With these messages clamoring for the attention of your client, as well as your attention as a skin care professional, it is important that you have a deeper scientific understanding than just advertising spin.
Many products and ingredients claim to be “clinically tested.” When a cosmeceutical rep enters your office with the latest and greatest in skin care innovation, one of the easiest ways to understand the real technology of the skin care formulation is to ask for the actual clinical study information. Once you obtain this information, what do you look for?
Cosmetic or cosmeceutical products do not fall under FDA approval like pharmaceuticals do. This means that there is not one standard to which all cosmetic or cosmeceutical claims must adhere, therefore clinical study testing for safety and efficacy is not a requirement for cosmetics. However, for cosmetic products or ingredients to hold scientific validity, there is a recognized “gold standard,” which is based upon the first phase of testing necessary for pharmaceuticals. Phase I testing for a pharmaceutical determines an unbiased proof of safety and effectiveness in humans. This is done to understand the drug metabolism, the relationship between structure and activity, mechanism of action, side effects associated with increasing doses, early evidence of effectiveness, and safety all during Phase I testing. To meet this strict standard, the clinical study should be a double-blinded, prospective, randomized, controlled, human clinical trial conducted by a third party research group with the finished formula. This all may sound overwhelming, so here are a few important terms to remember.
“Double-blind” means that neither the researcher nor the patient knows what products are being used during the study. This is important because then any bias toward or against a product by either the researcher or the patient is removed. Most cosmeceutical studies are “open label” studies, meaning both the researchers and the patient know what the product is, and these are usually conducted in-house. Open label studies allow for the results to be very biased and skewed.
“Prospective” is a term which means that the data is gathered by the researcher at specific points during the course of the study. A “randomized” trial is one where a computer randomly assigns which patients will receive the product to be tested or the control product.
“Controlled” trials are when the product is tested against another product – whether it is a placebo, a pharmaceutical, or another product. This is important for two reasons. The first is because there is something other than the baseline (starting point) to compare to. Second, you may have heard of the “placebo effect.” This is when patients feel better using something simply because they believe the product is having an effect. Using a placebo in a study takes out this element. However, testing against a pharmaceutical product that has already received FDA approval shows a higher level of efficacy than a product simply tested against baseline or a placebo.
Finally, the test should be with the actual product that will be sold on the store shelves, on human skin (known as in-vivo). Many companies do not make this step a priority. It is a priority though, because active ingredients tested in a laboratory (in-vitro) can often have very different results than the same active ingredient in a complete formulation on living, human skin.
All of these steps should then be done by an independent research facility. This again helps take out any bias that can occur during open label studies. It also ensures that the data is completely honest and hasn’t been modified to fit the desires of the marketing department.
The next thing to look for in clinical data is the statistics. For data on any product to be considered scientifically valid, it must show statistical significance which shows that there is enough difference between two things to produce a predictable result. This statistical significance result is measured with a “p-value.” For something to be statistically significant, the p-value must be p<0.05. At its most basic level, this means that if the exact same study is done over and over and over it will produce the same results 95 percent of the time. Statistical significance is different than numerical significance. Often companies will show results of a study, but no provide a p-value. If not p-value is provided, that may mean that there wasn’t an actual clinical difference.
As a skin care professional, you have the right to ask for this type of information from any company trying to sell you products. If the company cannot provide this type of clinical data, you might want to be careful about the promises being made about those products. Here is a brief listing of some of the ingredients with the highest quality of scientific data.

Retinoids
Darlings of the media, vitamin A derived retinoids are the most commonly recognized ingredients on the market today. There is also much scientific supporting evidence that retinoids are very effective at treating the visible signs of skin aging. The vast range of vitamin A derivatives include, but are not limited to, retinoic acid (Retin-A, Renova), retinol, isotretinoin (Accutane), tazarotene, and adapaline.
Generally contact irritation reactions will occur when first using products formulated with retinoids; however, these reactions may resolve in a matter of weeks with regular usage. Photosensitivity can also be an issue, so it is recommended that sunscreen is worn daily.
Products formulated with vitamin A and retinoids must also adhere to strict manufacturing and packaging guidelines. During manufacturing, UV and oxygen exposure must be avoided, and packaging should be opaque and air-tight in order to maintain ingredient integrity.

Exfoliating Acids
Hydroxy acids offer an alternative to retinoids to help treat visible signs of extrinsic aging via chemical exfoliation. If formulated properly, they can be very effective in a formula, for both home care and professional treatments.
There are three types of hydroxy acids, including alpha hydroxy acids (AHA), beta hydroxy acids (BHA), and poly hydroxy acids (PHA). AHAs are generally food or fruit-based, such as glycolic (from sugar cane), lactic (from milk products), mandelic (from almonds), malic (from apples), tartaric (from grapes), and citric (from citrus fruits). PHAs are gluconolactone (found in honey, fruit juices, and wine) and lacto-bionic (formed from gluconic acid and galactose). The most common BHA is salicylic acid (derived from willow bark).
In concentrations of less than three percent, AHA works as water-binding agents in the skin. If over four percent with a pH of 3 to 4, AHA will exfoliate the skin by breaking down the lipids that hold together the outer layers of corneocytes. It is used to treat photo-damaged skin, to normalize cell regeneration, and to increase epidermal thickness and dermal GAGs. In concentrations of 10 percent glycolic may increase photosensitivity, but it does have a mild antioxidant and anti-inflammatory effect. Lactic and citric acids activate tumor necrosis factor alpha (TNFa) and histamine inflammatory cascades. PHAs have strong humectant activity, and can be safely used on very sensitive skin.
Not to be overlooked in the cosmeceutical ingredient arena are dicarboxylic acids such as azelaic acid, derived from castor bean. Azelaic acid is keratolytic and comedolytic, and is an excellent option for treating acne, rosacea, and hyperpigmentation. Azelaic acid also helps deliver ingredients such as ursolic acid and peptides to targeted cell receptors in the skin.
Unless properly manufactured and packaged for stability, these types of ingredients will break down in strength. Preservative agents and pH adjusters must also be added to these formulas, which could create irritation and allergic responses in some individuals. To prevent oxidation which reduces effectiveness, it is best if the product comes in a securely packaged air-tight tube, with a one-way valve for product distribution.

Antioxidants
There are over 8,000 known antioxidants. Of these only 28 have ever undergone double-blind, controlled clinical studies, whereas only 14 showed any efficacy in skin care formulations.1,2
Vitamins that have clinical study information that verifies the activity in skin care product formulations are vitamin B3 (including niacinamide and nicotinic acid), vitamin B5 (panthenol), vitamin E (tocopherol), and vitamin C (ascorbic acid).
Vitamin B3 has been shown to improve visible aging in clinical trials. It is tricky to formulate with other anti-aging ingredients such as retinoids or hydroxy acids, as the pH level must be 5 to 7 to inhibit release of erythema-inducing nicotinic acid from niacinamide.
Panthenol, or vitamin B5, is a component of coenzyme Q10 (ubiquinone), a very well-known antioxidant. Panthotenic acid increases barrier function and hydration by increasing lipid synthesis. Vitamin B5 also protects against UV exposure and is anti-inflammatory.
Especially abundant in the stratum corneum, vitamin E has been shown in studies to provide skin protection and improve the symptoms of atopic dermatitis.3 Vitamin E works with vitamin C and ubiquinone to suppress destructive oxidation reactions. Alpha-tocopherol is difficult to deliver across the stratum corneum, and must be combined with at least two other active ingredients for efficacy.
L-ascorbic acid, or vitamin C, is an essential nutrient metabolized in the human body. However, the body needs a balance of antioxidants including vitamin A, ubiquinone, vitamin E, glutathione, ergotheionein, HAOH, and alpha lipoic acid in order to function at its best. High doses of a single antioxidant could actually become pro-oxidant and increase the incidence of disease. Vitamin C products are notoriously unstable, so it is very important to ask for stability data and clinical trial information on the final marketed product (not on a single ingredient). When exposed to light or air, vitamin C oxidizes quickly, losing efficacy.
Date palm extract is one of the highest food sources of antioxidant activity, and is clinically proven to reduce the signs of visible aging.4 In addition to providing anti-inflammatory, antimicrobial, and depigmentation properties, date palm is estrogenic to help reduce acne, sebaceous hyperplasia, atrophy, and abnormal facial hair growth.
It does not matter if there are antioxidants in a product if they are not at therapeutic concentrations. Also, if an antioxidant is not delivered to the proper cell receptor sites at the right concentration and right ratio, it will have minimal to no effect on the health of the skin. This is why it is vital to check for clinical studies on the marketed formula before making a commitment to a product simply because there are antioxidants in it.

Peptides
Much has been written recently about peptide technology becoming staple ingredients in the anti-aging and skin care industry. Peptides have the ability to synthesize fragments that mimic peptide sequences in collagen and elastin. Other skin component proteins have also been determined.
Cosmeceutical peptides include three types: signaling, carrier, and neurotransmitter modulating. Signaling peptides are helpful in stimulating collagen synthesis, GAG synthesis, keratinocyte and fibroblast proliferation, cell migration, re-epithelialization, and angiogenesis. For example, a potato tripeptide increases ceramide synthesis and a yeast tetrapeptide increases cholesterol synthesis, both factors that fortify and strengthen the skin barrier. Carrier peptides stabilize and deliver micro-nutrients. Neurotransmitter peptides are cell-communicating entities that allegedly produce a reaction similar to botulinum toxin (Botox).
Protein, peptide, and amino acid compounds have an incidence of triggering allergic contact dermatitis and contact urticaria (hives). Although the problem with most peptide products is delivery of the peptides through the stratum corneum, peptide sequences (receptor sites) can be modulated in order to provide potent drug delivery effect.

Growth Factors
Growth factors mediate cell-signaling pathways between and within cells. After any injury to the skin, there are 14 growth factors that function in skin diseases and maintain skin health. Due to the number of growth factors that play a role in the inflammation cascade, single growth factors such as transforming growth factor alpha or beta (TGFa or TGFb), or epidermal growth factor (EGF) produce very little effect. Due to their hydrophilic nature, growth factors have a hard time penetrating through the skin, but a small amount of penetration does create an amplification process. If that small amount could make its way through a hair follicle or eccrine sweat gland, more growth factors are synthesized, activating keratinocyte proliferation to stimulate more growth factors. However, this initial delivery is difficult. The potential safety problems with growth factors include allergic contact dermatitis and carcinogenesis.

Other Noteworthy Ingredients
Botanical ingredients are very popular right now, with product lines focusing on one particular key botanical ingredient. Since most of these botanicals have very little data showing efficacy in a formula, the important thing is to look for clinical studies with the botanical in the final marketed formulation, tested on living human skin. Only then will you know how effective the product is.
Genistein comes from soy, and provides antioxidant, along with anticarcinogenic benefits against several types of cancers. It also helps reduce UVA, UVB, and DNA damage, and provides weak phyto-estrogenic effects, stimulates collagen regeneration, and inhibits destructive MMPs.
Ursolic acid is present in many botanicals including apples, cranberries, rosemary, thyme, and lavender. It aligns collagen and elastin fibers into proper orientation to maximize tensile strength and prevent dermal atrophy. Ursolic acid also upregulates ceramides, one of the three key lipids contained in the skin barrier.
Other key botanical ingredients include feverfew (parthenolide-free), licorice, tea (green, black, white, oolong), coffeeberry, golden fern (polypodium leukotomos), curcumin (tumeric), aloe, arbutin, pycnogenol, chamomile, paper mulberry, lavender, and grape. Many of these have some clinical data to support initial theories of effectiveness.
What we are seeing is that formulations which have a mix of botanical ingredients are trending toward better results. Considering the skin is such a complex organ, a mix of ingredients that work in a number of different ways would seem to make the most sense.
The world of cosmeceutical ingredient formulations is an incredibly complex field. When researching skin care lines to carry in your practice, newly licensed as well as seasoned professionals can easily be overwhelmed by all the claims and information out there. It is an important part of client care that you thoroughly understand the technology behind the products that you recommend. Again, true clinical testing of cosmeceutical ingredient formulas is not a requirement for cosmetic companies – but those companies that do test according to the “gold standard” have gone the extra step to validate their marketing claims and provide a safe and effective product for your clients.

References

1. Pinnell SR. Cutaneous photodamage, oxidative stress and topical antioxidant protection. JAmAcadDermatol. 2003; 48: 1-19.
2. Thornfeldt CR. Review of effective cosmeceuticals. Pending Publication.
3. Burgess C. Topical vitamins in: skin care update: the role of natural products in clinical practice. J Drug Dermatol 2008; 7 (Suppl 7):52-56.
4. Bauza E, Dal Farra C, Berghi A, et al. Date palm kernel extract exhibits anti-aging properties and significantly reduces skin wrinkles. Int J Tissue React 2002; 24:131-136.

Krista Bourne, LE is an Esthetics Education Director at Episciences, Inc. A licensed aesthetician since 2003, Bourne has worked in plastic surgery and medical spas, performing clinical aesthetic and laser enhancement procedures. She has worked closely with Dr. Carl Thornfeldt at Episciences since 2006, and has helped develop procedure, skin care, and training protocols for Epionce skin care.