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

The topical application of drugs, such as nicotinates, affects cutaneous blood flow. Such a biological response, which is dependent on the drug and the individual, can be measured noninvasively using laser Doppler flowmetry. We illustrate the kinetics of vasodilation caused by topically applied benzyl nicotinate using a new frequency-selective laser Doppler flowmeter. This flowmeter measures the blood flow in the superficial dermal plexus and the deeper lying larger capillaries simultaneously and indirectly by determining the flow velocity. Both sets of data are compared with the skin temperature and redness. Four biological parameters are measured consecutively on a skin area treated with gel containing benzyl nicotinate and on an untreated control area. A linear relationship between both blood flows is observed. However, no correlation is obtained between the microcirculation with either the cutaneous temperature or the redness. These results indicate the transport of the drug in the blood from the upper to the deeper capillaries. Cutaneous temperature and redness are unsuitable parameters to measure the kinetics of the blood flow after topical application of drugs.

https://www.spiedigitallibrary.org/journals/Journal-of-Biomedical-Optics/volume-11/issue-01/014025/Comparison-of-blood-flow-to-the-cutaneous-temperature-and-redness/10.1117/1.2166370.pdf

Comparison of blood flow to the cutaneous temperature and redness after topical application of benzyl nicotinate.

Cutaneous characteristics, e.g., thickness of the SC and density of follicles, affect the penetration of topically applied substances. In the present study, the penetration of benzyl nicotinate, causing a vasodilation, was studied on three anatomic sites (forearm, forehead and calf) differing in their skin characteristics. Therefore, the blood flow of the superficial dermal plexus and that of the larger capillaries in the deeper skin layers was simultaneously measured using a laser Doppler flowmeter. In addition, the cutaneous temperature and redness were determined as a function of time. These four biological reactions were measured in turn on a skin area treated with a gel containing benzyl nicotinate and on an untreated control area. The highest basal levels were observed on the forehead. Topical application of benzyl nicotinate resulted in an increase in each biological response. Compared to the other sites, the maximal values were reached earliest on the forehead, which also showed the fastest decrease. No significant differences were obtained comparing the kinetic data of the calf with that of the forearm. The results indicate an additional contribution by the numerous vellus hair follicles of the forehead to the penetration and exposure of the drug.

Marco Kaiser

Papers

Porcine ear skin: an in vitro model for human skin

Comparison of blood flow to the cutaneous temperature and redness after topical application of benzyl nicotinate.

Kinetics of blood flow after topical application of benzyl nicotinate on different anatomic sites.