Validated models for predicting skin penetration from different vehicles

Abstract

The permeability of a penetrant though skin is controlled by the properties of the penetrants and the mixture components, which in turn relates to the molecular structures. Despite the well-investigated models for compound permeation through skin, the effect of vehicles and mixture components has not received much attention. The aim of this Quantitative Structure Activity Relationship (QSAR) study was to develop a statistically validated model for the prediction of skin permeability coefficients of compounds dissolved in different vehicles. Furthermore, the model can help with the elucidation of the mechanisms involved in the permeation process. With this goal in mind, the skin permeability of four different penetrants each blended in 24 different solvent mixtures were determined from diffusion cell studies using porcine skin. The resulting 96 kp values were combined with a previous dataset of 288 kp data for QSAR analysis. Stepwise regression analysis was used for the selection of the most significant molecular descriptors and development of several regression models. The selected QSAR employed two penetrant descriptors of Wiener topological index and total lipole moment, boiling point of the solvent and the difference between the melting point of the penetrant and the melting point of the solvent. The QSAR was validated internally, using a leave-many-out procedure, giving a mean absolute error of 0.454 for the log kp value of the test set.

Introduction

Skin is the largest organ of all mammals protecting the underlying muscles, bones, ligaments and internal organs as well as guarding the whole organism from exogenous molecules. Within skin the outermost layer, stratum corneum, is the formidable barrier to the exogenous compounds, limiting penetration of toxicants and drugs alike. Skin penetration of chemicals is an integral part of human health risk assessment of chemicals exposed via the dermal route (Shah, 1994). Skin has also been the focus of research by drug formulators as a site of drug administration, due to the advantages it may offer over other routes of drug delivery (Barry, 2007). Topical delivery affects the tissues under the site of application, while systemic delivery has an effect after distribution to the circulatory system. The rate of drug delivery through skin is influenced by factors including skin health status, age, race, anatomical region, thermodynamic activity of the drug in the formulation and interactions of the drug and formulation with the skin. Drug in the formulation needs to pass the stratum corneum's intercellular lipids that surround dead keratin-filled corneocytes and also the subcutaneous fat to reach the blood capillaries (Elias, 1983).

Penetration of a compound into skin is controlled by its physicochemical properties and the chemical structure. For example, it has been shown that lipophilicity and hydrogen bonding ability of a compound plays a major role on the skin absorption profile (Pugh et al., 1996, El Tayar et al., 1991). On the other hand, formulation ingredients can alter the skin penetration of a compound by affecting the barrier properties of the skin or by changing the partitioning of the compound into the SC. Therefore, penetration of the drug depends not only on the nature of the drug but also on the nature of the other ingredients present in the formulation. The vehicle in which a penetrant is dissolved or dispersed is of outmost significance. Vehicles can affect skin permeability by a range of mechanisms including delipidization, hydration, fluidization and desmosome disruption in the stratum corneum, and also by changing the polarity of the formulation mixture which is followed by a change in the penetrant solubility and partitioning to stratum corneum (Roberts et al., 2002). Solvents are also likely to affect the conformation of stratum corneum in a way that the diffusion and partitioning of the penetrants are modified (Kai et al., 1990, Raykar et al., 1988, Rosado et al., 2003). Pure solutes can in some cases enhance the skin permeability by a direct corrosive effect (Roberts et al., 2002, Zinke et al., 2002). Other common mixture components are surfactants and, in case of drug formulations, penetration enhancers. Surfactants are used in the pharmaceutical/cosmetic preparations, agrochemical products (e.g. herbicides) and industrial solutions. In industry surfactants are added to formulations in order to solubilise lipophilic active ingredients, and in transdermal drug delivery to solubilise lipids within the stratum corneum. Penetration enhancers may increase the diffusion coefficient of drugs in the stratum corneum (i.e. disrupt the barrier nature of the stratum corneum), may act to increase the effective concentration of the drug in the vehicle (for example, acting as an anti-solvent), could improve partitioning between the formulation and the stratum corneum (perhaps by altering the solvent nature of the skin membrane to improve partitioning into the tissue) or, less likely, by decreasing the skin thickness (perhaps by providing a permeation ‘shortcut’ as opposed to a tortuous pathway for a permeant) (Williams and Barry, 2004).

The effect of mixture/formulation components on the skin penetration of a compound depends on the nature of the component, i.e. its chemical structure and physicochemical properties. In other words, chemical structure of a formulation component can determine the effect that it will have on the stratum corneum or on the partitioning of the penetrant, leading to the observed changes in the skin penetration profile of the penetrant. The relationship between chemical structures of the formulation ingredients and the skin penetration modification can be studied quantitatively using Quantitative Structure–Activity Relationship (QSAR) techniques. QSAR has been previously applied to study the effect of structural variation of chemical enhancers on the skin penetration of various drugs (Ghafourian et al., 2004, Moss et al., 2002).

Most mechanistic studies on skin penetration are based on the penetration of individual chemicals (Flynn, 1990), with only few attempts towards a comprehensive investigation on the effect of chemical mixtures. Such a systematic study requires a large volume of tedious experimental measurements involving various penetrant/mixture-component combinations. Riviere and Brooks, 2005, Riviere and Brooks, 2007 have determined skin permeation coefficient of 12 compounds from a mixture of several solvents, a surfactant and methyl nicotinic acid (288 combinations). A QSAR analysis of the data revealed several penetrant/solvent properties that are significant contributors to the skin permeation coefficients (Ghafourian et al., 2010). The study also revealed several gaps in the chemical space of Riviere's penetrants in comparison with the well-established datasets of Flynn (1990) and Wilschut et al. (1995) which contain skin penetration data of aqueous solutions of over 100 compounds. In this investigation, four chemicals were selected from Flynn and Wilschut et al. datasets for further skin penetration studies using Riviere's experimental protocol which involves blending of each chemical with 24 mixture combinations. The selections were made from the identified gaps in the chemical space and the compounds are expected to add a high level of diversity to the dataset. These new measurements facilitated the development of statistically validated QSAR models. Statistically validated QSAR models can be used for the estimation of skin penetration of new compounds or the effect of new mixture components on the penetration of a penetrant. The models can aid the understanding of the mechanisms involved in skin penetration of compounds and the effect of mixture components.