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| Guest Article | Better skin protection with new barrier creams | Bernard Gabard, Sybille Schliemann-Willers |
Summary
Skin protection creams are considered judicially as cosmetics. Besides a good efficacy, a main requirement to be fulfilled by these preparations is maximal safety as they are often applied on lesioned skin. This justifies the development of a new skin protection cream to be conceived similar to the one of a corresponding drug. Correspondingly, an animal model was designed and standardized for the screening of several formulations. Pharmacological experiments ensured that the results of the screening would be relevant for human skin too. The quantification of the skin reactions with non-invasive skin bioengineering methods (transepidermal water loss, skin colour, skin hydration) played a central role.
A chronic irritation model with the model compound sodium lauryl sulfate (SLS) was standardized and was used for a broad screening of newly developed skin protection creams. The best results were obtained with formulations containing aluminium hydroxychloride as active principle. More protection was ensured after combining the aluminium salt with glycerin. The model was then transferred to human volunteers and used for optimization of the concentration of active components. Concentrations of 5 percent aluminium salt and 5 percent glycerin were shown to be optimal regarding skin protection, ease of formulation, and costs. Last, tolerance and efficacy of the new preparation were investigated in clinical studies.
Using this drug development approach as concept, it is shown that a useful screening can be conducted and active substances can be selected, which will be adapted to the particular situations encountered in skin protection. However, this concept has to be adapted to the European regulations concerning the use of animals for cosmetic research.
1. Introduction
Occupational dermatoses are among the most important problems in dermatology. Serious difficulties are encountered if work has to be restricted or even stopped because of the dermatological disease, and the following costs for the company and for public health also may be substantial. Skin protection creams are now considered as a significant component of the protection management in the workplace. They are judicially listed as cosmetics, although their use (e.g. application on diseased skin) and the high efficacy requirements besides maximal safety would justify a classification as drugs. It is symptomatic that efficacy data concerning skin protection creams are sometimes viewed with scepticism and are the subject of a lively debate [1, 2].
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In 1996, J.M. Lachapelle published a review about the efficacy of skin protection creams (see Figure 1). He showed that a change in the philosophy and conception of the development and efficacy proof of these products has to take place. Similarly to the development of a drug, in vitro tests should be first conducted, then animal research has to be done, and finally human studies after single and repeated application are required. At the very end, a clinical study should demonstrate the required efficacy of the product. P.J. Frosch first consequently standardized human experimental models and proposed the use of skin physiological measurements, which are now playing a central role [4].
2. Description of the method
The development of a new skin protection cream was conceived as similar to the one of a drug from the very beginning, evaluating the risk/benefit ratio taking into account that the risk should be minimal for cosmetics.
First, an animal model was designed, standardized, and used for the screening of several formulations. This model had to fulfil three main conditions:
1. To show similar pharmacological properties to human skin, ensuring the obtainment of relevant results. This means not only similar skin penetration or permeation properties to human skin, but also similar reactions to foreign substances, ensuring a meaningful comparison to the reactions of human skin to these irritants.
2. To allow testing of different irritants and of different concentrations of these substances as well as several formulations simultaneously (cost sparing).
3. To allow the quantification of the skin reactions with non-invasive skin bioengineering methods.
For these purposes, the hairless Yucatan Micropig was chosen, given the similarities in morphology, cellular composition, immunoreactivity and pharmacological properties of this animal's skin to human skin [5]. Using skin physiological measurements such as transepidermal water loss [6], skin hydration [7], and skin colour [8] it was shown that basic skin physiological parameters and pharmacological reactions were almost similar to those of human skin. The hairless Yucatan Micropig was thus considered to be a suitable investigation model [9].
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For screening purposes, a chronic irritation model was set up with 5 percent aqueous sodium lauryl sulfate (SLS) as irritant applied daily one hour during nine days [9]. During the experimental period, a clear increase in transepidermal water loss was observed (Figure 2), as well as the development of an erythema, which disappeared quickly at the end of the experiment. Only minor changes in skin hydration were noticed. As known in humans, irritation with sodium lauryl sulfate in the Yucatan Micropig showed a high variability.
3. Screening of new skin protection creams
This newly designed model was used for the screening of the protective efficacy of different galenical systems [10]. Therefore, the products were applied on the animal's skin one hour before starting with the irritation. Another treatment with the protection cream was conducted each afternoon. A well-known commercially available standard protection cream was used throughout as control. Before starting with the animal screening part of these investigations, the following working hypotheses were established as a basis for the galenical development:
1. Phospholipids and/or liposomes build bilayers penetrating the upper layers of the stratum corneum and create an intracorneal occlusion; additionally, different substances supposed active were incorporated such as charged compounds (polyquaternium-11) or polyfluoromethyethers;
2. Classical lipid-rich, W/O-emulsion or film-binding agents lay down a protecting layer on the skin surface;
3. Use active components incorporated in suitable emulsions, such as kaolin, glycerin (humectant), or aluminium chlorohydrate (well-known in dermatology for filling pores and impairing sweat secretion).
Formulations based on one or more of the principles defined in these hypotheses were also used. With emulsions based on phospholipids-containing and /or liposomal vehicles or with conventional W/O-emulsions, no protective effects were found. On the contrary, the majority of the tested products enhanced the irritative effect of sodium lauryl sulfate [10]. Neither polyfluoromethylether compounds nor charged components (Polyquaternium-11) were able to reverse this irritation-enhancing effect. Formulations containing glycerin showed a slight protective effect. Conventional O/W emulsions always showed some protective effects. Glycerin incorporation in this type of emulsion led to a clear enhancement of the protection. O/W-emulsions containing aluminum chlorohydrate as active substance showed very good protective effects.
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In the last series of experiments, the best concentrations of the active principles glycerin and aluminium chlorohydrate were determined. The vehicle itself, a conventional O/W-emulsion already showed some protection. Increasing concentrations of aluminium salt did lead to very good protective effects and additional incorporation of glycerin lead to maximal protection (Figure 3). However, the improvement of skin hydration lessened with increasing concentrations. The addition of glycerin maintained a good effect on skin hydration.
4. Final experiments in human volunteers
Based on these results, the concentration(s) of glycerin and of aluminum chlorohydrate were optimized using an identical model of irritation in healthy volunteers with aqueous sodium lauryl sulfate at a concentration of 1 percent [10]. The protective creams were applied 30 min before starting with the irritation, and also once more in the afternoon. The results of the animal experiments could be confirmed as far as to the excellent protection offered by a O/W-emulsion incorporating 5 percent each of glycerin and of aluminum chlorohydrate. This formulation was shown to be the best compromise between good protective efficacy, tolerance (as determined through different epicutaneous tests after single and repeated open or occluded application) and manufacturing costs. Finally, different clinical studies were conducted [11-14] to characterise the efficacy profile of the product, given the known specificity of skin protection requirements at the workplace.
5. Broadening the development concept
Using this development concept similar to the one used for developing drugs has been shown to have led to a successful product [10]. Conducting all these studies may not be always necessary, considering the European legislation about animal experiments and cosmetic research. However, as regard to skin protection creams, the conditions of their use require more development work than a simple test in healthy volunteers or even only in vitro testing. Thus, following this line of thinking, it is possible to conduct a targeted screening and to select active principles with simple but highly relevant experiments in humans.
As an example, the problems of a particular professional branch, the catering trade, are analysed. Irritative contact dermatitis amounts to 80-90 percent of the professional skin diseases in this working area [15]. Wearing gloves is often simply not possible. Using commercial skin protection creams in bakeries, cake shops or patisseries may alter taste, aroma and flavour of the goods. The proposition of incorporating foodstuffs-compatible ingredients (such as preservatives, food lipids or fats) in skin protection creams is therefore meaningful [16]. For this reasons, a potential skin protection effect of alimentary fats was investigated. These compounds may not have all the burdens described above. Still following a drug-like development concept, it is possible to conduct a targeted screening with these compounds as raw material without incorporation in any formulation. Using a simple human irritation model, some compounds have been shown to give some protection ([17]; Figure 4). Thus, they now may be incorporated in suitable galenically optimized formulations and further tests as described in paragraphs 4 and 5 may be conducted to select the best candidates leading to food-compatible skin protection creams. These formulations not only may protect the skin of people working in the catering industry, but also may improve the general safety in the food industry.
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6. Conclusion: the central role of the skin physiological measurements
Using a drug-like development for new skin protection creams should led to effective products well adapted to specific daily working situations. Given the efficacy and tolerance requirements for a cosmetic product, it was shown that a successful product was developed following this development concept.
At the same time, the central role of the new skin physiological measurements was underlined. Without the use of these measurement techniques, a meaningful screening and a well-aimed, cost-sparing and rapid selection of potential candidates would not have been possible. The role of this technique is now gaining more importance in view of the European legislation about animal experiments in cosmetic research. The example of alimentary fat components has shown that a simple but well-targeted basic screening may be conducted in healthy volunteers. It is noteworthy that a very good agreement was observed between the results of the skin bioengineering measurements and the visual evaluation usual in dermatology experiments. Additional information obtained from the measurement results have led to an optimization of the product, as shown with the combination of glycerin and aluminium salt for the skin hydration.
However, it is still necessary to adapt the amount of experimental work to the planned use of the definitive product. For skin protection creams, the conditions of their use require more development work than simple epicutan testing for tolerance or a simple proof of efficacy in healthy volunteers, or even only in vitro testing. The drug-like development concept may be adapted to any particular situation to look for, to select or to improve new or already known skin protective substances.
7. References
1. Pigatto, P.D., Bigardi, A.S., Legori, A., Altomare, G.F., Finzi, A.F.; Are barrier creams of any use in contact dermatitis? Contact Dermatitis 26 (1992): 197-198
2. Wigger-Alberti, W., Elsner, P.; Do barrier creams and gloves prevent or provoke contact dermatitis? Am J Contact Dermatitis 9 (1998):100-106
3. Lachapelle, J.M. ; Efficacy of protective creams and/or gels. Curr Probl Dermatol 25 (1996):182-192
4. Frosch, P.J., Kurte, A. ; Efficacy of skin barrier creams (IV). The repetitive irritation test (RIT) with a set of 4 standard irritants. Contact Dermatitis 31(1994):161-168
5. Lavker, R.M., Dong, G., Zheng, P., Murphy, G.F.; Hairless micropig skin: A novel model for studies of cutaneous biology. Am J Pathol 138(1991): 687-697
6. Pinnagoda ,J., Tupker, R.A., Agner, T., Serup, J. ; Guidelines for transepidermal water loss (TEWL) measurement. A report from the standardization group of the European Society of Contact Dermatitis. Contact Dermatitis 22(1990):164-178
7. Barel, A.O., Clarys, P., Gabard, B. ; In vivo evaluation of the hydration state of the skin: measurements and methods for claim support. In: Elsner, P., Merck, H.F., Maibach, H.I. (eds.) Cosmetics: controlled efficacy studies and regulation, Springer-Verlag Berlin Heidelberg New York (1999), pp.57-80
8. Elsner, P.; Chromametry: Hardware, measuring principles, and standardization of measurements. In Berardesca E, Elsner P, Maibach HI (eds.) Bioengineering of the skin: Cutaneous blodd flow and erythema, CRC Press, Inc., Boca Raton, (1995) pp 247-252
9. Gabard, B., Treffel, P., Charton-Picard, F., Eloy, R. ; Irritant reactions on hairless micropig skin: a model for testing barrier creams? Curr Probl Dermatol 23 (1995):275-287
10. Gabard, B., Treffel, P. ; Pre-clinical development of a new skin protection cream.
Dermatol Beruf Umwelt/Occup Environ Dermatol 49 (2001): 59-66
11. Gloor, M., Gabard, B., Fluhr, J.W., Lehmacher, W. ; Action of an aluminium chlorohydrate and glycerol containing skin protection cream in experimental skin irritation produced by sodium laurylsulfate and solvents. Dermatol Beruf Umwelt/Occup Environ Dermatol 49 (2001): 67-70
12. Bock, M., Wulfhorst, B., Gabard, B., Schwanitz, H.J. ; Effektivität von Hautschutzcremes zur behandlung irritativer Kontaktekzeme bei Friseurauszubildenden. Dermatol Beruf Umwelt/Occup Environ Dermatol 49 (2001): 73-76
13. Berndt, U., Wigger-Alberti, W., Gabard, B., Elsner, P.; Vergleich einer Hautschutzcreme und ihrer Grundlage bezüglich Wirksamkeit gegen das berufsbedingte irritative Handekzem bei Krnakenschwestern/Eine Anwendungsuntersuchung. Dermatol Beruf Umwelt/Occup Environ Dermatol 49 (2001): 77-80
14. Bock, M., Wulfhorst, B., Gabard, B., Schwanitz, H.J.; Okklusionseffekt von Schutzhandschuhen/Effizienz einer Aluminiumchlorohydrate-haltigen Hautschutzcreme. Dermatol Beruf Umwelt/Occup Environ Dermatol 49 (2001): 85-87
15. Tacke, J., Schmidt, A., Fartasch, M., Diepgen, T.L.; Occupational contact dermatitis in bakers, confectioners and cooks. A population-based study. Contact Dermatitis 33 (1995): 112-117
16. Lange, M. ; Welches Hautschutzmittel ist für Franz Mustermann optimal? In: Grieshaber R, Schneider W (Herausgeber) "Prävention von arbeitsbedingten Gesundheitsgefahren und Erkrankungen-7. Erfurter Tage" monade Verlag und Agentur Leipzig, pp. 209-213 (2001)
17. Schliemann-Willers, S., Wigger-Alberti, W., Kleesz, P., Grieshaber, R., Elsner, P.; Hautschutz durch Nahrungsfette. In: Grieshaber R, Schneider W (Herausgeber) "Prävention von arbeitsbedingten Gesundheitsgefahren und Erkrankungen-7. Erfurter Tage" monade Verlag und Agentur Leipzig, pp. 243-248 (2001)
Author
Dr. Bernard Gabard
Dipl.-Ing. Dr. rer. nat. Bernard Louis Gabard founded Iderma AG in Münchenstein, Switzerland in 2001. Iderma is the first independent Swiss test institute for dermatology and cosmetics. From 1988 to 2001 he was head of the Department of Biopharmacy of the Swiss company Spirig Pharma Ltd. since 1988. He is in charge of efficacy and safety assessments of dermatological and cosmetic products. He is a pharmacological expert and member in the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) and in the European Society of Toxicology (EST).
Dr. Bernard Gabard
iderma
CH-4142 Münchenstein
Tel.: +41 61 411 4080
Fax: + 41 61 411 4081
e-mail: b.gabard@iderma.ch
Co-author of this article is Dr. med. Sibylle Schliemann-Willers, Department of Dermatology, Friedrich-Schiller-University, Jena (Germany).
The German version of this article authored by Bernard Gabard and Sybille Schliemann-Willers "Effizienter Hautschutz durch neue Hautschutzpräparate" was published in SÖFW-Journal, 4 (128) 2002, pp.2-7.
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