Cosmeceuticals: A Practical Approach

J. S. Dover, MD, FRCPC, FRCP
SkinCare Physicians, Chestnut Hill, MA, USA
Yale University School of Medicine, New Haven, CT, USA
Dartmouth Medical School, Hanover, NH, USA

Introduction

The cosmeceutical industry has undergone phenomenal growth over the past decade, and much of this expansion can be attributed to an aging population wanting to sustain a youthful appearance. The availability on drug store shelves of biologically active compounds that exhibit both cosmetic and drug-like effects has created a new group of agents, whose degree of efficacy, in many cases, has been unsubstantiated by science, and they remain unregulated. As such, acquiring a basic knowledge of the major classes of active ingredients that are found in cosmeceuticals will enable healthcare professionals to provide accurate and educational information to consumers.

Categorization and Regulation of Agents

According to US FDA Food, Drug, and Cosmetic Act of 1938:

1. A drug is “intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease,” i.e., it affects the structure or function of the body.
2. A cosmetic is intended to be “rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or party thereof for cleaning, beautifying, promoting attractiveness, or altering the appearance of skin,” i.e., the product cannot alter the structure or function of skin.

• Many do contain biologically active ingredients.
• Some alter the structure and/or function of skin, thus, according to the regulatory definition, these could be categorized as drugs.
• Most undergo safety testing, but efficacy is not often assessed.
• Categorization and regulation will depend upon how product claims are presented to the public.
• The term “cosmeceutical” is not recognized by the North American regulatory agencies.
• Products considered to be cosmeceuticals circumvent regulation. Under this category, a lower barrier exists for market entry.

Major Classes of Cosmeceuticals

Sunscreens

• Considered as OTC drugs; sun protection factor - must be proven by in vitro and in vivo studies.
• Regarded by dermatologists as the single most - important formulation that should be applied daily.
• Products formulated to meet individual preferences, such as scent and feel, can improve compliance.

Retinoids

• Natural and synthetic derivatives of vitamin A
• Drugs: retinoic acid (tretinoin), adapalene, and tazarotene
  
  • Substantial scientific data confirm their anti-aging and anti-acne benefits.2
  • Retinoic acid is considered by dermatologists to be the anti-aging gold standard.
  • Available only through a doctor’s prescription
• Cosmeceuticals: retinol, retinaldehyde, retinyl propionate, retinyl palmitate
  
  • In many cases, bioavailability and activity are unproven when formulated.

Moisturizers

• Include emollients, occlusives, and humectants.
• Considered to be the most useful product for the management of various skin conditions (e.g., atopic dermatitis, psoriasis, pruritus, aging skin).

Other vitamins and minerals

Antioxidants

• Include vitamins A, C, and E; alpha lipoic o acid; ubiquinone (coenzyme Q-10); idebenone; polyphenols (e.g., catechins, flavenoids); kinetin; botanicals (e.g., teas, grapeseed, grape skins and stems, coffeeberry).
• Enhance the skin's natural antioxidant protection o system with topical application.
• Reduce free-radical damage by blocking the o oxidative processes in cells.
• Inhibit inflammation that causes collagen depletion.
• Protect against photodamage and skin cancer.
• Do not reverse signs of photoaging.

Hydroxy acids (alpha, beta, poly)

• Include glycolic acid, lactic acid, citric acid, tartaric o acid, pyruvic acid, and malic acid.
• Can improve skin texture and dyspigmentation.
• Can induce actual structural changes in skin, so the o potential exists for regulatory scrutiny.

Lightening agents

• At best, depigmenting agents can achieve modest levels of efficacy.
• Hydroquinone is considered to be the most effective.
  
  • Presently under re-evaluation by the US FDA.
  • Sunscreen use is required due to drug-induced photosensitivity.
• Other examples include kojic acid, glabridin (licorice extract), arbutin, azelaic acid, n-acetyl glucosamine, and vitamin C.

Botanicals/ plant extracts

• Have experienced a rapid rise due to the popularity of "natural" compounds.
• Represent the largest group of additives found in marketed products.
• Limited scientific data to support efficacy and safety.

Epidermal growth factors

• Naturally occurring chemicals in the body that influence cellular proliferation and differentiation.
• Potential applications include regeneration of damaged or aged skin.

Proteins/ peptides

• Can trigger skin repair as needed. There are some indications that they can reduce the signs of aging and accelerate the skin's healing processes.^3,4

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Specific Agents of Recent Interest

OTC Retinoids

• They reduce wrinkles and lentigines.
• Common side-effects include redness, irritation, and an increase in photosensitivity.
• Certain retinoid analogues within the same class of molecules have been shown to provide less irritation, but maintain comparable levels of efficacy.⁵
• 3 classes of retinoids exhibit distinct properties:
  
  • vitamin A metabolites - trans-retinoic acid, retinaldehyde, adapalene, and tazarotene
  • vitamin A - retinol
  • vitamin A esters - retinyl acetate, retinyl propionate, and retinyl palmitate.
  • In randomized, double-blind, placebo-controlled, human studies comparing retinol, retinyl acetate, retinyl propionate and trans-retinoic acid⁵:
  • propionate exhibited the highest rating when evaluated for efficacy and non-irritation.
  • 0.30% retinyl propionate demonstrated superior reductions in wrinkles, redness and hyper-pigmentation vs. 0.15% retinol.

Niacinamide (vitamin B3)

• In a left-right randomized, double-blind, placebo-controlled study in women aged 25-60 years.
  
  • Patients applied a formulation containing niacinamide twice daily for 8-12 weeks.
  • Results showed a decrease in transepidermal water loss through increased barrier layer lipids.^6,7
• Another placebo-controlled, double-blind, left-right randomized study looked at 60 women of Japanese descent aged 25-60 years.
  
  • Split-face treatment twice daily for 8 weeks showed substantial improvement on lentiginous lesions.⁸
• A meta-analysis showed significant reduction in fine lines, wrinkles, hyperpigmented spots, blotchiness, sallowness, sebum production, irritation, and improvement to the skin’s barrier function.⁹

Topical Peptides (retinoid alternative)

• Regarded as cellular messengers that are formed from amino acids designed to mimic peptide fragments with endogenous biologic activity; one is a 5 amino acid fragment (pentapeptides lysine-threonine-threonine-lysine-serine [KTTKS]).
• KTTKS plays a role in signaling fibroblasts to produce collagen in the skin,10 which can improve the appearance of wrinkles.
  
  • One variation, known as palmitoyl-lysine-threonine-threonine-lysine-serine (Pal-KTTKS) was tested in a controlled, double-blind, left-right randomized, split-face study of 92 photoaged women with Fitzpatrick I-III type skin between 35-55 years of age.
  • Pal-KTTKS concentration was 3ppm; both groups were treated twice daily for 12 weeks
  • Improvements in wrinkle appearance and length were observed.
  • When 3ppm pal-KTTKS was combined with 3.5% niacinamide vs. placebo, an even greater reduction in wrinkle length was noted.

N-Acetyl Glucosamine (NAG)

• A placebo-controlled study¹¹ comparing 3.5% NAG with the combination of 3.5% NAG + 3.5% niacinamide on hyperpigmented spots showed a superior reduction in pigmentation in the combination treatment group vs. both the placebo and NAG only groups.
  
  • When combined, the agents produced synergistic effects.

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Use of Scientific Testing to Forecast Future Discoveries

• High throughput screening is presently in use to identify the next generation of active agents for cosmeceutical applications. This method has the capacity to screen thousands of compounds in a matter of days, or even hours.
• Genomic assays can be used to define all genes expressed in the skin. One application includes identifying targets for the management or prevention of skin and other disorders.
• Proteonics is a method of identifying proteins that are encoded by a genome. By promoting an understanding of the molecular mechanisms that cause human diseases, the development of novel therapeutic agents is possible.
• Metabonomics analyzes alterations in the metabolic end-products and the active pathways that result as a response to drugs, environmental influences, and diseases.

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Conclusion

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References

1. Kligman AM, et al. 1. J Am Acad Dermatol 15(4 Pt 2):836-59 (1986 Oct).
2. Sorg O, et al. 2. Dermatol Ther 19(5):289-96 (2006 Sep-Oct).
3. Gold MH, et al. 3. J Drugs Dermatol 6(10):1018-23 (2007 Oct).
4. Lupo MP. 4. Dermatol Surg 31(7 Pt 2):832-6 (2005 Jul).
5. Bissett DL. Topical retinyl priopionate – clinical comparison: a low irritation retinoid for diminishing wrinkles and 5. hyperpigmentation in photoaged human skin. Presented at: The 60th Annual Meeting of the American Academy of Dermatology; New Orleans, LA; February 22-27, 2002. Poster #P78.
6. Tanno O, et al. 6. Br J Dermatol 143(3):524-31 (2000 Sep).
7. Bissett D. 7. Cutis 70(6 Suppl):8-12 (2002 Dec).
8. Hakozaki T, et al. 8. Br J Dermatol 147(1):20-31 (2002 Jul).
9. Bissett DL, et al. 9. Dermatol Surg 31(7 Pt 2):860-5 (2005 Jul).
10. Katayama K, et al. 10. J Biol Chem 268(14):9941-4 (1993 May 15).
11. Kimball AB, et al. Topical formulation containing N-acetyl glucosamine and niacinamide reduces the appearance of 11. hyperpigmented spots on human facial skin. Presented at: The 64th Annual Meeting of the American Academy of Dermatology; San Francisco, CA; March 3-7, 2006. Poster #P235.

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