Dataset Information

Skin Permeation Enhancement in Aqueous Solution: Correlation With Equilibrium Enhancer Concentration and Octanol/Water Partition Coefficient.

ABSTRACT: The effectiveness of skin penetration enhancers and the enhancer concentration required for effective skin permeation enhancement are difficult to predict. A comprehensive quantitative structure-enhancement relationship of chemical penetration enhancers for skin permeation is not currently available. The present study (a) investigated the relationship between skin permeation enhancement and chemical enhancer concentration and (b) examined a simple quantitative structure-enhancement relationship for predicting skin permeation enhancement to guide enhancer formulation development. In the present analysis, data from previous skin permeation studies that used the symmetric/equilibrium configuration and skin parallel pathway model were summarized to determine the relationship between enhancement factor and enhancer concentration. Under the equilibrium conditions, semilogarithmic linear relationships between enhancement factor (E) and enhancer aqueous concentration (C) were observed and an enhancer potency parameter (?) was defined. A correlation between the potency parameter ? and enhancer octanol/water partition coefficient (Koct) was obtained. The enhancement factor relationship was derived: Log E = 0.32 ? C ? Koct. The results suggest that a "threshold" of (C ? Koct) > 0.5 M is required to induce effective skin permeation enhancement under these conditions. Consistent with the analyses in previous studies, the data suggest that octanol represents the skin barrier microenvironment for the penetration enhancers.

SUBMITTER: Li SK

PROVIDER: S-EPMC6492937 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Skin Permeation Enhancement in Aqueous Solution: Correlation With Equilibrium Enhancer Concentration and Octanol/Water Partition Coefficient.

Li S Kevin SK Chantasart Doungdaw D

Journal of pharmaceutical sciences 20180827 1

The effectiveness of skin penetration enhancers and the enhancer concentration required for effective skin permeation enhancement are difficult to predict. A comprehensive quantitative structure-enhancement relationship of chemical penetration enhancers for skin permeation is not currently available. The present study (a) investigated the relationship between skin permeation enhancement and chemical enhancer concentration and (b) examined a simple quantitative structure-enhancement relationship ...[more]

PMID: 30165068

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Project description:The SAMPL Challenges aim to focus the biomolecular and physical modeling community on issues that limit the accuracy of predictive modeling of protein-ligand binding for rational drug design. In the SAMPL5 log D Challenge, designed to benchmark the accuracy of methods for predicting drug-like small molecule transfer free energies from aqueous to nonpolar phases, participants found it difficult to make accurate predictions due to the complexity of protonation state issues. In the SAMPL6 log P Challenge, we asked participants to make blind predictions of the octanol-water partition coefficients of neutral species of 11 compounds and assessed how well these methods performed absent the complication of protonation state effects. This challenge builds on the SAMPL6 p[Formula: see text] Challenge, which asked participants to predict p[Formula: see text] values of a superset of the compounds considered in this log P challenge. Blind prediction sets of 91 prediction methods were collected from 27 research groups, spanning a variety of quantum mechanics (QM) or molecular mechanics (MM)-based physical methods, knowledge-based empirical methods, and mixed approaches. There was a 50% increase in the number of participating groups and a 20% increase in the number of submissions compared to the SAMPL5 log D Challenge. Overall, the accuracy of octanol-water log P predictions in SAMPL6 Challenge was higher than cyclohexane-water log D predictions in SAMPL5, likely because modeling only the neutral species was necessary for log P and several categories of method benefited from the vast amounts of experimental octanol-water log P data. There were many highly accurate methods: 10 diverse methods achieved RMSE less than 0.5 log P units. These included QM-based methods, empirical methods, and mixed methods with physical modeling supported with empirical corrections. A comparison of physical modeling methods showed that QM-based methods outperformed MM-based methods. The average RMSE of the most accurate five MM-based, QM-based, empirical, and mixed approach methods based on RMSE were 0.92 ± 0.13, 0.48 ± 0.06, 0.47 ± 0.05, and 0.50 ± 0.06, respectively.

Project description:BackgroundThe goal of physiologically based pharmacokinetics (PBPK) is to predict drug kinetics from an understanding of the organ/blood exchange. The standard approach is to assume that the organ is "flow limited" which means that the venous blood leaving the organ equilibrates with the well-stirred tissue compartment. Although this assumption is valid for most solutes, it has been shown to be incorrect for several very highly fat soluble compounds which appear to be "diffusion limited". This paper describes the physical basis of this adipose diffusion limitation and its quantitative dependence on the blood/water (Kbld-wat) and octanol/water (Kow) partition coefficient.MethodsExperimental measurements of the time dependent rat blood and adipose concentration following either intravenous or oral input were used to estimate the "apparent" adipose perfusion rate (FA) assuming that the tissue is flow limited. It is shown that the ratio of FA to the anatomic perfusion rate (F) provides a measure of the diffusion limitation. A quantitative relationship between this diffusion limitation and Kbld-wat and Kow is derived. This analysis was applied to previously published data, including the Oberg et. al. measurements of the rat plasma and adipose tissue concentration following an oral dose of a mixture of 13 different polychlorinated biphenyls.ResultsSolutes become diffusion limited at values of log Kow greater than about 5.6, with the adipose-blood exchange rate reduced by a factor of about 30 for a solute with a log Kow of 7.36. Quantitatively, a plot of FA/F versus Kow is well described assuming an adipose permeability-surface area product (PS) of 750/min. This PS corresponds to a 0.14 micron aqueous layer separating the well-stirred blood from the adipose lipid. This is approximately equal to the thickness of the rat adipose capillary endothelium.ConclusionsThese results can be used to quantitate the adipose-blood diffusion limitation as a function of Kow. This is especially important for the highly fat soluble persistent organic chemicals (e.g. polychlorinated biphenyls, dioxins) whose pharmacokinetics are primarily determined by the adipose-blood exchange kinetics.

Dataset Information

Skin Permeation Enhancement in Aqueous Solution: Correlation With Equilibrium Enhancer Concentration and Octanol/Water Partition Coefficient.

Publications

Skin Permeation Enhancement in Aqueous Solution: Correlation With Equilibrium Enhancer Concentration and Octanol/Water Partition Coefficient.

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