Retinoids in cosmetics: application possibilities

Alla Belovol , Ph.D., Associate Professor, Head of the Department of Dermatology, Venereology and Medical Cosmetology, Kharkov National Medical University (Ukraine, Kharkov)
Svetlana Tkachenko, Ph.D., Associate Professor, Department of Dermatology, Venereology and Medical Cosmetology, Kharkov National Medical University (Ukraine, Kharkov)

Appearing at the end of the 20th century following drugs with retinoids, retinol-based cosmetics not only contributed to the retinoid boom in cosmetology, but also caused wariness and prejudice among some consumers and professionals

Despite numerous clinical studies of the effectiveness of products with retinoids, some specialists are skeptical about their results and are in no hurry to implement them into their practice. The safety of retinoids in cosmetics is also a subject of debate. However, in recent years, new data have emerged on the clinical effectiveness and safety of cosmetics with retinoids, which may seem convincing even to the last skeptics.

Retinoids are natural or synthetic compounds that exhibit similar effects to retinol (vitamin A). Of the more than four thousand retinoids studied to date, only a few compounds have reached the stage of clinical use and are included in the formulations of drugs and cosmetics. This is retinol (vitamin A) and its isomers - retinaldehyde, retinol esters (retinyl acetate, retinyl palmitate); non-aromatic retinoids – tretinoin, isotretinoin, alitretinoin; monoaromatic retinoids – etretinate, trans-acitretin, motretinide; polyaromatic retinoids – adapalene, tazarotene, bexarotene; new retinoids – seletinoid G, arotinoid, etretin.

The topical action of retinoids in cosmetology has several points of application (Scheme 1). Thanks to their elastic-stimulating and elastoprotective effects, they are successfully used in anti-aging programs, and suppression of angiogenesis, melanogenesis and restoration of the Langerhans cell population make it possible to successfully use retinoids for photoaging, rosacea, and hypermelanosis. Retinoic peels, in addition to the above properties, also exploit the keratolytic effect and the ability to enhance the synthesis of epidermal lipids and restore the epidermal barrier. The comedolytic, sebostatic, anti-inflammatory, regenerating and antibacterial effects of retinoids make them a popular ingredient in anti-acne cosmetics.

From the history of retinoids
The history of retinoids dates back to ancient Egypt, where bovine liver was used to treat night blindness. During World War I, a number of vital functions of vitamin A in mammals were discovered. In the early 1930s, the chemical structure of retinol was determined and the first studies using the vitamin to treat acne were conducted (published in 1943). Tretinoin, or transretinoic acids, was first used in dermatological therapy in 1959, after a decade of active research. In the early 1980s, Albert Kligman of the University of Pennsylvania, testing trans-retinoic acid for the treatment of acne in women, found that it smoothed out wrinkles caused by sun exposure, and in 1997, the medicinal cream Renova (tretinoin) appeared to treat photoaging. In the same year, tazarotene (a retinoid for the systemic treatment of psoriasis) demonstrated efficacy in the treatment of skin photoaging in studies of topical use.

Subsequently, formulations with tretinoin were subjected to various modifications to neutralize the irritating effect (Retin-A micro gel, Avita cream). The first medicinal cream with tazarotene (Evage) appears to correct photoaging of the skin.

The problem of finding different retinoids to solve dermatocosmetic problems is due to the fact that cellular metabolism is regulated by different retinoid receptors, which are responsible for different processes that are sensitive to different retinoids, so the action of one retinoid can differ significantly from the action of another. In addition, retinoic acid (tretinoin) has side effects, and such drugs are quite expensive. Now research in this area is aimed at finding the optimal retinoid for cosmetology, which would remain effective without side effects and would be economically affordable for the consumer.

Cellular metabolism of retinoids

Retinoids penetrate the skin directly through the stratum corneum (transepidermal route) and through the excretory ducts of the glands (transfollicular route). In the epidermis, retinoids control the processes of keratinization and pigmentation, and in the dermal layer they contribute to the restoration of the intercellular matrix. The transfollicular route allows you to obtain an increased concentration of retinoids directly in the follicles, which is especially valuable in the correction of acne.

Retinol, contained in food and cosmetic preparations, easily penetrates the membrane and is metabolized in the cell into retinal, retinoic acid, or deposited as an ester. Retinal, an unstable form of vitamin A, is easily converted into retinoic acid, and more readily into retinol ester (Scheme 2). This limits its ability to accumulate in the cell. Vitamin A esters (retinyl palmitate and retinyl acetate) are more stable, but poorly penetrate the cell membrane and act on the surface (healing, scarring). In the skin cell, the enzyme esterase hydrolyzes the ester to retinol, which is then oxidized to its active metabolite, retinoic acid. It should be noted their lower permeability through the stratum corneum compared to tretinoin.

Tretinoin (trans-retinoic acid) has a fairly high irritant potential and has been used for medical purposes for a limited time. With systemic and topical use, it easily passes through the cell membrane, so its use should be controlled: excess vitamin A leads to skin irritation.

Isotretinoin. In 1991, the results of a study on the use of isotretinoin at a concentration of 0.05% for the correction of photoaging of the skin were published. The cream was well tolerated, which made it possible to increase the concentration of isotretinoin to 0.1% in the second part of the experiments.

Isotretinoin was effective in correcting skin photoaging (response to treatment was recorded at 36 weeks of use), was well tolerated and did not cause significant irritation. In addition, the combination of isotretinoin 0.5% with sunscreen also improved photodamaged skin (as measured by profilometry) and showed a high tolerance profile.

Tazarotene. 10 years after the isotretinoin studies, the results of a study of tazarotene gel 0.1% for photoaging skin were published. The gel was effective in reducing skin roughness and fine wrinkles, improving skin hydration, reducing epidermal atrophy and keratinocyte atypia. Later, other histological effects of tazarotene were discovered: an increase in the thickness of the epidermis and thickening of the stratum corneum. The effectiveness of various concentrations of tazarotene was studied in comparison with tretinoin 0.05%. A more rapid response to tazarotene was noted at weeks 12 and 20 of treatment, but at the end of the full course of therapy there was no difference in overall improvement between tretinoin and tazarotene. Subsequent 24-week and 28-week studies demonstrated the benefits of tazarotene 0.1% gel. Clinical improvement with tazarotene continued to increase and did not reach a plateau by week 52 of treatment. In addition, there was no systemic accumulation of the drug, and plasma levels of tazarotenic acid were lower than those of endogenous retinoids.

Retinol and its derivatives

Indeed, stable and concentrated vitamin A can be invaluable for people who cannot tolerate retinoids or cannot afford them. Today, cosmetics use retinoic acid (only professional peelings), retinol, retinaldehyde, and retinol esters. The anti-aging effect of retinoids is due to the following effects: elastic-stimulating and elastoprotective, antioxidant, anti-angiogenesis, antimelanogenesis. Traditionally used for photoaging. Retinaldehyde is also successfully used in anti-acne cosmetics (antibacterial action against P. acnes and S. aureus). Retinol esters are an effective UV filter operating in the UV-B spectrum (similar to the SPF 20 photo filter).

Recent clinical studies of cosmetic products with retinol have significantly expanded the range of its use in the correction of age-related skin changes. The cosmetic effect of retinol use in severe chronobiological aging was studied. The group of volunteers included patients over 80 years of age with severe chronoaging of the skin, who used 0.4% retinol lotion three times a week for 24 weeks (according to the regulations). Applications were made to the inner surface of the forearm, that is, an area that was practically not subject to photoaging. Taking into account the weak barrier properties of the skin in this area (due to physiological characteristics, age-related atrophy) and the development of temporary contact reactions, the application schedule was changed in some cases, so in fact the skin was treated 1.6 times a week. In the group of women who used retinol lotion, a significant smoothing of fine wrinkles, an increase in the level of GAG (by 40%), collagen I (by more than 2 times), and an improvement in tactile sensations were recorded. Retinol showed a positive effect in correcting skin photoaging, for example, in correcting thickening of the epidermis, increased activity of metallomatrix proteinases, and decreased collagen synthesis, although it was 20 times less active than tretinoin. On the other hand, retinol is less irritating than its natural metabolite tretinoin. However, retinol is very unstable and easily degrades into inactive metabolites. Studies of the clinical effectiveness of a combination of retinol and hydroquinone, compared with tretinoin, showed equal effectiveness in smoothing periocular wrinkles and reducing skin roughness over 4.8 and 12 weeks. Both substances have the property of reducing overall skin pigmentation over 4, 8, 12 weeks, but in combination their effectiveness turned out to be higher.

Vitamin A derivatives (retinol, retinaldehyde, retinol acetate and palmitate) do not bind directly to retinoic receptors, so they are not classified as true retinoids. Vitamin A is converted into retinoic acid (tretinoin and other retinoids) in the cell, the degree of which varies from person to person and is the subject of debate among scientists around the world. The inability to determine the amount of tretinoin after retinol application is associated with activation of the 4-hydroxylase PK enzyme that metabolizes tretinoin. Induction of this enzyme results in decreased accumulation of tretinoin in the skin and accounts for the higher effective concentrations of retinol with less irritation. Therefore, only stable and highly concentrated retinol preparations are capable of producing a retinoid-like effect. In practice, either the concentration of vitamin A is so low that it is not enough to be converted into retinoids, or it is quickly destroyed in the skin, being unstable. This partly explains the higher cost of medicinal cosmetics with retinoids compared to extemporaneous prescriptions or mass-market products.

Retinol derivatives such as retinol propionate and N-formyl aspartame retinol have been proposed as ingredients in anti-photoaging cosmetics because they are more stable and have shown some beneficial effects in experimental studies. Retinaldehyde, a natural precursor of tretinoin and a metabolite of retinol, has biological activity and is well tolerated in the treatment of skin photoaging. Retinaldehyde cream 0.05% is effective in correcting photoaging, which has been demonstrated using ultrasound and rheological methods. Optical profilometry showed that retinaldehyde at a concentration of 0.05% significantly reduced wrinkles and unevenness in photodamaged skin. In addition, retinaldehyde was better tolerated than tretinoin.

Safety considerations for retinoid cosmetics

When using retinoid cosmetics, slight flaking, dryness, and irritation may occur from time to time, which requires a reduction in the frequency of application and the additional use of emollients. Such drugs are not recommended in cases of hyperreactive skin, and the incidence of allergic dermatitis is on average 5%. Retinoids should not be used for a week after aggressive cosmetic procedures (epilation, peelings, etc.), before sun exposure, or combined with taking large doses of vitamin A, photosensitizers (thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides). Despite the low concentration and negligible absorption into the blood, it is better to avoid topical retinoids during pregnancy. In animal experiments, exceeding the dose of tretinoin by 320 times did not cause a teratogenic effect, but increasing it by 1,000 times did. It is unknown whether topically applied tretinoin passes into human milk, so caution is advised in lactating women. Cosmetics based on retinol isomers are considered absolutely safe for pregnant women, given the weak conversion of retinol to tretinoin, however, when using it, it is necessary to avoid the breast and nipple area during lactation. It should be remembered that changes in the physiological parameters of the skin in pregnant and lactating women can affect the tolerability of cosmetics with retinol and its isomers.

Rules for using retinoid cosmetics:

• apply to dry skin 30 minutes after washing;
• Apply for the first time at night; if the skin is sensitive, rinse after 1 hour;
• if irritation occurs, reduce the frequency of application (once every 2-3 days);
• apply at night, if tolerated well - twice a day;
• apply a small amount to the entire affected surface, avoid contact with eyes and mouth;
• Always use sunscreen in the morning;
• If necessary, apply moisturizer before or after using the retinoid.

When prescribing anti-aging agents with retinoids, proper interaction between the specialist and the patient is necessary. A patient’s refusal to use this cosmetic may be due to its improper use (use on macerated skin, after home peeling, use of a large volume of the drug); a natural contact reaction of the skin is often mistaken for an allergic reaction (mild hyperemia, burning, peeling are interpreted as allergic dermatitis ). Medicinal cosmetics based on retinol and its isomers have a serious scientific basis and convincing results of clinical studies. The specialist must explain to the client the rules for using retinoid anti-aging cosmetic drugs, set them up for a long course (at least 3–6 months), warn about possible discomfort that does not require discontinuation of the drug, teach them how to change the mode of use and supplement the course with emollients and photoprotectors if necessary.

First published: KOSMETIK international journal, No. 1 (47) / 2012