Transdermal skin delivery: predictions for humans from in vivo, ex vivo and animal models.

Liposomes and skin: from drug delivery to model membranes.

The assessment of percutaneous permeation of molecules is a key step in the evaluation of dermal or transdermal delivery systems. If the drugs are intended for delivery to humans, the most appropriate setting in which to do the assessment is the in vivo human. However, this may not be possible for ethical, practical, or economic reasons, particularly in the early phases of development. It is thus necessary to find alternative methods using accessible and reproducible surrogates for in vivo human skin. A range of models has been developed, including ex vivo human skin, usually obtained from cadavers or plastic surgery patients, ex vivo animal skin, and artificial or reconstructed skin models. Increasingly, largely driven by regulatory authorities and industry, there is a focus on developing standardized techniques and protocols. With this comes the need to demonstrate that the surrogate models produce results that correlate with those from in vivo human studies and that they can be used to show bioequivalence of different topical products. This review discusses the alternative skin models that have been developed as surrogates for normal and diseased skin and examines the concepts of using model systems for in vitro-in vivo correlation and the demonstration of bioequivalence.

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Skin models for the testing of transdermal drugs

The ideal way to determine the percutaneous absorption of a compound in humans is to do the actual study in humans. Mechanism and parameters of percutaneous absorption elucidated in vivo with human skin are most relevant to the clinical situation. However, many compounds are potentially too toxic to test in vivo in humans, and so their percutaneous absorption must be tested in animals. Likewise, until more complete animal-to-human validation studies become available, not all investigators will have access to human volunteers. Mechanistic studies and studies on factors affecting absorption must, therefore, be conducted using animals and in vitro techniques. We have two basic criteria to judge whether an animal model is good. First, the animal model should give the same percutaneous absorption as that in humans. If this is not possible, then percutaneous absorption in the animal model should be consistently different from that in humans. Therefore, this chapter stresses studies where percutaneous absorption in an animal model (or the skin from that animal) is compared directly to that in humans.

Animal models for percutaneous absorption

Viable skin efficiently absorbs and metabolizes bisphenol A

Background/purpose: Porcine ear skin is used in studies of percutaneous penetration as a substitute for human skin. The structure of this tissue, including hair follicles, was studied qualitatively and quantitatively in comparison with human skin.

Methods: Sections of shock-frozen biopsies, biopsies embedded in paraffin and cyanoacrylate skin surface biopsies were investigated using microscopy. The thickness of the different skin layers and the follicular characteristics were determined.

Results: The thickness of the stratum corneum was 17–28 μm, whereas the viable epidermis was 60–85 μm thick. On 1 cm2, 11–25 hairs were detected, showing a diameter of 58–97 μm and a maximal extension depth of 0.96–1.38 mm into the skin. The orifices of the porcine infundibula showed a diameter of approximately 200 μm.

Conclusions: The results obtained are similar to those of human skin, indicating the suitability of this porcine tissue as a model for human skin.

Porcine ear skin: an in vitro model for human skin

Capillary refill time (CRT) is used to assess circulatory status in the pediatric emergency department patient. It is recommended by the World Health Organization and is part of the Pediatric Early Warning Score. Current manual assessment methods show high inter-observer variability. Assessment of CRT using polarized reflectance imaging could eliminate this problem and improve the reliability. A Canon EOS M100 camera was used to obtain videos (50 fps) of CRT tests from 15 pediatric emergency patients aged ≤ 6, with a variety of chief complaints. The system was easy to use, well tolerated and produced highly consistent assessments of CRT. 

Rani Toll

Papers

Porcine ear skin: an in vitro model for human skin

Polarized reflectance imaging: an objective way to assess capillary refill time in children (Conference Presentation)