du film). De plus, nous avons étudié comment le taux de transpiration affectait ces mécanismes et comment la dose d'application d'écran solaire influençait la protection UV en cas de transpiration. Comme l'on pouvait s'y attendre, des taux de sueur plus élevés ont entraîné une perte importante de protection contre les UV, tandis qu'une dose d'application plus importante a conduit à des quantités plus importantes d'écran solaire lavé et redistribué, mais a également fourni une protection contre les UV plus élevée avant et après la transpiration.

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

Combination of MALDI-MSI and cassette dosing for evaluation of drug distribution in human skin explant.

Study of skin penetration and distribution of the drug compounds in the skin is a major challenge in the development of topical drug products for treatment of skin diseases. It is crucial to have fast and efficacious screening methods which can provide information concerning the skin penetration and the distribution of the drug molecules in the region of the target. Mass spectrometry imaging (MSI) such as matrix-assisted laser desorption/ionization (MALDI)-MSI offers the opportunity to analyze the drug distribution at micrometer scale, but is a low throughput technique. Cassette dosing of drug molecules has been widely used for two decades as a high throughput screening tool for plasma pharmacokinetic analysis. The purpose of this study is to evaluate the utility of combining MALDI-MSI with cassette dosing to obtain a medium throughput screening technique for drug distribution in the skin directly from thin tissue sections. Excised fresh human skin was treated with two different formulation types containing both single drugs and a cassette with four drugs. Biopsies were taken and analyzed with traditional UHPLC-MS/MS and MALDI-MSI. The results reveal that skin penetration data of the four drugs administered together were in agreement with skin penetration data obtained when the molecules were administered individually. Furthermore, the MALDI-MSI data reveal different distribution profiles of the four drugs which were not possible to deduce from the UHPLC-MS/MS bioanalysis. These findings suggest that combination of MALDI-MSI and cassette dosing can be used as a medium throughput screening tool at an early stage in the drug discovery/development process. Graphical abstract Investigation of drug distribution in human skin explant by MALDI-MSI after cassette dosing.

Design of cyclic RKKH peptide-conjugated PEG liposomes targeting the integrin α2ß1 receptor.

Peptide conjugation to the surface of stealth liposomes has been studied for liposomal drug targeting to cells expressing specific receptors to provide a site-specific drug delivery. This study investigated the potential of peptide-conjugated liposomes for targeting cells expressing the human integrin α(2)ß(1) receptor. A 12 amino acid head-to-tail cyclic peptide derived from the Jararhagin protein containing the Arg-Lys-Lys-His (RKKH)-specific binding site was conjugated to the distal ends of poly(ethylene glycol) (PEG) chains on PEGylated liposomes. Epithelial cells expressing the receptor showed increased cellular association and uptake of peptide-conjugated liposomes at 4 °C, compared to liposomes conjugated with a non-specific peptide. The interaction between cells and peptide-conjugated liposomes was significantly increased at 37 °C suggesting that a possible uptake mechanism might be energy-dependent endocytosis. In keratinocyte cell cultures, the ligand-conjugated liposomes loaded with the vitamin D(3) analogue calcipotriol induced transcription of the gene encoding the antimicrobial peptide cathelicidin, which is activated through the vitamin D(3) receptor upon binding of vitamin D(3) analogues. This suggests that the liposomes are internalized and that calcipotriol is delivered intracellularly and released in an active form. In conclusion, the 12 amino acid head-to-tail cyclic RKKH peptide seems promising for targeting of liposomes to the integrin α(2)ß(1) receptor.