About Skin: Cosmeceuticals and Skin Care Products

Cosmeceuticals and Skin Care Products

During the past few years, many new and effective skin care therapies have become available to correct and protect against the effects of aging. Almost all of the currently marketed skin care products incorporate one or more of the following agents.

Features of aging skin include:

thinning of the epidermis and dermis;
coarsening of the skin texture, including enlargement of pores;
laxity with wrinkling;
discoloration, including yellowing, bronzing, and brown spots;
telangiectasia, or "broken veins".

These unwelcome changes are brought about by the relentless pull of gravity and cumulative damage to DNA, collagen, and cell membranes by free radicals produced from normal cellular metabolism, environmental elements, and exposure to solar radiation.

"Cosmeceuticals" can be roughly defined as products which have a therapeutic benefit, but without necessarily having a biologic or physiologic benefit. As an example, if a manufacturer claims that a product improves the appearance of wrinkles (a therapeutic benefit), that product would be considered a cosmetic by law. If however, the manufacturer added the claim that the product increased collagen thickness in the skin by a specific physiologic mechanism, the product would then be considered a pharmaceutical, or drug.

Although it's clear that many of these cosmeceuticals work by altering physiologic processes in the skin (thus meeting the legal definition of a drug), manufacturers will often avoid making specific claims or holding clinical trials to avoid subjecting their product to the lengthy and expensive US Food and Drug Administration (FDA) approval process.

There is no legal category named "cosmeceutical"; the FDA legally defines products by their intended use as claimed by the manufacturer, as either cosmetic or drugs. Cosmetics are defined as products "intended to be [applied] ...to the human body for cleansing, beautifying, promoting attractiveness, or altering appearance", whereas drugs are defined as articles (other than food) "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.....or intended to affect the structure or any function of the body of man or other animals." Under these definitions, some products, such as deodorants, flouride toothpastes, AHA's, etc. have intended uses as both cosmetics and drugs, and hence must comply with requirements for both.

Sunscreens: Although skin loses about 1% of its collagen and elastic tissue per year after age 25, it is the effect of ultraviolet light from the sun that causes most of the visible effects of "aging" skin. Regular use of an effective sunscreen is the single most important step one can take to maintain healthy, youthful-looking skin.

Ultraviolet radiation (UVR) from the sun damages proteins, elastin, and DNA in the skin, and is the major cause of skin aging and skin cancer. Short wavelength ultraviolet rays, or UVB, are absorbed primarily in the upper layers of skin (the epidermis), while the longer wavelength, or UVA, rays are more penetrating, causing damage in the upper, or papillary dermis. UVB damage to DNA in the cells of the epidermis s the most common cause of skin cancer, while UVA damages the delicate collagen and elastic fibers in the papillary dermis, causing loss of elasticity, wrinkling, discoloration and telangiectasia ( "broken veins"). Unlike UVB, UVA is only partially blocked by glass and atmospheric water vapor (clouds), and is less affected by time of day, season, and geography. Only UVB rays induce tanning, which is a protective response to radiation damage to the epidermis; the longer wavelength UVA rays such as those used in tanning booths, do not induce a true protective tan.

There is no such thing as a safe tan! The presence of a tan is evidence that the skin has been damaged by ultraviolet radiation. Damage induced by ultraviolet radiation is cumulative over a lifetime, and is not related to activity at the time of exposure (for example, 100 3 minute exposures while running errands is equivalent to 5 hours of continuous exposure lying on a beach).

Although it's almost impossible to eliminate exposure to UVR entirely, it can be minimized by protective clothing and proper use of an effective sunscreen. Effective protection from photoaging UVA is more demanding than that required for the cancer-causing UVB. The commonly used "SPF" refers only to UVB rays, and does not translate into UVA protection. Most "drugstore" sunscreen preparations are effective UVB blockers, but allow most of the more penetrating UVA energy to pass through and age the skin.

Traditional chemical sunscreens act primarily by binding to skin protein and absorbing UVB (280-320nm) photons, and most are based on para-aminobenzoic acid (PABA or its derivatives such as Padimate O), cinnamates such as methoxycinnamate, and various salicylates (Octyl salicylate). Many commercial preparations contain weaker UVB/UVA absorbers, including benzophenones (Oxybenzone, Benzophenone), dibenzoylmethanes, and anthraline (Menthyl anthralinate) derivatives, which have a limited UVA (320-400nm) absorption as well. Octocrylene is a weak but stable UVB absorber used to protect other agents from degrading. Avobenzone (Parsol-1789) is a benzophenone with fair UVA protection, but it degrades readily and tends to be irritating. All of these organic sunscreens (especially PABA) can cause allergic or irritant contact dermatitis, photoxic, and photoallergic reactions and no single organic agent gives complete protection from UVA and UVB radiation.

Physical agents, or sunblocks, act as barriers which reflect or scatter radiation. Direct physical blockers include metal containing compounds such as iron, zinc, titanium and bismuth. Iron oxide pigments are incorporated in many cosmetics, and provide protection from not only UV radiation, but visible and IR (infrared) as well. Zinc Oxide (ZnO) and Titanium Dioxide (TiO2) are highly reflective white powders, whose optical properties vary with particle size. Traditional ZnO sunblocks such as those commonly used by lifeguards are opaque white, but when the particle size of the zinc oxide or titanium dioxide powder is decreased to 100-150nm (submicron or "ultrafine" particles), they transmit visible light while retaining their UV blocking properties, rendering the sunblock invisible on the skin. Submicron zinc oxide is somewhat more stable than submicron titanium dioxide and offers better UVA protection. Allergic or irritant contact dermatitis or phototoxicity do not occur with these agents. Currently, preparations containing at least 2-6% submicron Zinc Oxide are the preferred sunscreens for comprehensive UVA protection.

Other ingredients that may be found in suncreens include "extender" substances such as mica or talc, and organic polymers such as micronized nylon and chitin. Aside from improving the "feel" of the sunscreen preparation, these substances can help scatter energetic photons and act as a "scaffold" for the active sunscreen ingredients, increasing the effective thickness of the active sunscreen layer.

Moisturizers: Moisturizers usually incorporate Emollients to smooth the skin surface by working their way into the non-living outer layers of the skin, filling spaces between the layers and lubricating, and Humectants to help skin cells absorb and retain moisture in these layers.

Commonly used emollients include mineral oil, petrolatum, shea butter, cocoa butter, and animal oils including squalane, mink oil, emu oil, and lanolin. Long-chain fatty acid esters such as myristates, palmitates, cetyrates, stearates, various triglycerides, and cholesterol and derivatives are often included in the formulation as thickening agents.

Humectants often used in moisturizers include glycerin and glycol derivatives, such as propylene or polyethylene glycol (PEG), hyaluronic acid and its salts, mono- and polysaccharides such as fructose, sorbitol, polysorbates, cellulose, and glucosamine and hyaluronates, phospholipids including ceramides and sphingolipids, amines such as triethanolamine and diazolinyl urea, and silicones such as dimethicone, which also has excellent emollient properties and contributes to the "feel" of the moisturizer.

Most commercially available contain a wide variety of other substances, including fragrances, antioxidants, A- and BHAs, preservatives (such as methylparaben), soothing agents such as bisabolol, allantoin, aloe, licorice, chamomile, green tea extract, etc., and various sunscreens.

Despite the common belief that moisturizers are the mainstay of skin care, they are often unnecessary and may even be detrimental in some patients, especially those with oily or especially sensitive skin. All moisturizers have the potential to clog pores and cause irritation, and should only be used when the skin is truly dry.

Alpha Hydroxy Acids (AHAs): AHAs, or "Fruit acids" are mild organic acids present in various foods. The most commonly used AHA is Glycolic Acid, derived from sugar cane; other AHAs used therapeutically include Lactic Acid (milk), Citric Acid (oranges, grapefruits, lemons), Tartaric Acid (grapes), Pyruvic Acid (bananas and other fruits), and Malic Acid (apples). AHAs are commonly used in low concentrations in cleansers, moisturizers, and toners, and in higher concentrations as light peel solutions.

The principal effect of AHA's is to loosen dead skin cells in the outer layers of the epidermis, increase cell turnover, and increase the deposition of glycosaminoglycans in the upper dermis. This refines the texture and appearance of the skin, unclogs pores, and weakens the epidermal barrier to allow effective penetration of other topical agents, including moisturizers, retinoids, bleaching creams, antioxidants, etc.

AHA's are also hypergolic, or water binding, and thus are outstanding hydrating agents. The net effect of this exfoliation and hydration is smoother and healthier looking skin.

The beneficial effects of AHAs have been known since antiquity. Legend has it that Cleopatra bathed in sour milk and Marie Antoinette in champagne, containing lactic and tartaric acid, respectively. A typical AHA regimen would include at least two weeks of daily use of a home care product, followed by a series of 3-6 light facial ("lunchtime") peels, spaced about 2 weeks apart. Other topical agents, such as bleaching creams, retinoids, etc. may be added gradually after the first peel. The home care AHA products are continued, and "maintenance" peels can be formed every few months as needed. Some patients will "plateau" after a while, and the concentration of AHA may be increased, and/or other therapies, such as light peels or microdermabrasion, added to the skin care regimen.

The efficacy of AHAs is directly related to the amount of free acid present in the product. A low pH (pKa) means more free acid, and greater penetration into the dermis, but with a greater potential for adverse reactions. Many products are prepared with a high concentration of an AHA, but are "buffered" with an alkaline solution such as NaOH or NH4OH, decreasing the acidity (raising the pH) and irritation potential of the product. This is why some products containing as little as 2% AHA can be more effective (and more irritating!) than products containing 20% or even more AHA. As AHAs became a more popular ingredient in skin care products over the last decade, the incidence of adverse reactions seen with high concentrations, such as severe erythema, blistering, pigmentary changes and eye irritation, prompted the Cosmetic Ingredient Review Panel of the FDA to limit consumer products containing AHA's to a 10% or less concentration, and salon products to less than 30% concentration or pH 3.0 or higher. Physicians may use AHA's in higher concentrations and lower pH, either alone or in combination with other agents.

Beta Hydroxy Acid (BHA): There is only one clinically important beta hydroxy acid, Salicylic Acid. This substance, a close relative of the common aspirin, is repelled by water and highly soluble in fats and oils, and is used primarily to open comedones and expedite penetration of less fat soluble AHAs into oily skin. It's most commonly used in combination with AHAs in light peeling solutions.

Retinoids: Retin-A (retinoic acid or tretinoin), originally approved for the treatment of acne, has been shown to be effective for the prevention and treatment of sun-induced skin aging. Effects include increased collagen and circulation in the upper or papillary dermis, reduction in hyperpigmentation and brown spots, increased cell turnover in the upper layers of skin, including blackheads and pores, and an overall improvement in the appearance of the skin. These beneficial effects of retinoids are related to the dose and duration of use, with the optimum effect noted after at least a year of treatment. Unfortunately, topical retinoids tend to be very irritating, with most patients experiencing redness, flaking, and increased skin sensitivity. Increased sensitivity to the sun is another drawback of retinoid therapy. A less well known drawback of retinoid therapy is that prolonged use (>4 months) is needed to produce significant improvement in the appearance of the skin . New and improved preparations of tretinoin, including Retin-A Micro and Renova, use improved delivery methods to minimize irritation.

Newer "Third Generation" topical retinoids, such as Differin (adapalene) and Tazorac and Avage (tazarotene) are currently approved for treatment of acne and photoaging. Avage (tazarotene) has been accepted as the "gold standard" topical retinoid for cosmetic use. Like other retinoids, it exerts its action on cellular receptors, and appears to be somewhat less irritating and photosensitizing, as well as more effective for both acne and photoaging, than Retin-A. Some of the effects of Avage include:

improvement of collagen synthesis and repair
decreased production and aggregation of melanosomes, thereby improving pigmentary abnormalities
increased production of ground substance (hyaluronic acid), thus "plumping" the skin and improving wrinkles
normalization of differentiation of keratinocyte differentiation, which decreases formation of clogged pores and scaly premalignant patches.

Retinoid activity is related to binding on nuclear retinoic acid receptors (RAR's) thereby regulating specific gene expression.

Like other retinoids, Avage needs to be properly incorporated into a skin care regimen to avoid unecessary irritation and maximize its effects. For more information on the proper use of Avage.

Retinol: Vitamin A, or Retinol, is converted to retinoic acid (tretinoin, Retin-A) in living cells. When applied to skin, Retinol penetrates betterthan retinoic acid, and does not produce the same irritating effects. Although its clinical effects are not as dramatic as retinoic acid, retinol is available without prescription and has been incorporated into many skin care products. Regular exfoliation with AHAs may enhance the effects of Retinol.

Bleaching Agents: Hydroquinone is the most commonly used agent for "bleaching" brown marks, liver spots, melasma, etc. Acting to block the formation of the skin pigment melanin, hydroquinone's bleaching activity is reversible, that is, the pigment returns when the hydroquinone is discontinued. Kojic acid, extracted from mushrooms, is a slighly less effective agent. Either may be compounded with AHA's. As with any bleaching agent, aggressive exfoliation and sun protection are necessary for good results. Either agent may produce redness and irritation, especially with prolonged use. Arbutin, extracted from bearberries (licorice), also is an inhibitor of of melanin production, and is often used in skin care products as a soothing agent.

Antioxidants: The ability of the body to turn nutrients into energy involves Oxidation. in which nutrients are "burned" in a controlled manner to provided energy for growth and repair. An inevitable result of this process is the production of free radicals. Free radicals may also be produced by processes other than oxidation, most notably from ionizing solar radiation, including UVA and UVB.

A free radical is an atom or molecule containing an unpaired electron. Elevated to an excited state by some energetic reaction, the unpaired electron will seek to attain a lower energy state by pairing up with another electron or electron rich molecule, as with 2 highly reactive free oxygen atoms pairing up to form the stable O2 molecule. The most significant free radicals in biological systems are those involving oxygen, such as the superoxide (HO2) and hydroxyl (OH) radicals, produced during normal cellular respiration.

By providing an electron, antioxidants may convert the free radical to a non-radical species, or to a more stable radical form. The pigment Melanin is an example of a stable radical form, where highly excited electrons are "shared" throughout the aromatic structure of the macromolecule, dissipating the electronic energy as heat. Another example of stable radical forming compounds are the spin trap compounds (see below). Dioxygen (O2) itself is a free radical (actually a diradical).

Free radicals play an indispensable role in normal biological processes, but these extremely reactive molecules can cause damage to normal cellular processes and structure, and are a key contributor to the aging process. To defend against damage from free radicals produced in the normal course of cellular function, biological systems have evolved Antioxidants.

Biologic antioxidant systems include:

Antioxidant enzymes such as superoxide dismutase, catalase, peroxidase

dietary antioxidants such as the tocopherols, carotenes, ascorbic acid, alpha-lipoic acid, glutathione, resveratrol, polydatin, etc.

"solid state" antioxidants such as melanin

DNA repair systems

Antioxidants are often incorporated into skin care products to protect the skin from free radical damage produced by normal aging, pollution, and UV radiation from sun exposure. Many of these antioxidants are available as dietary supplements, or "nutraceuticals", and have been demonstrated to have a plethora of beneficial effects, at least in the laboratory. Their role as topical agents is less well documented.

Vitamin C: Vitamin C, or ascorbic acid. is essential for collagen production, but exerts its antioxidant effects by quenching free oxygen radicals produced by ultraviolet radiation and by assisting Vitamin E in protecting cell membranes.

Although the photoprotective effects of l-ascorbic acid are well established, it readily degrades in the presence of UV radiation, and does not penetrate the skin well, except at high concentrations and high acidty. Vitamin C esters, although more stable, have limited bioavailability when used topically.

Vitamin E: The active form of Vitamin E, alpha tocopherol, has been shown to inhibit enzymes which promote breakdown of collagen and to protect cell membranes from oxidation (lipid peroxidation). Contrary to popular opinion, topically applied vitamin E has not been demonstrated to have a significant effect on scar formation.
Spin Traps: Spin traps are special molecules that can trap and detoxify damaging free radicals which age the skin. They are commonly incorporated into preparations which include other antioxidants.

The term "spin trap" is derived from the technique used to detect and identify free radicals, electron spin resonance. The most commonly used spin traps are nitrone derivatives, such as 5,5,-dimethyl-1-pyrroline-N-oxide (DMPO), alpha-(4-pyridyl-1-oxide)-N-tert-butly nitrone (POBN), and alpha-phenyle-N-tertbutly nitrone (PBN), themselves stable free radicals. Reactive free radicals are attracted and bound to the beta carbon atom in the spin trap, forming a spin adduct and effectively "trapping" the free radical, allowing the structure of the trapped radical to be deduced.

Spin Traps show promise as blocking agents for inflammation caused by UV exposure. Unlike traditional sunscreens, which prevent UV mediated inflammation when used before exposure, spin trap compounds scavenge free radicals and minimize the inflammatory response during and for up to 12 hours after exposure to UV light. By interfering with the inflammatory cascade, these compounds may prevent collagen and elastin degradation, and thus premature aging of the skin.

Coenzyme Q10: Also known as ubiquinone, Coenzyme Q10 is a component of all cell membranes, and is a vital component of the electron transport chain. It acts to shuttle electrons in normal metabolism, trap free radicals, and help regenerate other antioxidants present in the cell, especially vitamin E.

CoQ10's role in oxidative metabolism and ATP synthesis has been well described. It acts primarily as a electron carrier in the mitochondria, with a more theoretical role as a cellular antioxidant. It has been postulated that CoQ10 may play a major role in preventing lipid peroxidation in mitochondrial membranes. Oral administration of CoQ10 has had some anecdotal benefit in patients with a variety of mitochondrial cytopathies and disorders of energy metabolism.

Idebenone: Similar in structure to Coenzyme Q10, idebenone is a more efficient free radical scavenger, and functions incidentally as an electron carrier. It has been used outside the U.S. for years as an anti-aging compound, as well as a cognition enhancer in patients with Alzheimer's disease and other neurologic disorders.
Alpha-lipoic acid (thioctic acid) is a potent antioxidant normally found inside cells, acting to protect delicate cellular membranes from free radical damage during normal cellular respiration
Resveratrol and Polydatin deserve special mention as the substances responsible for the "French Paradox"; that is, the very low incidence of heart disease in residents of Southern France, despite high rates of smoking and a diet high in saturated fats. This effect has been attributed to a high consumption of red wine, a rich source of resveratrol.

Resveratrol and Polydatins are glucopyranosides found in many fruits and vegetables, the highest concentrations being found in grape skins, which synthesize these compounds in response to exposure to UVA/B and fungal pathogens. Biologic activities of these glucopyranosides include potent free radical scavenging activity, with cardio- and neuroprotection and inhibition of lipid peroxidation similar to that seen with vitmins C and E.

Boldine
Glutathione
Beta-Carotene: occuring in many vegetables, notably carrots and tomatoes, this compound helps minimize lipid peroxidation of cell membranes, and is especially effective at quenching UV-induced singlet oxygen.
Anthocyanins: these bioflavonoid compounds, extracted from pine bark ("Pycnogenol") and grape seeds actively quench free radicals and potentiate the effect of vitamins C and E.
Green Tea extract contains antioxidant poyphenols which have been shown to protect against redness and swelling induced by UV radiation.
Ginko Biloba: Often used as a dietary supplement, Ginko Biloba leaves contain an assortment of polyphenols and bioflavonoids. In addition to antioxidant effects, Ginko Biloba extracts has been demonstrated to increase collagen production in cultured fibroblasts, although this effect has not been conclusively demonstrated in living skin.

Human Growth Factors: Harvested as a by-product of tissue-cultured human skin, various human growth factors have been incorporated into topical preparations, the best known of which is TNS Recovery Complex. These substances, essential for wound healing and recovery, have been shown to reduce the number and depth of wrinkles and fine lines, as well as improve skin texture and elasticity when used over time.

Some of the growth factors found in tissue culture media include transforming growth factor beta (TGF-B), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF). Other substances found in cell culture media include matrix proteins, procollagens, interleukins, cytokines, and other compounds with biologic activity. As with any topical prepartion, penetration through the stratum corneum limits the bioavailability of these substances.

Peptides: Peptides are fragments or pieces of proteins, which have a variety of effects on cellular function. Many of the newer cosmeceutical preparations include both synthetic and naturally occuring peptides demonstrated in the laboratory to have a biologic effect on aging or damaged skin. Certain peptides may stimulate skin metabolism and repair, others inhibit the breakdown of collagen, and still others to decrease muscle movement, thus improving dynamic wrinkles.

Cosmeceutical peptides may act as "carrier" agents, to facilitate delivery of other agents into the skin, most notably copper, an important cofactor in collagen produbtion, as "signaling" molecules, by activating fibroblasts and inhibiting matrix metalloproteinases (MMP) which degrade collagen, and as inibitors of neuromuscular transmission by interfering with the activity of membrane proteins necessary for calcium dependent exocytosis and release of acetycholine.

Despite a better understanding of role of peptides in skin metabolism, repair, and aging, there's very little evidence that they have an actual effect on the appearance of skin, or even manage to get to the area in the skin or muscle to exert their physiologic activity.

Botanical Agents: Herbal remedies have been used since time immemorial, and a variety of botancial agents may be incorporated in skin care preparations.These agents are usually listed on the label as "extracts", and although there may be a rationale for their use based on folklore or in some cases in-vitro studies of the extract or its components, in most cases there is little if any scientific evidence that they are any more efficacious than placebo. Many of these may be toxic, or interact with other drugs when taken internally, and cause irritation, dermatitis, and/or photosensitivity when used topically. A lack of standardization of the various preparations further complicates any assessment of their efficacy.

Arnica Montana (arnica) has been used topically to reduce or minimize bruising and swelling, and and as a general soothing agent. Although studies have demonstrated these effects in the laboratory, rigourous clinical trials on patients have shown no significant effect.

Aloe Vera (aloe) has been demonstratede to enhance wound healing in patients with frostbite, and superfical abbraded wounds, although some studies have shown delayed wound healing, especially in deeper or complex wounds.

Berberis Aristata (barberry) extract contains berberine, a compound that has antiseptic and antinflammatory properties, but may also be a potent skin irritant in some patients.

Bromelain (pineapple) is an enzyme extracted from pineapple stems, which when taken internally, may help decrease swelling and speed the resolution of bruising when taken before a procedure.

Calendula officinalis (calendula) from the common marigold, has mild antinflammatory and antiseptic properties

Centella Asiatica (Hawaiian pennywort) extract or asiatic acid has known antinflammatory properties and may hasten wound healing.

Chamomile extract has been shown to have mild anti-irritant, soothing, and antioxidant properties.

Echinacea purpureae (purple coneflower)

Hammamelis (witch hazel)

Symphytum officiale (comfrey) Another traditional healing/soothing agent for swelling and bruising, comfrey has demonstrated liver toxicity and carcinocenicity in laboratory rats, and is not reccommended for internal use.

Mentha piperita (peppermint oil) is a mild antibacterial and antifungal agent, and can exert a cooling effect on the skin.

Melaleuca alternifolia (tea tree oil) may antibacterial and antifungal when used topically.

Solanum Dulcamara (bittersweet)

Thuja (red cedar) extract is a mild antiseptic and used as a "calming" agent because of mild vasoconstrictive properties.

Thyme extract, from the herb, contains potent antioxidants

Copper: Copper is found in most biologic systems, and acts as a cofactor in collagen and elastin production, production of new blood vessels, and deposition of glycosaminoglycans in the skin. Unlike copper salts, which are highly toxic, copper atoms are stabilized with peptide complexes (short lengths of protein molecules-see above) to assist delivery into the skin. Copper peptide complexes used topically have been shown to increase procollagen formation and may help retard some signs associated with skin aging.

Zinc: Zinc is an essential element for many biologic processes, and acts as a cofactor for collagen repair and remodeling, control of damaging free radicals in the skin, and proper expression and replication of DNA. Topical uses of zinc-containing preparations include wound healing, anti-inflammation, seborrhea (dandruff), and acne preparations. The two best known zinc containing preparations are zinc pyrithione (for dandruff) and zinc oxide ointment.

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