INTRODUCTION

Are certain topically applied metal ions simply innocuous treatments or do they provide real technical benefit? Their use goes back to the earliest recorded medical text (∼1500 BC), the Ebers papyrus of ancient Egypt. For example, calamine (a natural material containing zinc oxide) was described for treating many skin and eye ailments; green copper-based minerals (likely malachite) were used for burn wounds and itching. Many of these applications have withstood the ensuing 3500 years of history, providing a first clue of real technical merit. For example, zinc is still the first choice to soothe a crying baby’s bottom.

This anecdotal support for the importance of metal ions is substantiated by more rigorous investigations, such as those that describe the impact of nutritional deficiencies. A deficiency of zinc can occur either by diet or as a result of a genetic condition that blocks the intestinal uptake, resulting in acrodermatitis enteropathica (AE). AE manifests itself as severe dermatitis in the vicinity of the mouth, nose, ears, and anal areas (orifices), and on the skin and nails of the fingers and toes (acra). Likewise, a disease resulting in copper deficiency, Menkes syndrome, causes defective keratinization in skin and hair growth, manifested by the formation of kinky hair.

While ancient empiricism, practical utility, and clinical manifestations of deficiency support the conclusion that metal ions are important to skin health, a deeper level of understanding is required to confirm this. The molecular basis for these empirical and clinical observations is beginning to emerge that provides strong reinforcement of the links between metal ions and skin condition.

This review will focus specifically on five metals—zinc, copper, selenium, aluminum, and strontium—which are currently used in cosmeceuticals. Each metal will be covered sequentially, reviewing commonly used materials followed by clinical and scientific data supporting their use. There are many other metals that have found usage in cosmeceuticals (see Table 13.1). Searching the skin-related literature (Medline, 1993–present) demonstrates that there is substantial scientific activity exploring the technical basis for utilization of some of these metals. Also summarized in Table 13.1 for some of the metals is the introduction of new personal care products containing them; substantial commercial activity is evident.

Table 13.1 Overview of cosmeceutical metals

ZINC IN COSMECEUTICAL PRODUCTS

• Materials

There are 55 different zinc-containing materials listed in the International Cosmetic Ingredient (INCI) Dictionary and Handbook (a tabulation of all materials used in cosmetic and personal care products). Of those, seven have been approved by the US Food and Drug Administration (FDA) for over-the-counter (OTC) usage as safe and effective for a range of benefits, including skin protection, antimicrobial activity, and astringency (Table 13.2). The skin protective benefits of these zinc materials find applications treating various inflammatory dermatitis conditions such as poison ivy and diaper rash. The wide range of zinc materials approved by the FDA provides a strong indication of the general utility of zinc as an effective treatment.

Table 13.2 Zinc materials approved for use by the FDA for OTC use

In most of these materials, zinc ion itself appears to be the primary source of the benefit. All of these materials utilize zinc in its ionic form (Zn²⁺) with different counterions that result in an electrically neutral compound. These counterions can modulate the solubility and bioavailability of the zinc species itself. For example, zinc sulfate is water soluble whereas zinc oxide is only sparingly soluble. Zinc sulfate would be expected to be highly available initially with rapid depletion whereas zinc oxide tends to have a lower level of initial activity, but sustained for a long time. By choice of the specific material, the cosmeceutical formulator can tailor the physical properties and activity to the product function.

The other zinc-containing materials utilized in cosmeceuticals, but not specifically accepted by the FDA for OTC drugs, can likewise be expected to have the potential to deliver zinc-based benefits. However, since the use of these materials is not as widespread, the product formulator must exhibit greater pharmacology expertise to assure that the intended benefits are delivered; bioavailability becomes a complex interaction of material interacting with the product matrix.

• Basis for use of zinc materials

CLINICAL PERSPECTIVE

Damaged skin repairs itself in a very complex process. In the case where the damage is physical and a wound results, a well-defined process ensues: inflammation, re-epithelialization, granulation tissue formation, wound contraction, and tissue remodeling. During wound healing, the requirement for zinc increases dramatically. In rat wound models, local zinc levels are seen to increase after wounding, demonstrating the physiologic need for this metal in the repair process. Topically applied zinc compounds have been shown to speed repair, for example in leg ulcers; the rate of delivery of zinc to the damaged site may be initially rate-limiting in the repair process. The rate of re-epithelialization was increased with topical zinc in a pig model; the nature (bioavailability) of the zinc material was found to be important—sparingly soluble zinc oxide was superior to soluble zinc forms. An indirect measure of local zinc ion activity at a wound repair site comes from monitoring metallothionein (MT), which is responsible for the storage and delivery of zinc to other proteins and enzymes requiring zinc for their function. MT upregulation can be found in vivo by exposure to zinc; treatment of keratinocytes in vitro with a material that selectively binds zinc, inhibits the upregulation of MT and slows cellular proliferation.

Where the damage to skin is more of a ‘chemical’ nature, the dominant manifestation is inflammation. There is a growing body of evidence that zinc has anti-inflammatory activity. Zinc reduces the irritancy caused by surfactants in the oral cavity. This effect has been observed in vitro as well as in skin cultures by monitoring interleukin (IL)-1α production and demonstrating that pyrithione zinc inhibits surfactant-induced IL-1α release. The inflammatory conditions bullous pemphigoid and decubitus ulcers are accompanied (caused?) by low serum zinc levels. The anti-inflammatory benefits of zinc most likely also play a role in the wound-healing process discussed above.

In addition to facilitating repair processes, zinc appears to confer a protective function via providing antioxidant activity. Zinc has been shown to reduce the cellular and genetic damage caused by exposure to ultraviolet (UV) light and enhance resistance of skin fibroblasts to oxidative stress.

Zinc has also recently been shown to improve skin elasticity, reducing the signs of aging skin.

SCIENTIFIC FOUNDATION

An average human contains 2.5 g of zinc and requires 15 mg/day to remain healthy (this is exceeded only by iron for trace elements). The vast majority of the zinc is present in metalloenzymes and proteins. This field was opened in 1940 with the discovery that carbonic anhydrase, a ubiquitous enzyme required for maintaining physiologic pH, was zinc-containing and that the zinc was required for catalytic activity. Since that time, over 300 enzymes requiring zinc for activity have been structurally characterized. Even more impressive are the thousands of zinc-containing proteins that require zinc for conferring a three-dimensional structure that allows them to regulate replication of DNA and transcription of RNA. These proteins form the class called ‘zinc fingers’ and regulate the fundamental biologic process of transcribing genetic information to functional proteins. At least 3% of all proteins encoded for by the human genome have zinc fingers; this has led Berg to coin the phrase ‘galvanization of biology’ to acknowledge the importance of this metal in human physiology.

While it is beyond the scope here to review many of the zinc-containing biomolecules (see Table 13.3

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