Peptides and proteins in cosmetics: Part 1

What are they and their regulatory status

For now and for the sake of argument, lets ignore the controversy surrounding the term “cosmeceuticals” (more on this later) as proteins and peptides as used in cosmetics conveniently fall under such an umbrella term.

The term “cosmeceuticals” was coined more than 25 years ago by Professor Albert Klingman and has quickly entered cosmetic lexicon since then (more than 1.5 million hits on Google). The term is basically a contraction of “cosmetic” and “pharmaceutical” and therefore holds the promise that such ingredients have drug-like effects to skin aging and other skin conditions. It therefore implies that such ingredients hold a degree of physiological action, blurring the lines between cosmetic and active pharmaceutical ingredients, also more on this later.

One such example of a cosmeceutical ingredient could be that of niacinamide, a chemically defined substance that is used widely in cosmetics with the functions to improve barrier function of skin, moisturising of skin, UV-damage protection, and anti-inflammatory properties that alleviate acne and irritation.

Proteins and skin function

With such exciting functions and claims, it is no wonder that the cosmeceuticals enjoy a healthy market. According to research by Mordor Intelligence, the cosmeceutical market within Northern America is expected to increase on average 8.24% per annum, reaching $18 billion in turnover in 2024.

As mentioned above, cosmeceuticals are ingredients that impart a physiological action. This is by definition what a protein or peptide does. Specifically, one can think of proteins and peptides as keys that unlock molecular locks that result in molecular changes which ultimately manifest as observable physiological changes. More succinctly, proteins and peptides dictate everything that makes you who you are.

We are familiar with genes, the code of life. However, it is proteins and peptides that are the functional units that allow genes to exert their traits. Specifically, proteins encoded from their respective genes effect appearance by dictating the level of melanin deposition in eye and skin. More melanin deposition, the darker the eye and skin colour. Another characteristic determined by proteins is that of physical strength. Myofibrils, which enable muscle contraction, are filaments composed of actin, myosin, and titin along with other proteins that hold them together. The role of proteins in immunity is also integral since antibodies, cytokines, and chemokines are peptides and proteins by nature. It is the same story with brain function as many neurotransmitters are peptides.

Finally, and most interestingly for cosmetics, peptides and proteins play an integral role in the structure and integrity of the skin. Elastin, the protein of the extracellular matrix imparts the elasticity properties of skin allowing it to maintain shape after stretching or contracting. Filaggrin is essential for the regulation of epidermal homeostasis and the skin barrier function within the stratum corneum, the outermost layer of skin. Once keratin is deposited in the epidermis, it is responsible for the waterproofing and strength of skin. Similarly to elastin and keratin, collagen is responsible for skin’s strength and elasticity. Given that it is the main component in skin, its degradation leads to wrinkles that accompany aging and is therefore the most obvious target for anti-aging treatments. In addition, all these structural skin proteins are under the control of growth factors such as epidermal (EGF) and fibroblast growth factor (FGF), meaning that their expression is tightly controlled under normal physiological conditions.

Decoding the INCI – what’s in a name?

It is obvious that proteins and peptides play an integral, and often complex role in the health of skin, and as such, are very attractive targets for cosmetic brands aiming to reverse the ravages of ageing. However, to further understand these proteins and how we evaluate their safety, we must first understand on a more granular level what they are, how they are named, and what the regulatory status is of these interesting ingredients.

Briefly, one can think of a protein or peptide as a string of beads, each bead comprising of one of the 22 amino acids. Depending on the sequence of these amino acids, the protein or peptide may fold into very specific 3D conformations. These conformations are what imparts the protein’s function as the key. A specifically shaped key (peptide) interacts and unlocks a specific lock (cell receptor) leading to a cascade of intermolecular mechanisms that ultimately manifest as some biological function (increased collagen synthesis for instance).

The nomenclature of proteins and peptides may seem confusing at first, but is rather simple and logical. For instance, a protein is any sequence of amino acids longer than 50 while a peptide is more than 25. As such, the only difference between a protein and peptide is just size, and peptides can be thought of as smaller proteins.

Furthermore, the Greek qualifier prefixes are used when denoting the INCI of peptides and proteins used in cosmetics. For instance, di-, tri, tetra-, pentapeptide denote peptides of 2, 3, 4, and 5 amino acids in length, and so on. To further decode the INCI op peptides, INCIs are also superseded by a number which denotes a unique sequence of amino acids. For instance, dipeptide-9 is the sequence glutamate and lysine, while dipeptide-10 is alanine and histidine.

Further confusing things, more prefixes may be added to the INCI that indicate the chemical modification the peptide may have underwent. These chemical modifications are usually done to improve the permeability and stability of the peptide.

Finally, peptides may either be designated as SH- (synthetic human) or RH- (recombinant human), the latter banned for use in cosmetics under the cosmetics regulation EC 1223/2009. This is due to concerns regarding potential human spongiform encephalopathy and certain virus diseases that can arise from mammalian cell culture given that many reagents used in cell culture are derived from bovine by-products such as foetal calf serum. As such, only SH- peptides and proteins are allowed on the European market whose starting gene is a synthesised copy of the human gene rather than directly isolated from a human cell. Examples of INCIs are shown below:

 Table 1: examples of INCI for peptides used in cosmetics

MacromoleculeSequence
Dipeptide-9Glu-Lys
Dipeptide-10Ala-His
Tripeptide-9Asp-Lys-Val
Tripeptide-10Asp-Leu-Lys
Palmitoyl Tripeptide-5Palmitoyl-Lys-Val-Lys
Acetyl Tripeptide-8Acetyl-Lys-Val-Lys
SH-polypeptide-51Superoxide Dismutase produced by fermentation in E.coli. The starting gene is a synthesized copy of the human gene
RH-polypeptide-51Superoxide Dismutase produced by fermentation in E.coli. The starting gene is directly isolated from a human cell

Anti-aging peptides

Altering the molecular structure of skin through changing expression of key proteins involved in maintaining skin health is therefore a very desirable outcome. This is achieved by exogenous (meaning introduced into the body) peptides able to exert changes in the complex pathways regulating expression of skin proteins.

Briefly, this is done by 4 different mechanisms; improving delivery of trace elements needed for processes, stimulate production, decrease muscle contraction, and inhibit enzyme processes related to ageing. There are a number of commercially available raw materials working at these different levels, with the claim of anti-aging functions. These are presented below:

Table 2: examples of peptides with anti-aging molecular modes of action

Types of peptides used in cosmeticsMechanism of anti-ageingExample
Carrier peptidesImprove dermal delivery of trace elements necessary for anzymatic processes (wound healing)Copper peptide-GHK
Signal peptidesStimulate fibroblast production of collagen, proliferation of elastin, fibronectin, laminin, etc.Syn®-coll (Palmitoyl Tripeptide-5)
Decorinyl™ (a tetrapeptide)

Neurotransmitter-inhibiting peptides
To decrease facial muscle contraction, and consequently lines (muscle relaxing)Argireline®,Vialox® and Syn®-ake
Enzyme-inhibiting peptidesInhibit an enzyme related to ageing processGlycine soya protein (Preregen®) and Sericin

Regulatory status

It is evident that peptides offer interesting functions for cosmetics, with already various raw materials present on the market promising such effects corroborated by beautiful efficacy studies showing increased thickness of epidermis, increased production of collagen, reduced wrinkles, etc. We have already touched on some of the regulatory requirements regarding the origin of the starting genes above. However, they do not end there. In fact, most of the legislation revolves around the function of these peptides (since they have been shown to have physiological activity), and how such effects are communicated and perceived by the general public.

As alluded to at the beginning, the term “cosmeceutical” is considered controversial, since ingredients can only be perceived as a cosmetic, or a drug; “cosmeceutical” implies both as is not accepted by regulatory bodies either side of the Atlantic. Briefly, a cosmetic ingredient is intended to “cleanse, beautify, promote attractiveness, or alter the appearance” [FD&C Act, 201 (i)] while a drug is intended to “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 product 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 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 apparent therefore that the distinction between a cosmetic and a drug is its intended use. So how is intended use established? Well, this is done through the product’s claims, consumer perception, and if ingredients have a well-known therapeutic use. It should also be stressed as to why a cosmetic brand would like to steer clear of drug-like claims and therefore products since there are considerable differences as to how cosmetics and drugs are tested, registered, and approved. One obvious difference is that drugs require significant testing for safety and efficacy through preclinical and clinical studies before approval for the market. As such, sticking to cosmetic intended uses will save millions of dollars and years of development.

Claims

Intended use is established through the claims brought forward by the product in the form of product labelling, advertising, and descriptions through popular media. Claims can either establish a product to be a drug even though it is meant to be a cosmetic. Claims that indicate treatment of prevention of disease or as altering the physiological structure and/or function of the human body are indicative of drugs. Claims of soothing and maintenance are perceived as cosmetic intended uses. Clear and decisive claims may be considered as drug claims, while claims on appearance may be considered as cosmetic claims as exemplified below. Further examples may be found on the FDA website since all warning letters issued by the FDA for cosmetic products with drug claims are published.

Table 3: Cosmetic and their respective drug claims

Cosmetic claimDrug claim
“Improves fine lines and wrinkles”“Removes fine lines and wrinkles”
“Soothes mottled or rough skin”“Repairs damaged skin”
“Suitable for acne prone skin”“Treats acne”
“Alleviates the appearance of age spots”“Prevents age spots”
“Maintains skin firmness”“Increases epidermal thickness”

Consumer perception

This involves the conception of why the consumer is purchasing the product and what do they expect it to do. This is also partly driven by the company’s reputation that is selling the product. For example, a product is perceived by consumers to treat and prevent acne based on the claims put forward, how it is advertised, and how the company is perceived. As such, one can see that claims once again plays a huge role in not only informing intended use, but also consumer perception.

Ingredient used

Certain ingredients may have a well-known therapeutic use and therefore mark a cosmetic as a drug even though the product is meant to be a cosmetic. An example of this fluoride being well known to prevent tooth cavities. Therefore toothpastes with fluoride may be considered drugs regardless of claims in the US, while in the EU fluoride toothpaste is accepted as a cosmetic provided certain provisions (0.15% limit and a label indication presence of fluoride).

Ultimately, cosmetics and drugs are distinguished based on their intended uses which is primarily driven by their claims. However, based on the Working Group on Cosmetic Products manual on borderline products, substances which restore, correct, or modify physiological functions by exerting pharmacological activities are identified by “virtue of its presentation” (so claims as described above), or “by virtue of its function”. The latter is “assessed by considering all characteristics of the product including absorption, concentration, route of administration, frequency of application, application site, and the degree of penetration”. These are all tenants of toxicology, and is rather important, since this indicates that cosmetic and drugs are not only distinguished by intended use driven by claims, but also toxicology. This is poignant since peptides as used in cosmetics have shown already to hold promising anti-aging activities and therefore do have a physiological function. However, the function they exert, and also potential side-effects, are not dictated by claims, but rather by science and biology.

Conclusion

In conclusion, peptides and proteins are interesting cosmetic ingredients given their anti-aging activities. There is already a plethora of peptide-based cosmetic raw materials on the market, with more being researched constantly. So far, regulation of these ingredients largely involves genetic origin and claims. However, there exists a balance with pronounced physiological activity often accompanied by side-effects that have to be investigated. In the next part, I will discuss how we evaluate the safety of these next-generation ingredients especially in today’s world where animal testing has been banned. The evaluation of these ingredients does not only serve to ensure safe cosmetic products, but as has been indicated above, may be integral in informing the distinction between cosmetic and drug for these interesting and cutting-edge ingredients. 

Article by
Dr. Boris Krivoshiev,
Principal Toxicologist