Clinics in Dermatology (2009) 27, 428–430
Cosmeceuticals versus pharmaceuticals Mohamed Amer, MD ⁎, Mina Maged, BSc Pharm Department of Dermatology and Venerology, Zagazig University, Zagazig, Egypt
Abstract Four major categories of interest in the cosmeceutical market are nonbleaching agents, antioxidants, peptides, and growth factors. The trend toward introducing natural products considered to be safe is influenced by media hype and consumer interest. This is driving the cosmeceutical market to develop safer products that are naturally derived. Some of these naturally derived products have proven to be helpful, whereas more evidence is needed for other products before physicians can consider recommending their use. © 2009 Elsevier Inc. All rights reserved.
Introduction In contemporary dermatologic practice, there is a need to differentiate between cosmeceuticals and pharmaceuticals. Pharmaceuticals are agents intended to alter, change, or protect skin from abnormal or pathologic conditions. Cosmeceuticals represent a category of products placed between nonprescription and prescription products. The term was popularized by Albert Kligman, who recognized that even water could alter the structure and function of skin. Cosmeceuticals may also be considered to be hybrids between cosmetics and pharmaceuticals that are then intended to enhance the health and beauty of skin. Cosmeceuticals remain a dynamic force in the skin care marketplace.1 Representative cosmetic active agents currently found in the cosmeceutical marketplace are • • • • •
Retinoids B vitamins Peptides Polyhydroxy acids Botanicals
⁎ Corresponding author. E-mail address: [email protected]
(M. Amer). 0738-081X/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.05.004
Retinoids exemplify premier evidence-based cosmeceuticals, as they function through surface cell receptor interaction to produce a clinically defined effect. Pro-B vitamins, such as niacinamide and panthenol, function differently by physically enhancing barrier properties of stratum corneum rather than chemically. Other alterations in skin function pertain to collagen production, which may be induced by aminopeptides. Fewer clinical data support the later technology. Data are available for hydroxyl acids as potent exfoliants of aging keratinocytes. The most promising botanically derived substances are polyphenols, such as those found in green tea.2 In this contribution we will consider the new “hot” ingredients in the cosmeceutical market. Four categories will be addressed: new nonhydroquinone bleaching agents for skin lightening, new generation antioxidants beyond traditional vitamins and coenzymes, peptides, and growth factors.
Nonbleaching agents for skin lightening For medical and cosmetic reasons, it is often desirable to alter skin color. Currently available topical agents include
Cosmeceuticals versus pharmaceuticals
tyrosinase inhibitors, retinoids, hydroquinones, and agents toxic to melanocytes. The results of these treatments are sometimes disappointing, creating a need for more effective and safer agents that are less irritating. Currently, there is a universal trend favoring natural treatments.
Protease-activated receptor 2 pathway Protease-activated receptor 2 (PAR-2) is expressed on keratinocytes but not on melanocytes. It is a seven transmembrane G-protein-coupled receptor that is activated by a serine protease cleavage. Trypsin and mast cell tryptase are natural activators of PAR-2. Their regulatory role in pigmentation is possible only when keratinocytemelanocyte contact is established. This regulation occurs through phagocytosis of melanosomes by the keratinocytes.3 Inhibition of PAR-2 activation by synthetic serine protease inhibitors results in depigmentation. Serine protease soybean-derived soyseed and soy milk contain such inhibitors. Examples are soybean trypsin inhibitor and Bowman-Birk inhibitor. These inhibitors act through inhibition of PAR-2 cleavage affecting cytoskeletal and cell surface organization, thus preventing keratinocytemelanocyte contact that results in reducing melanosome phagocytosis by keratinocytes. The depigmentation effect is reversible in vivo, excluding a toxic effect on melanocytes after treatment. The depigmenting activity of soybean derivatives and their ability to prevent pigmentation induced by ultraviolet (UV) light has been demonstrated both in vitro and in vivo. These results imply that inhibition of PAR-2 pathway by soy milk may be used as a natural alternative to skin lightening.4 Other nonbleaching agents such as vitamins C and E, and a polyphenol ellagic acid have been reported to decrease tyrosinase activity. Pycnogenol, a standardized extract of Pinus pinaster, bark has been reported to decrease UVinduced pigmentation.
Antioxidants New methods to protect skin from photodamage, cancer, and photoaging are highly desirable. Sunscreens are useful, but protection is not ideal because of inadequate use,
incomplete spectral protection, and risk of toxicity. Although skin naturally uses antioxidants to protect itself from photodamage, the system can be overloaded by excessive exposure to various sources of prooxidants.5 Photochemical reactions occur in skin as a result of solargenerated UV light that is absorbed by various chromophores in skin. These reactions may result in DNA alterations such as oxidation of nucleic acids. Oxidative reactions can also modify proteins and lipids, leading to changes in cell function and tissue aging. Reactive oxygen species are an inherent part of the anabolism and catabolism of tissues, including skin. The increase of reactive species increases oxidative stress. This is observed at high metabolic demands, such as excessive exposure to sun light, smoking, and pollution.6 Free radicals, defined as atoms or molecules with an unpaired electron, cause much of the damage. Examples include superoxide anion, peroxyl radical, and hydroxyl radical. These molecules are extremely chemically reactive and short-lived, reacting near the location where they are generated.
Natural skin defense Two mechanisms are involved in natural skin defense: (1) enzymatic, examples are glutathione peroxidase, glutathione reductase, catalase, copper-zinc superoxide dismutase, manganese superoxide dismutase, and extracellular superoxide dismutase; and (2) nonenzymatic, examples are antioxidants (Table 1).6 Antioxidants complex with free radicals as a result of the normal respiratory process or through UV exposure, ultimately leading to their reduction, minimizing cross linkage and DNA damage, and improving the process of cellular elimination.
Topical antioxidants Topical antioxidants are desirable as adjunctive treatment in response to the increase in demand for physiologic antioxidants of skin.7 Existing antioxidants may undergo rapid depletion. Further, oral antioxidants may not reach the skin in sufficient amounts to be effective. This creates the need for topical antioxidants. For topical application of antioxidants to be effective, several obstacles must be
Vitamin C Glutathione Vitamin E Ubiquinol/ubiquinone
Diet Synthesized Diet Synthesized
Aqueous phase Cytoplasm Membrane, lipid Mitochondria
Concentration (nmol/g skin) Epidermis
… 7600.0 ± 2498.0 484.3 ± 81.4 34.2 ± 4.6
… 1311.0 ± 559.0 84.8 ± 18.0 ± 1.1
430 overcome: (1) instability, these compounds can easily be reduced or oxidized; (2) color, it is difficult to produce an acceptable aesthetic product; (3) penetration into skin; and (4) photoprotection of the antioxidant. More recent categories of antioxidants include a variety of agents such as flavonoids, a polyphenol found in plants. Flavonoids typically have a bright color and offer protection from UV damage. Among flavonoid subgroups are isoflavonoids, including genistein found in soybean and catechins found in grape seed extract. Grape seed extract induces vascular endothelial growth factor expression in keratinocytes, which has beneficial effects on dermal wound healing. Other claimed benefits are enhancement of the sun protection factor (SPF) of sunscreens and free radical scavenging. Green tea extract is a catechin-based polyphenolic flavonoid that acts as an anti-inflammatory and pathway modulator in cell proliferation. Green tea contains epigallocatechin 3-gallate, which stimulates proliferation of epidermal keratinocytes, increases epidermal thickness, inhibits UV-induced apoptosis of keratinocytes, and may inhibit cancer cell formation. Pycnogenol, a pine bark extract, is used as an antioxidant, anti-inflammatory, and anticarcinogenic. It is rich in proanthocyanidins that include polyphenolic bioflavonoids. These compounds may stabilize collagen and elastin as it binds to elastic fibers, decreasing the rate of degeneration of the fibers by elastases. Further, it blocks release of inflammatory factors. Other botanically derived antioxidants are carotinoids are lycopene, an acyclic hydrocarbon carotinoid that is also an anti-inflammatory and anticarcinogenic. It blocks apoptosis after UVB injury and is protective against UVB-induced photodamage through inhibition of epidermal ornithine decarboxylase. Idebenone is another compound believed to have a role in the inhibition of post-UVB nuclear thymidine photo protection. It decreases oxidation of cell membrane lipids.8
Peptides New peptides have been recently identified as potential cosmeceutical agents. The peptide palmitoyl pentapeptide-3 (Matrixyl) has been shown to be helpful in wound healing. It contains a pal pentapeptide of the sequence Lys-Thr-ThrLys-Se, which is the minimum sequence for collagen synthesis, a fragment of procollagen. Matrixyl stimulates the synthesis of collagen I and II in addition to formation of fibronectin by fibroblasts. A new approach to assess the efficacy of peptides uses artificial skin.9
M. Amer, M. Maged
Growth factors Growth hormones are used as external supplements to compensate for the decrease of normal levels as cells age. Growth hormones upgrade cellular processes of healing and regeneration. Topical growth hormones may stimulate new collagen formation and help to thicken the epidermis, resulting in smoother skin and wrinkle reduction.10
Conclusions The latest trends are focused on nonirritating, stimulating, and protective ingredients to improve the appearance of skin. Natural products may greatly help to expand the field of cosmeceuticals with more effective, safe armaments. The active ingredients in these natural products should be identified and evaluated using advanced technology to confirm efficacy and safety of their use in cosmeceutical products.11,12 Further information about many of these technologies may be found in the contributions that follow.
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