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

Background
The objective of the present study was the investigation of hair follicle morphology in eight mammalian species in order to evaluate the species-specific contribution of hair follicles to skin penetration particularly with regard to the utilization of the different animal species as skin models for human skin.

Methods
Cyanoacrylate skin surface biopsy method (CSSB), light microscopy and also digital photography were used for the measurements of hair follicle morphology.

Results
The results revealed species-specific differences regarding the pattern of hair follicle distribution and also differences with regard to hair follicle parameters and characteristics. The results also showed that hair follicles generally possess enormous reservoir capacities, regarding the follicular volume. In all examined species, hair follicles reached at least one-fifth of stratum corneum storage capacity. The results were compared with human data obtained in a previous study.

Conclusion
With regard to hair follicle morphology and skin structure, the porcine skin seems to be the most appropriate skin model for human skin analog to previous investigations, whereas the skin of dog, cat, and rabbit showed the most significant differences.

Comparative study of hair follicle morphology in eight mammalian species and humans.

It is a given fact that hair follicles play an important role in the penetration process of topically applied drugs and cosmetics. Since exact knowledge of the potential follicular reservoir is essential for understanding and calculating the penetration process, this knowledge may indeed help to optimize the development of topically applied drugs and cosmetic products. We know that variability in skin properties exists among the human population, but it is the deciphering and quantification of these differences that may help to explain racial disparities in dermatological disorders and provide a basic approach for treatment and prevention. Data pertaining to structural and functional differences within ethnic skin types (reviewed in this paper) support the assumption that hair follicles in the various skin types are not equal. Thus, the need to investigate follicular morphology in non-Caucasian skin types becomes more than apparent. The aim of the present study was to determine the potential reservoir of vellus hair follicles in non-Caucasian skin types in order to estimate their contribution to the penetration of topically applied substances. Cyanoacrylate skin surface biopsies were taken from seven body sites of Asians and African-Americans. To determine the follicular reservoir, the samples were evaluated under the light microscope. Follicular parameters were measured with the help of a digital imaging software program. In the evaluation and comparison of the results with those of Caucasians, significant differences were detected. Compared with Whites, follicular density on the forehead is significantly lower in Asians and African-Americans. Smaller values were detected for volume, surface, follicular orifice and hair shaft diameter on the thigh and in calf regions in Asians and African-Americans. Furthermore, the follicular reservoir, characterized by follicular volume, is generally higher in Caucasians. In comparison to African-Americans, larger follicular volumes on the forehead, back and on the upper arm were determined in Asians. The fairly similar density in these sites revealed that Asians have a higher follicular reservoir in these sites. Due to significant ethnic differences in the follicular reservoir, particularly on the calf and forehead, prospective skin absorption experiments need to be performed on different skin types in order to be representative. Likewise, the development of topically applied drugs should take place under adequate consideration of ethnic differences in skin physiology.

Susanne Mangelsdorf

Papers

Porcine ear skin: an in vitro model for human skin

Comparative study of hair follicle morphology in eight mammalian species and humans.

Ethnic Variation in Vellus Hair Follicle Size and Distribution