Assessment of drug permeability distribution in two different model skins

University of Strathclyde, Glasgow, Scotland, United Kingdom
International Journal of Pharmaceutics (Impact Factor: 3.65). 11/2005; 303(1-2):81-7. DOI: 10.1016/j.ijpharm.2005.07.005
Source: PubMed


Past in vitro studies with human skin have indicated that drug permeability coefficient (Kp) distributions do not always follow a Gaussian-normal pattern. This has major statistical implications, exemplified by the fact that use of t-tests to evaluate significance is limited to normally distributed populations. Percutaneous absorption research often involves using animal or synthetic skins to simulate less readily available human skin. However, negligible work has been performed on assessing the permeability variabilities of these model membranes. This paper aims to fill this gap. To this end, four studies were undertaken representing two different drugs (caffeine and testosterone) with each drug penetrating through two different model skins (silicone membrane and pig skin). It was determined that in the silicone membrane studies, both compounds' Kp distributions could be fitted to a normal pattern. In contrast, in the pig skin studies, there were notable differences between each drug. While the testosterone Kp values could be fitted to a normal distribution, this was not possible with the caffeine Kp data, which could be fitted to a log-normal distribution. There is some evidence from the literature as well as physicochemical considerations that these outcomes may reflect general trends that are dependent upon both membrane and penetrant properties.

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    • "Additionally, PAMPA filters may become blocked, leading to inaccurate permeability data (Avdeef et al., 2001; Hamalainen and Frostell-Karlsson, 2004; Seo et al., 2006). These factors and possibilities lead inevitably to significant differences in permeability study outcomes (Chilcott et al., 2005; Frum et al., 2007; Khan et al., 2005) when compared to data present in the Flynn permeability database (Parnas et al., 1997, 1998). Furthermore, only Kp values presenting the permeation rate can be determined – the absorbed dose or the remaining compound in the skin layers, which are both relevant parameters for toxicological evaluation, cannot be predicted. "
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    ABSTRACT: Models of the outer epithelia of the human body - namely the skin, the intestine and the lung - have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.
    11/2015; 32(4):327-378. DOI:10.14573/altex.1510051
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    • "Often models are based on parameters such as the lipophilicity and molecular weight (or size) of a drug (Magnusson et al., 2004; Ng et al., 2012; Potts and Guy, 1992; Singh and Roberts, 1996), although other, related physicochemical parameters have been investigated in an attempt to improve the predictivity of the models . Another approach employed to predict the ability of a drug to permeate the skin is to employ in vitro based model systems, for example those that have been successfully used to predict other biological permeations; such as those based on the blood–brain barrier (Sinkó et al., 2012), using electrokinetic chromatography (Wang et al., 2009), simple silicone membrane skin models (Khan et al., 2005; Waters et al., 2013) and most recently, chromatographic techniques (Hidalgo-Rodríguez et al., 2013). Simple models , such as a silicone membrane, are particularly suited to studies that require comparative values, for example, with variations in the presence of additional excipients or temperature changes (Waters et al., 2013) but may struggle to achieve absolute data. "
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    ABSTRACT: This study evaluates the potential application of micellar liquid chromatography (MLC) to predict skin permeation with a series of model compounds. MLC has previously been found to be useful in the prediction of partition coefficient values (logP) for pharmaceutical compounds, yet has not been incorporated in skin permeability models prior to this work. This article provides statistically supported data that this technique enhances the ability to predict the permeability of similar drugs through the skin (Kp). The replacement of a traditional physicochemical parameter, namely the octanol-water partition coefficient (logPow) with a chromatographically determined value (logPmw), results in a quantitative partition-permeability relationship that is robust to variation. MLC offers many benefits compared with the traditional techniques employed to obtain logP values.
    European Journal of Pharmaceutical Sciences 08/2013; DOI:10.1016/j.ejps.2013.08.002 · 3.35 Impact Factor
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    • "It should be remembered that the use of normal distribution can be theoretically justified in situations where a large number of effects act additively and independently together. The porous media, LBM and fluid factors used in these experiments can be a first approach to the effective permeability distribution of caffeine and testosterone solutions in silicone membrane (Khan et al., 2005). "

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