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In this work, we developed a number of generalised skin diffusion based pharmacokinetic models to relate published in vivo urinary excretion data to matching experimentally generated in vitro human skin permeation test (IVPT) data for a series of topically applied salicylate esters. A simplified linear in vivo model was found to inadequately describe the time course of urinary excretion over the entire sampling period. We represented the skin barrier as both a one layer (stratum corneum) and a two-layer (stratum corneum with viable epidermis) diffusion model and convoluted their Laplace solutions with that for a single exponential disposition phase to describe the urinary excretion profiles in the Laplace domain. We also derived asymptotic approximations for the model and estimated the conditions under which they could be used. We then sought to develop in vitro - in vivo relationships (IVIVR) for topically applied methyl, ethyl and glycol salicylates using our experimental IVPT data and the literature urinary excretion data. Good linear IVIVRs for ethyl and glycol salicylates were obtained, but the IVIVR for methyl salicylate was poor, perhaps because of topical stimulation of local skin blood flow by methyl salicylate. The ratio of the hydrated to dehydrated skin permeation for all salicylate esters was the same in both the IVPT and in vivo studies. A diffusion based one compartment pharmacokinetic model was also developed to describe the urinary excretion of solutes after removal of topical products and to compare the methyl salicylate skin permeation for five different body sites. The work presented here is consistent with the development of skin IVIVRs, but suggests that different skin conditions, application sites and local skin effects may affect model predictions., Competing Interests: Declaration of interest The authors have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

The primary objective of this study is to introduce a simple and flexible mathematical approach which models transport processes in skin using compartments. The main feature of the presented approach is that the rate constants for exchange between compartments are derived from physiologically relevant diffusional transport parameters. This allows for better physical interpretation of the rate constants, and limits the number of parameters for the compartmental model. The resulting compartmental solution is in good agreement with previously published solutions for the diffusion model of skin when ten or more compartments are used. It was found that the new compartmental model with three compartments provided a better fit of the previously publish water penetration data than the diffusion model. Two special cases for which it is difficult to implement the diffusion model were considered using our compartmental approach. In both cases the compartmental model predictions agreed well with the diffusion model., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The mathematical model describing drug flux through microporated skin was previously developed. Based on this model, two mathematical equations can be used to predict the microporatio-enhanced transdermal drug flux: the complex primal equation containing a variety of experimentally-determined variables, and the simplified straightforward equation. In this study, experimental transdermal fluxes of three corticosteroids through split-thickness human skin treated with a microneedle roller were measured, and the values of fluxes compared with those predicted using both the more complex and simplified equations. According to the results of the study, both equations demonstrated high accuracy in the prediction of the fluxes of corticosteroids. The simplified equation was validated and confirmed as robust using regression analysis of literature data. Further, its capability and ease of use was exemplified by predicting the flux of methotrexate through the skin microporated with laser and comparing with published experimental data., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Public health concerns continue to exist over the safety of zinc oxide nanoparticles that are commonly used in sunscreen formulations. In this work, we assessed the effects of two conditions which may be encountered in everyday sunscreen use, occlusion and a compromised skin barrier, on the penetration and local toxicity of two topically applied zinc oxide nanoparticle products. Caprylic/capric triglyceride (CCT) suspensions of commercially used zinc oxide nanoparticles, either uncoated or with a silane coating, were applied to intact and barrier impaired skin of volunteers, without and with occlusion for a period of six hours. The exposure time was chosen to simulate normal in-use conditions. Multiphoton tomography with fluorescence lifetime imaging was used to noninvasively assess zinc oxide penetration and cellular metabolic changes that could be indicative of toxicity. We found that zinc oxide nanoparticles did not penetrate into the viable epidermis of intact or barrier impaired skin of volunteers, without or with occlusion. We also observed no apparent toxicity in the viable epidermis below the application sites. These findings were validated by ex vivo human skin studies in which zinc penetration was assessed by multiphoton tomography with fluorescence lifetime imaging as well as Zinpyr-1 staining and toxicity was assessed by MTS assays in zinc oxide treated skin cryosections. In conclusion, applications of zinc oxide nanoparticles under occlusive in-use conditions to volunteers are not associated with any measurable zinc oxide penetration into, or local toxicity in the viable epidermis below the application site., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The use of nanoparticulate zinc oxide (ZnO-NP) in sunscreens and other cosmetic products has raised public health concerns. The two key issues are the extent of exposure to ZnO-NP and the likely hazard after the application of ZnO-NP in sunscreen and cosmetic products to humans in vivo. Our aims were to assess exposure by the extent of ZnO-NP penetration into the viable epidermis and hazard by changes in the viable epidermal redox state for a number of topical products. Of particular interest is the role of the particle coating, formulation used, and the presence of any enhancers. Multiphoton tomography with fluorescence lifetime imaging microscopy (MPT-FLIM) was used to simultaneously observe ZnO-NP penetration and potential metabolic changes within the viable epidermis of human volunteers after topical application of various ZnO-NP products. Coated and uncoated ZnO-NP remained in the superficial layers of the SC and in the skin furrows. We observed limited penetration of coated ZnO-NP dispersed in a water-in-oil emulsion formulation, which was predominantly localized adjacent to the skin furrow. However, the presence of ZnO-NP in the viable epidermis did not alter the metabolic state or morphology of the cells. In summary, our data suggest that some limited penetration of coated and uncoated ZnO-NP may occur into viable stratum granulosum epidermis adjacent to furrows, but that the extent is not sufficient to affect the redox state of those viable cells., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

A simple and rapid high performance liquid chromatographic method was developed, validated and applied for the simultaneous determination of marbofloxacin (MBX) and trovafloxacin (TVX) in sheep plasma. Samples were extracted with 20% perchloric acid and MBX and TVX were separated on a C(18) column using a gradient mobile phase system consisting of 17.5mM of NaH(2)PO(4) and 1.5mM of tetrabutylammonium hydroxide aqueous solution, pH 3 (A) and 50% acetonitrile and 50% methanol (B), with UV detection at 293 and 270 nm. The retention times of MBX and TVX were 4.9 and 6.6 min respectively. The detection and quantification limits for MBX and TVX were 2 ng/mL and 10 ng/mL respectively for both compounds. The calibration curves were linear over a concentration range of 10-50,000 ng/mL for both antibiotics. The linearity, precision, accuracy, recovery and stability of the assay were evaluated from spiked sheep plasma. The method was successfully applied to sheep plasma samples obtained from MBX and TVX pharmacokinetic studies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

New multiphoton and confocal microscope technologies and fluorescence lifetime imaging techniques are now being used to non-invasively image, in space (three dimensions),in time, in spectra, in lifetime and in fluorescence anisotropy (total of 7 dimensions), fluorescent molecules in in situ and in vivo biological tissue, including skin. The process involves scanning a 2D area and measuring fluorescence at a given tissue depth below the surface after excitation by a laser beam with a wavelength within the one-photon or two-photon absorption band of the fluorophores followed by the stacking together of a series of 2D images from different depths to reconstruct the full spatial structure of the sample. Our aim in this work is to describe the principles, opportunities, limitations and applications of this new technology and its application in defining skin morphology, disease and skin penetration in vitro and in vivo by drugs, chemicals and nanoparticles. A key emphasis is in the use of fluorescence lifetime imaging to add additional specificity and quantitation to the detection of the various exogenous chemicals and nanoparticles that may be applied to the skin as well as endogenous fluorescent species in the skin. Examples given include equipment configuration; components in skin autofluorescence in various skin strata; imaging and quantification of coexisting drugs and their metabolites; skin pH; nanoparticle zinc oxide skin penetration; liposome delivery of drugs to deeper tissues; and observations in skin ageing and in various skin diseases., (Copyright © 2011 Elsevier B.V. All rights reserved.)