The term “cosmeceutical” is a contraction of “cosmetic” and “pharmaceutical” and indicates, as the name suggests, a drug-like effect on the skin. It was coined more than 25 years ago by Professor Albert Klingman and has quickly entered the vocabulary used by cosmetologists (more than 8.4 million hits on Google). Furthermore, given that these cosmeceuticals hold promise for physiological and drug-like effects, they straddle precariously the drug vs cosmetic regulatory definition. As such, the term “cosmeceutical” is rather controversial and is not recognised by the FDA.
Proteins and skin function
A number of cosmetic ingredients are used due to their physiological action. For instance, niacinamide is used to improve the barrier function of skin, moisturising of skin, UV-damage protection, and anti-inflammatory properties that alleviate acne and irritation. Similarly, hydrocortisone is used to reduce swelling, itching, and redness. Finally, there are a number of ingredients that have shown skin-bleaching effects and are used to lighten darkened skin from sun exposure, melasma, age spots, and acne scars.
With such interesting functions, the market for cosmeceuticals enjoys rapid growth. According to market analysis reports, the cosmeceutical market within Northern America is expected to increase at a compound annual growth rate of 8.24% reaching $18 billion in revenue by 2024.
The positioning of peptides and proteins in the market of cosmeceuticals becomes obvious since these ingredients may infer a physiological action, and peptides and proteins are by definition the functional units of bodily function. More specifically, peptides and proteins are integral in making you who you are, translating information from a molecular level to observable physical traits and capabilities. Genes encode all information necessary for life, but it is proteins and peptides that exert those encoded traits. For instance, eye and skin colour are dictated by the amount of melanin production and deposition, processes under the control of peptides and proteins. Proteins also play a significant role in dictating immunity and brain function since antibodies and neurotransmitters are proteins and peptides respectively by nature.
Perhaps most interesting from a cosmetics perspective is that peptides and proteins have a fundamental role in establishing and maintaining the integrity and structure of skin. For instance, the protein elastin that is found in the extracellular matrix is integral in maintaining the elasticity and shape of skin. Filaggrin is a protein that is essential for the regulation of epidermal homeostasis and further influences the barrier function of skin by incorporating within the lipid envelope of the stratum corneum. Cells in the epidermis contain a structural matrix of keratin, which makes this outermost layer of the skin almost waterproof, and along with collagen and elastin gives skin its strength. Collagen is a hard, insoluble, and fibrous protein that makes up one-third of the protein in the human body. In most collagens, the molecules are packed together to form long, thin fibrils to give skin its strength and elasticity. Most interestingly, collagen production decreases with age, contributing to skin wrinkling and sagging.
As can be seen, the appearance, strength, and elasticity of skin is a complex interplay between a number of key proteins. Further compounding this is the fact that skin function is under the tight regulation of other proteins rather than just the structural proteins discussed above. For instance growth factors such as epidermal growth factor and fibroblast growth factor are proteins that are secreted by cell types in the dermis and epidermis that regulate cellular growth, proliferation, and differentiation under controlled conditions. As such, they too play an essential part in maintaining healthy skin structure and function.
Cosmetic peptides and anti-aging
Given the role of proteins and peptides in maintaining skin function, structure, and health, altering the molecular structure of skin through active cosmetic ingredients is a desirable result. This has been attempted in two ways previously; either by providing the structural proteins in formulations, or by harnessing the body’s own ability to synthesize these structural proteins by altering the complex pathways regulating expression of skin proteins. Briefly, this is done by 4 different mechanisms; improving delivery of trace elements needed for molecular processes, stimulate production of these structural proteins, decrease muscle contraction, and inhibition of enzyme processes related to ageing. As such, there are already a number of raw materials available to formulation chemists affected one or a number of these mechanisms:
Table 1: peptides and raw materials with anti-aging molecular modes of action
| Types of peptides used in formulation | Anti-aging molecular mechanism | Commercially available
examples |
| Carrier peptides | Improve dermal delivery of necessary cofactors for enzymatic processes such as wound healing and protein synthesis | Copper peptide-GHK |
| Signal peptides | Stimulate fibroblast production of collagen, elastin, fibronectin, laminin, etc. | Syn®-coll and Decorinyl™ |
| Neurotransmitter-inhibiting peptides | Decrease facial muscle contraction and therefore visible lines | Argireline® and Syn®-ake |
| Enzyme-inhibiting peptides | Inhibit enzymes involved in the ageing process | Preregen® and Sericin |
Further highlighting the potential physiological activities are actual preclinical and clinical efficacy studies for these raw materials. Palmitoyl pentapeptide-4 is a small, highly specific, biologically active peptide which has been reported to stimulate the production of elastin, fibronectin, glucosaminoglycan and collagens, support of the extracellular matrix, and wound healing. Its structure is related to the precursor of collagen type I. The stimulatory effect of palmitoyl pentapeptide-4 on collagen and fibronectin seems to relate mainly to the biosynthetic pathway, rather than the export and degradation pathways. Indeed, palmitoyl pentapeptide-4 has been shown to significantly increase procollagen secretion and upregulate type I collagen and hyaluronic acid synthase-1 expression by human fibroblasts in vitro (Farwick et al., 2011). Clinical studies indicated that palmitoyl pentapeptide-4 exhibited significant improvement in skin roughness, wrinkle volume, and wrinkle depth, compared to vehicle control (Schagen, 2017).
A similar peptide, tetrapeptide GEKG, was also found to visibly improve wrinkles after 8 weeks of treatment twice daily (Figure 1). Skin biopsies and histochemical analysis of the volunteers indicated that treatment with tetrapeptide GEKG, but not with placebo, increased the formation of procollagen, hyaluronic acid, and fibronectin. The results indicated that topical application of the matrikine GEKG to human skin stimulates ECM protein expression of collagen at the mRNA and protein level, and of hyaluronan and fibronectin, respectively, and that this is associated with a significant improvement of skin physiological and clinical parameters such as skin wrinkles and skin roughness reflecting skin ageing (Farwick et al., 2011).
Figure 2: After treatment with 50 ppm GEKG or O/W vehicle (=placebo 1) for 60 days on buttock skin, biopsies were taken for immunohistochemical assessment of procollagen I, hyaluronic acid and fibronectin (Farwick et al., 2011).
The above examples highlight how peptides and proteins are interesting cosmetic ingredients given their impact on skin aging and structure along with defined molecular modes of action.
Regulatory considerations
Peptides able to influence the skin’s appearance and therefore structure is evidently of interest, with various raw materials already on the market offering similar promising results by affecting different functions. However, given that these peptides may have physiological activity, the distinction between cosmetic ingredient and drug may be impacted. The implied function of the ingredient would indicate whether it is a cosmetic or drug, and this is achieved by its intended use, claims, and consumer perception.
As already indicated, the term “cosmeceutical” is considered controversial as the name suggests a level of physiological activity while maintaining its a status as a cosmetic ingredient. More specifically, the FDA indicates a cosmetic ingredient to “cleanse, beautify, promote attractiveness, or alter the appearance” [FD&C Act, 201 (i)] while a drug is intended to “affect the structure or any function of the body of man” as according to the FDA [FD&C Act, 201 (g)(1)]. Similarly in the EU, a cosmetic ingredient is defined as having the function to clean, perfume, change the appearance, and/or correcting body odours, and/or protecting and keeping in good condition. A drug on the other hand is defined as a substance having properties for treating or preventing disease in humans or with the functions to restore, correct, or modify physiological functions. It is therefore clear how a cosmetic ingredient with physiological activity may blur these lines. The impact of designating an ingredient as a drug rather than a cosmetic can be significant, as drugs are systematically tested which require a large financial outlay and years of development. It is apparent therefore that the distinction between a cosmetic and a drug is its intended use which is established taking a number of factors into consideration; the product’s claims, consumer perception, and if ingredients have a well-known therapeutic use.
Claims and consumer perception
Claims can be indicated on the labelling, advertising, or description of ingredient or product and the nature of the claims is integral in identifying whether and ingredient or product is a cosmetic or drug. Claims that assert treatment or prevention of disease or by altering physiological function are classified as drug claims. On the other hand, claims regarding maintenance, appearance, or cleansing are considered as cosmetic claims. Furthermore, it is apparent that drug claims are clear and conclusive, asserting well-defined functions and effects while cosmetic claims are less so. Examples highlighting this are indicated as case studies as identified in warning letters issued by the FDA for cosmetic products deemed to have drug claims:
Claims such as “treats acne”, “acne treatment”, “acne medication”, and “controls acne breakout” was considered as drug claims by the FDA. The corresponding cosmetic claims would likely be “improves appearance of acne”. Similarly, “natural antiseptic”, “anti-bacterial”, “anti-inflammatory”, “reduces inflammation” were all examples of drug claims as identified by the FDA because it is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease.
Claims can influence consumer expectations of the ingredient and/or product, and if drug-like claims are used, consumers would expect drug-like efficacy. As such, claims serve as the pivotal factor differentiating between drug and cosmetic, and since many peptide and protein cosmetic ingredients have shown interesting physiological functions, these functions need to be suitably communicated.
Toxicological aspects
Ultimately, distinguishing between drugs and cosmetics is mainly managed by the claims and subsequent consumer perception of these interesting ingredients. However, there are toxicological aspects that may weigh in on the discussion. Specifically, the Working Group on Cosmetic Products manual on borderline products indicates that substances which restore, correct, or modify physiological functions by exerting pharmacological activities are identified by “virtue of its presentation” or “by virtue of its function”. The former highlights the importance of claims and consumer perception as discussed above. However, the latter indicates that virtue of function is further assessed by “considering all characteristics of the product including absorption, concentration, route of administration, frequency of application, application site, and the degree of penetration”.
This offers and interesting opportunity for science and biology to frame the debate of drug vs cosmetic, since it seems rather rudimentary to base this only on claims and advertising. For instance, as indicated in “Safety of peptides & proteins as cosmetic ingredients”, the stratum corneum is a formidable barrier to penetration of large substances such as peptides and proteins. However, for argument’s sake, assume a growth factor was designed to penetrate the skin and alter physiological function; its activity and therefore potential side-effects would not be impacted by what is indicated on the products packaging and rather a systematic approach is needed to identify drug vs cosmetic designation. Furthermore, absorption, concentration, exposure, metabolism, bioactivity, etc. are all aspects investigated when trying to identify the toxicological profile and therefore risk to human health of cosmetic ingredients and drugs. As such, this allows a systematic approach in identifying not only risk to human health but also designation as a drug or cosmetic based on robust scientific approaches.
Conclusion
Given their potential anti-aging activities, peptides and proteins are interesting cosmetic ingredients. However, given their potential physiological activity, peptides and proteins along with other similar “cosmeceutical” ingredients may blur the line between cosmetic and drug. So far, designation as a drug or cosmetic relied on claims and consequent consumer perception. However, there is evidence that toxicology and robust scientific approaches may soon weigh in on such debates. This would also be a logical step since a bioactive peptide would not alter its activity and therefore potential side-effects based on what is indicated on its packaging. Instead, a systematic and robust approach based on accepted scientific principles would provide a more accurate overview of the drug vs cosmetic debate regarding these interesting ingredients.
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Published by Boris Krivoshiev, PhD – Founder and Principal Toxicologist at kriTOX
References
Farwick, M. et al. (2011) ‘Bioactive tetrapeptide GEKG boosts extracellular matrix formation: in vitro and in vivo molecular and clinical proof’, Experimental dermatology, 20(7), pp. 602–604.
Schagen, S. K. (2017) ‘Topical peptide treatments with effective anti-aging results’, Cosmetics, 4(2), p. 16. doi: 10.3390/cosmetics4020016.