Annette L. Bunge

A New Method for Estimating Dermal Absorption from Chemical Exposure. 1. General Approach

To evaluate systemic chemical exposure from dermal absorption, one must know the mass of chemical absorbed including the portion that has entered the skin but not yet entered the bodys interior system. Algebraic equations are presented for estimating dermal absorption including the effects of exposure time and chemical nature of the compound, in particular lipophilicity and molecular weight. The proposed equations account for larger absorption rates during the initial exposure period as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. These algebraic expressions are shown to represent adequately the exact solution of the unsteady-state diffusion equations for a two-membrane composite. Finally, procedures are proposed for estimating a priori the required physicochemical data when experimental values are not available. Specifically, the Potts and Guy permeability correlation is split into parts separately representing stratum corneum partitioning and diffusivity.

Mathematical models of skin permeability: An overview

Mathematical models of skin permeability play an important role in various fields including prediction of transdermal drug delivery and assessment of dermal exposure to industrial chemicals. Extensive research has been performed over the last several decades to yield predictions of skin permeability to various molecules. These efforts include the development of empirical approaches such as quantitative structure-permeability relationships and porous pathway theories as well as the establishment of rigorous structure-based models. In addition to establishing the necessary mathematical framework to describe these models, efforts have also been dedicated to determining the key parameters that are required to use these models. This article provides an overview of various modeling approaches with respect to their advantages, limitations and future prospects.

A New Method for Estimating Dermal Absorption from Chemical Exposure: 2. Effect of Molecular Weight and Octanol-Water Partitioning

A new method for estimating dermal absorption including the effects of exposure time and chemistry is described generally in Part 1 of this series. This method accounts for the larger absorption rates during the initial exposure period as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. A key parameter in this procedure, the ratio of the stratum corneum and epidermis permeabilities (B) depends on molecular weight and octanol-water partitioning. Several approaches for approximating B and its affect on the dermal absorption prediction are discussed here. Generally, the parameter B is only important for highly lipophilic chemicals which also have relatively small molecular weights. When B is important, the recommended prediction for B is based on the Potts and Guy correlation for human stratum corneum permeability.

Determining dermal absorption parameters in vivo from tape strip data

AbstractPurpose: Tape stripping the outermost skin layer, the stratum corneum (sc), is a popular method for assessing the rate and extent of dermal absorption in vivo. Results from tape strip (TS) experiments can be affected significantly by chemical diffusion into the sc during the time required to apply and remove all of the TSs, tTS. Here, we examine the effects of this problem on the interpretation of TS experimental results. Methods: Dermal absorption of 4-cyanophenol (4CP) in humans was studied using TS experiments to assess conditions in which diffusion alters TS results. Mathematical models were developed to assess the effects of diffusion on parameter estimation. Results: For an experiment with tTS > tlag (i.e., the lag time for a chemical to cross the sc), the permeability coefficient for 4CP, Psc,v, calculated including tTS, was consistent with values from the literature (i.e., 0.0019 cm/h). When diffusion during stripping was not included in the model, Psc,v was 70% smaller. Conclusions: Calculations show that chemical concentrations in TSs can be affected by diffusion during tape stripping, but if tTS < 0.2 tlag and the exposure time is > 0.3 tlag, TS concentrations are not significantly affected by tTS.

Quantitative structure-permeation relationships for solute transport across silicone membranes

AbstractPurpose. The purpose of this work was to assess the molecular properties that influence solute permeation across silicone membranes and to compare the results with transport across human skin. Methods. The permeability coefficients (log Kp) of a series of model solutes across silicone membranes were determined from the analysis of simple transport experiments using a pseudosteady-state mathematical model of the diffusion process. Subsequently, structure-permeation relationships were constructed and examined, focusing in particular on the difference between solute octanol/water and 1,2-dichloroethane/water partition coefficients (Δlog Poct-dce), which reported upon H-bond donor activity, and the computationally derived molecular hydrogen-bonding potential. Results. The hydrogen-bond donor acidity and the lipophilicity of the compounds examined greatly influenced their permeation across silicone membranes. Furthermore, for a limited dataset, a significant correlation was identified between solute permeation across silicone membranes and that through human epidermis. Conclusion. The key molecular properties that control solute permeation across silicone membranes have been identified. For the set of substituted phenols and other unrelated compounds examined here, a similar structure-permeation relationship has been derived for their transport through human epidermis, suggesting application of the results to the prediction of flux across biological barriers.

A diffusion model for reversible comsumption in emulsion liquid membranes

Abstract This work extends previous diffusion models for emulsion globules in which a solute reacts with an internal reagent. This model allows for reversible consumption of the solute by the internal reagent. Local concentration of the internal reagent is nonzero and satisfies reaction and phase equilibria within the reacted zone. Predicted solute absorption rates are lower for the reversible consumption model than for irreversible models.

Improved Bioequivalence Assessment of Topical Dermatological Drug Products Using Dermatopharmacokinetics

PurposeA dermatopharmacokinetic (DPK) approach, in which drug levels in the stratum corneum (SC) are measured as a function of time post-application and post-removal of the product using tape-strip sampling in vivo in humans, has been considered for the comparative assessment of topical bioavailability. Its application to-date has been limited by contradictory results and concerns that variability in the method necessitates large numbers of treatment sites and volunteers. The objective of this study was to test whether a revised protocol could better assess bioequivalence.MethodsA blinded study of three 1% econazole nitrate cream products, for which the SC is the site of action, was conducted to examine several modifications to the DPK methodology. In addition to protocol changes designed to reduce experimental variability, bioequivalence was assessed at a single uptake time and a single clearance time measured in duplicate in each subject.ResultsConclusive determinations of bioequivalence were achieved with only four treatment sites per product in each of 14 volunteers, which was less than one-third the number required in a previous DPK investigation.ConclusionsComparative bioequivalence can be assessed conclusively with fewer treatment sites in fewer subjects with robust methods that should be less sensitive to inter-laboratory differences.

Increased permeability for polyethylene glycols through skin compromised by sodium lauryl sulphate

Abstract:  In this in vivo human study we assessed the influence of skin damage by sodium lauryl sulphate (SLS) on percutaneous penetration of polyethylene glycols (PEGs) of different molecular weights (MW).

Does Epidermal Turnover Reduce Percutaneous Penetration

AbstractPurpose. After its removal from the skin surface, chemical remaining within the skin can become systemically available. The fraction of chemical in the skin that eventually enters the body depends on the relative rates of percutaneous transport and epidermal turnover (i.e., stratum corneum desquamation). Indeed, some investigators have claimed that desquamation is an efficient mechanism for eliminating dermally absorbed chemical from the skin. Methods. The fate of chemical within the skin following chemical contact was examined using a mathematical model representing turnover of and absorption into the stratum corneum and viable epidermis. The effects of turnover rate, exposure duration, penetrant lipophilicity, and lag time for chemical diffusion were explored. Results. These calculations show that significant amounts of chemical can be removed from skin by desquamation if epidermal turnover is fast relative to chemical diffusion through the stratum corneum. However, except for highly lipophilic and/or high molecular weight (>350 Da) chemicals, the normal epidermal turnover rate is not fast enough and most of the chemical in the skin at the end of an exposure will enter the body. Conclusions. Epidermal turnover can significantly reduce subsequent chemical absorption into the systemic circulation only for highly lipophilic or high molecular weight chemicals.

Percutaneous Absorption of Benzoic Acid Across Human Skin. I. In Vitro Experiments and Mathematical Modeling

The percutaneous absorption of benzole acid across human skin in vitro was experimentally and mathematically modeled. Skin partition coefficients were measured over a range of benzoic acid concentrations in both saline and distilled water. The permeation of benzoic acid was measured across isolated stratum corneum, stratum corneum and epidermis, and split-thickness skin. These experiments demonstrated that the stratum corneum was the rate-limiting barrier and that the flux is proportional to the concentration of the undissociated species. The permeation data were analyzed with a comprehensive non-steady-state mathematical model of diffusion across skin. Two adjustable parameters, the effective skin thickness and diffusivity, were fit to the permeation data by nonlinear regression.